Compendium of Cancer Genome Aberrations

HAEM5:Acute myeloid leukaemia with BCR::ABL1 fusion: Difference between revisions

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{{DISPLAYTITLE:Acute myeloid leukaemia with BCR::ABL1 fusion}}
{{DISPLAYTITLE:Acute myeloid leukaemia with BCR::ABL1 fusion}}
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (5th ed.)]]
 
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]


{{Under Construction}}
{{Under Construction}}


<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|This page was converted to the new template on 2023-11-03. The original page can be found at [[HAEM4:Acute Myeloid Leukemia (AML) with BCR-ABL1]].
<blockquote class="blockedit">{{Box-round|title=Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification|This page was converted to the new template on 2023-12-07. The original page can be found at [[HAEM4:Acute Myeloid Leukemia (AML) with BCR-ABL1]].
}}</blockquote>
}}</blockquote>
==Primary Author(s)*==


Kay Weng Choy MBBS, Monash Medical Centre
<span style="color:#0070C0">(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ <u>HGVS-based nomenclature for variants</u>], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>].)</span>


__TOC__
==Primary Author(s)*==


==Cancer Category/Type==
Xinxiu Xu, Vanderbilt University Medical Center
==WHO Classification of Disease==


Acute Myeloid Leukemia (AML)
{| class="wikitable"
 
!Structure
==Cancer Sub-Classification / Subtype==
!Disease
 
AML with BCR-ABL1
 
==Definition / Description of Disease==
 
AML with BCR-ABL1 is a rare subtype of AML that is now included as a provisional entity under the heading of “AML with recurrent genetic abnormalities” in the 2016 revised World Health Organization (WHO) classification of myeloid malignancies<ref name=":0">Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. Revised 4th Edition. IARC Press: Lyon, France, p140.</ref>. It must be distinguished from myeloid blast crisis of chronic myeloid leukemia (CML-MBC) and mixed phenotype acute leukemia (MPAL) with BCR-ABL1, which are separate entities in the WHO classification. The t(9:22)(q34.1;q11.2) results in the formation of the Philadelphia chromosome and the chimeric BCR-ABL1 fusion gene. It is worth noting that the fusion gene is the cytogenetic hallmark of chronic myelogenous leukemia (CML) and is frequently found in high-risk acute lymphoblastic leukemia (ALL).
 
 
Table [adapted from <ref name=":1">Arber DA, et al., (2017). Acute Myeloid Leukemia, in Hematopathology, 2nd Edition. Jaffe E, Arer DA, Campo E, Harris NL, and Quintanilla-Fend L, Editors. Elsevier:Philadelphia, PA, p817-846.</ref>] - Differentiating CML-MBC from AML with BCR-ABL1
{| class="wikitable sortable"
|-
|-
!CML-MBC!!AML with BCR-ABL1
|Book
|Haematolymphoid Tumours (5th ed.)
|-
|-
|Previous blood disorder, idiopathic leucocytosis||No previous blood disorder
|Category
|Myeloid proliferations and neoplasms
|-
|-
|Splenomegaly||No splenomegaly
|Family
|Acute myeloid leukaemia
|-
|-
|Basophilia (≥2%)||No basophilia
|Type
|Acute myeloid leukaemia with defining genetic abnormalities
|-
|-
|~100% marrow cellularity||<100% marrow cellularity (median 80%)
|Subtype(s)
|Acute myeloid leukaemia with BCR::ABL1 fusion
|}
 
==WHO Essential and Desirable Genetic Diagnostic Criteria==
<span style="color:#0070C0">(''Instructions: The table will have the diagnostic criteria from the WHO book <u>autocompleted</u>; remove any <u>non</u>-genetics related criteria. If applicable, add text about other classification'' ''systems that define this entity and specify how the genetics-related criteria differ.'')</span>
{| class="wikitable"
|+
|WHO Essential Criteria (Genetics)*
|
|-
|-
|Typical AML blast crisis phenotype||Aberrant CD19, CD7 and TdT more common
|WHO Desirable Criteria (Genetics)*
|
|-
|-
|Ph+ in ~100% of cells||Ph+ in <100% of cells
|Other Classification
|-
|
|P210 transcript in >99% of cases||p190 and p210 detected in nearly equal distribution
|-
| ||Loss of ''IKZF1'' and ''CDKN2A'' and cryptic deletions within ''IGH'' and ''TCR'' genes
|}
|}
 
<nowiki>*</nowiki>Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the [https://tumourclassification.iarc.who.int/home <u>WHO Classification of Tumours</u>].
 
==Related Terminology==
Most cases which carry the BCR-ABL1 fusion have been described as ''de novo'' AML; there are only a few cases described where acquisition of the Philadelphia chromosome upon disease relapse or transformation of antecedent myelodysplastic syndrome into AML occurred<ref name=":2">{{Cite journal|last=Neuendorff|first=Nina Rosa|last2=Burmeister|first2=Thomas|last3=Dörken|first3=Bernd|last4=Westermann|first4=Jörg|date=2016|title=BCR-ABL-positive acute myeloid leukemia: a new entity? Analysis of clinical and molecular features|url=https://www.ncbi.nlm.nih.gov/pubmed/27297971|journal=Annals of Hematology|volume=95|issue=8|pages=1211–1221|doi=10.1007/s00277-016-2721-z|issn=1432-0584|pmid=27297971}}</ref>. Based on one model of leukemogenesis in which two driver mutations are required (a class-II mutation, conferring inhibition of differentiation and apoptosis, and a class-I mutation conferring a proliferative advantage), BCR-ABL1 is likely to represent a class-I mutation<ref name=":2" />.
<span style="color:#0070C0">(''Instructions: The table will have the related terminology from the WHO <u>autocompleted</u>.)''</span>
 
==Synonyms / Terminology==
 
Not applicable
 
==Epidemiology / Prevalence==
 
It is reported that up to 3% of all AML carry BCR-ABL1 fusions. The overall incidence is mainly estimated from larger case series without any standardized definition<ref name=":2" />.
 
==Clinical Features==
 
Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table'') </span>
{| class="wikitable"
{| class="wikitable"
|'''Signs and Symptoms'''
|+
|EXAMPLE Asymptomatic (incidental finding on complete blood counts)
|Acceptable
 
|
EXAMPLE B-symptoms (weight loss, fever, night sweats)
 
EXAMPLE Fatigue
 
EXAMPLE Lymphadenopathy (uncommon)
|-
|-
|'''Laboratory Findings'''
|Not Recommended
|EXAMPLE Cytopenias
|
 
EXAMPLE Lymphocytosis (low level)
|}
|}


==Gene Rearrangements==


<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Features|The content below was from the old template. Please incorporate above.}}
Little is known about the characteristics clinical features of BCR-ABL1 positive AML. In contrast to CML, BCR-ABL1 positive AML has no antecedent hematologic disease/abnormality and no splenomegaly. Unexplained leucocytosis and/or splenomegaly point towards the diagnosis of CML myeloid blast crisis (CML-MBC) than AML<ref name=":2" />. Soupir et al. reported 16 cases of BCR-ABL1 positive AML, noting there was some overlap phenotypically and morphologically with CML myeloid blast crisis, but BCR-ABL1 positive AML cases presented less often with splenomegaly, lacked basophilia and had lower bone marrow cellularity<ref name=":3">{{Cite journal|last=Soupir|first=Chad P.|last2=Vergilio|first2=Jo-Anne|last3=Dal Cin|first3=Paola|last4=Muzikansky|first4=Alona|last5=Kantarjian|first5=Hagop|last6=Jones|first6=Dan|last7=Hasserjian|first7=Robert P.|date=2007|title=Philadelphia chromosome-positive acute myeloid leukemia: a rare aggressive leukemia with clinicopathologic features distinct from chronic myeloid leukemia in myeloid blast crisis|url=https://www.ncbi.nlm.nih.gov/pubmed/17369142|journal=American Journal of Clinical Pathology|volume=127|issue=4|pages=642–650|doi=10.1309/B4NVER1AJJ84CTUU|issn=0002-9173|pmid=17369142}}</ref>.
</blockquote>
==Sites of Involvement==
Bone marrow
==Morphologic Features==
BCR-ABL1 positive AML features include myeloid blasts >20% found in the bone marrow, below a blast count of 20% the WHO classification currently describes diagnosis of BCR-ABL1 AML as controversial. It is helpful to note several features that may help in the differential diagnosis of BCR-ABL1 positive AML: basophilia (>2% in white blood cells) strongly diminishes the probability of ''de novo'' AML (most cases of BCR-ABL1 positive AML are ''de novo'' AML); prior signs of myelodysplastic syndrome (MDS) in peripheral blood or bone marrow may support the diagnosis of secondary AML<ref name=":2" />.
==Immunophenotype==
Co-expression of lymphoid markers have been reported in BCR-ABL1 positive cases. Atfy et al., reported an aberrant lymphoid co-expression in seven of nine BCR-ABL1 positive AML cases<ref>{{Cite journal|last=Atfy|first=Maha|last2=Al Azizi|first2=Nashwa M. A.|last3=Elnaggar|first3=Amina M.|date=2011|title=Incidence of Philadelphia-chromosome in acute myelogenous leukemia and biphenotypic acute leukemia patients: And its role in their outcome|url=https://www.ncbi.nlm.nih.gov/pubmed/21612824|journal=Leukemia Research|volume=35|issue=10|pages=1339–1344|doi=10.1016/j.leukres.2011.04.011|issn=1873-5835|pmid=21612824}}</ref>. Soupir et al. reported that there was no significant difference in the blast immunophenotype by flow cytometry between the BCR-ABL positive AML and CML-MBC cases. In nearly all cases in both groups, the blasts expressed CD13, CD33, and CD34<ref name=":3" />. However, compared to CML-MBC, aberrant CD19, CD7 and TdT have been found to be more common in BCR-ABL1 positive AML<ref name=":1" />.


Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.'')</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Finding!!Marker
!Driver Gene!!Fusion(s) and Common Partner Genes!!Molecular Pathogenesis!!Typical Chromosomal Alteration(s)
!Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
|-
|-
|Positive (universal)||Myeloid antigens (CD13 and CD33), CD34
|<span class="blue-text">EXAMPLE:</span> ''ABL1''||<span class="blue-text">EXAMPLE:</span> ''BCR::ABL1''||<span class="blue-text">EXAMPLE:</span> The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.||<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)
|<span class="blue-text">EXAMPLE:</span> Common (CML)
|<span class="blue-text">EXAMPLE:</span> D, P, T
|<span class="blue-text">EXAMPLE:</span> Yes (WHO, NCCN)
|<span class="blue-text">EXAMPLE:</span>
The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). BCR::ABL1 is generally favorable in CML (add reference).
|-
|-
|Positive (subset)||CD19, CD7, TdT
|<span class="blue-text">EXAMPLE:</span> ''CIC''
|<span class="blue-text">EXAMPLE:</span> ''CIC::DUX4''
|<span class="blue-text">EXAMPLE:</span> Typically, the last exon of ''CIC'' is fused to ''DUX4''. The fusion breakpoint in ''CIC'' is usually intra-exonic and removes an inhibitory sequence, upregulating ''PEA3'' genes downstream of ''CIC'' including ''ETV1'', ''ETV4'', and ''ETV5''.
|<span class="blue-text">EXAMPLE:</span> t(4;19)(q25;q13)
|<span class="blue-text">EXAMPLE:</span> Common (CIC-rearranged sarcoma)
|<span class="blue-text">EXAMPLE:</span> D
|
|<span class="blue-text">EXAMPLE:</span>
 
''DUX4'' has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).
|-
|-
|Negative (universal)||
|<span class="blue-text">EXAMPLE:</span> ''ALK''
|-
|<span class="blue-text">EXAMPLE:</span> ''ELM4::ALK''
|Negative (subset)||
|}


==Chromosomal Rearrangements (Gene Fusions)==


Put your text here and fill in the table
Other fusion partners include ''KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1''
|<span class="blue-text">EXAMPLE:</span> Fusions result in constitutive activation of the ''ALK'' tyrosine kinase. The most common ''ALK'' fusion is ''EML4::ALK'', with breakpoints in intron 19 of ''ALK''. At the transcript level, a variable (5’) partner gene is fused to 3’ ''ALK'' at exon 20. Rarely, ''ALK'' fusions contain exon 19 due to breakpoints in intron 18.
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Rare (Lung adenocarcinoma)
|<span class="blue-text">EXAMPLE:</span> T
|
|<span class="blue-text">EXAMPLE:</span>


{| class="wikitable sortable"
Both balanced and unbalanced forms are observed by FISH (add references).
|-
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
|<span class="blue-text">EXAMPLE:</span> ''ABL1''
!Diagnostic Significance (Yes, No or Unknown)
|<span class="blue-text">EXAMPLE:</span> N/A
!Prognostic Significance (Yes, No or Unknown)
|<span class="blue-text">EXAMPLE:</span> Intragenic deletion of exons 2–7 in ''EGFR'' removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways.
!Therapeutic Significance (Yes, No or Unknown)
|<span class="blue-text">EXAMPLE:</span> N/A
!Notes
|<span class="blue-text">EXAMPLE:</span> Recurrent (IDH-wildtype Glioblastoma)
|<span class="blue-text">EXAMPLE:</span> D, P, T
|
|
|-
|-
|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)
|
EXAMPLE 30% (add reference)
|
|Yes
|
|No
|
|Yes
|
|EXAMPLE
|
 
|
The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).
|
|}
|}


<blockquote class='blockedit'>{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}
<blockquote class="blockedit">{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}</blockquote>


The t(9:22)(q34.1;q11.2) results in the formation of the Ph chromosome and the chimeric BCR-ABL1 fusion gene. In AML, the most common BCR-ABL1 transcripts p190 and p210 have been detected in nearly equal distribution<ref name=":2" />. Since p190 is very rare in CML (p210 transcripts in >99% of cases), the presentation with a p190 transcript is in favour of the diagnosis of AML rather than CML<ref name=":1" />.
The t(9:22)(q34.1;q11.2) results in the formation of the Ph chromosome and the chimeric BCR-ABL1 fusion gene. In AML, the most common BCR-ABL1 transcripts p190 and p210 have been detected in nearly equal distribution<ref name=":2">{{Cite journal|last=Neuendorff|first=Nina Rosa|last2=Burmeister|first2=Thomas|last3=Dörken|first3=Bernd|last4=Westermann|first4=Jörg|date=2016|title=BCR-ABL-positive acute myeloid leukemia: a new entity? Analysis of clinical and molecular features|url=https://www.ncbi.nlm.nih.gov/pubmed/27297971|journal=Annals of Hematology|volume=95|issue=8|pages=1211–1221|doi=10.1007/s00277-016-2721-z|issn=1432-0584|pmid=27297971}}</ref>. Since p190 is very rare in CML (p210 transcripts in >99% of cases), the presentation with a p190 transcript is in favour of the diagnosis of AML rather than CML<ref name=":1">Arber DA, et al., (2017). Acute Myeloid Leukemia, in Hematopathology, 2nd Edition. Jaffe E, Arer DA, Campo E, Harris NL, and Quintanilla-Fend L, Editors. Elsevier:Philadelphia, PA, p817-846.</ref>.


{| class="wikitable sortable"
{| class="wikitable sortable"
Line 142: Line 134:
|}
|}


<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
</blockquote>




<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
<blockquote class="blockedit">{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
* Chromosomal Rearrangements (Gene Fusions)
* Chromosomal Rearrangements (Gene Fusions)
* Individual Region Genomic Gain/Loss/LOH
* Individual Region Genomic Gain/Loss/LOH
* Characteristic Chromosomal Patterns
* Characteristic Chromosomal Patterns
* Gene Mutations (SNV/INDEL)}}
* Gene Mutations (SNV/INDEL)}}</blockquote>


BCR-ABL1 positive AML is an emerging entity. The proliferation of BCR-ABL1 positive blasts present a diagnostic dilemma. While it may be difficult, it is essential to distinguish between BCR-ABL1 positive AML and CML-MBC, in order to choose the most appropriate therapy (e.g., intensive induction chemotherapy versus tyrosine kinase inhibitor (TKI) followed by an early allogeneic stem cell transplant). After the exclusion of acute leukemia of ambiguous lineage (a separate entity according to WHO) by flow cytometry, it is helpful to note any past history of antecedent hematological disease. Absence of basophilia and absence of splenomegaly favour the diagnosis of BCR-ABL1 positive AML (over CML-MBC). The detection of p190 transcript and the occurrence of any BCR-ABL1 transcript in less than 100% of metaphases supports the diagnosis of AML rather than CML. Persistent CCyR (Complete Cytogenetic Response) after conventional chemotherapy is unusual for CML-MBC and supports the diagnosis of BCR-ABL1 positive AML<ref name=":2" />.  
BCR-ABL1 positive AML is an emerging entity. The proliferation of BCR-ABL1 positive blasts present a diagnostic dilemma. While it may be difficult, it is essential to distinguish between BCR-ABL1 positive AML and CML-MBC, in order to choose the most appropriate therapy (e.g., intensive induction chemotherapy versus tyrosine kinase inhibitor (TKI) followed by an early allogeneic stem cell transplant). After the exclusion of acute leukemia of ambiguous lineage (a separate entity according to WHO) by flow cytometry, it is helpful to note any past history of antecedent hematological disease. Absence of basophilia and absence of splenomegaly favour the diagnosis of BCR-ABL1 positive AML (over CML-MBC). The detection of p190 transcript and the occurrence of any BCR-ABL1 transcript in less than 100% of metaphases supports the diagnosis of AML rather than CML. Persistent CCyR (Complete Cytogenetic Response) after conventional chemotherapy is unusual for CML-MBC and supports the diagnosis of BCR-ABL1 positive AML<ref name=":2" />.  
Line 155: Line 150:
The overall prognosis of BCR-ABL1 positive AML is generally unfavourable. The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for AML categorise this entity into the poor-risk group, comparable with complex aberrant karyotype AML<ref>O’Donnell MR, Tallman MS, (2016). NCCN Clinical Practise Guidelines in Oncology: AML. Version 1. Available at: NCCN.org.</ref>. It appears that the prognosis of BCR-ABL1 positive AML depends more on the genetic background (concurrent aberrations) than on BCR-ABL1 itself. Unlike in CML, BCR-ABL1 does not appear to be the key driver in AML though may provide a proliferative advantage to a particular BCR-ABL1 positive subclone There is currently no standardized treatment approach for BCR-ABL1 positive AML. Therapy with TKI alone does not produce sustained responses in BCR-ABL1 positive AML. This may be due to a very rapid clonal evolution, resulting in resistance in a much higher proportion of patients and in a significantly shorter time than in CML<ref name=":2" />.
The overall prognosis of BCR-ABL1 positive AML is generally unfavourable. The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for AML categorise this entity into the poor-risk group, comparable with complex aberrant karyotype AML<ref>O’Donnell MR, Tallman MS, (2016). NCCN Clinical Practise Guidelines in Oncology: AML. Version 1. Available at: NCCN.org.</ref>. It appears that the prognosis of BCR-ABL1 positive AML depends more on the genetic background (concurrent aberrations) than on BCR-ABL1 itself. Unlike in CML, BCR-ABL1 does not appear to be the key driver in AML though may provide a proliferative advantage to a particular BCR-ABL1 positive subclone There is currently no standardized treatment approach for BCR-ABL1 positive AML. Therapy with TKI alone does not produce sustained responses in BCR-ABL1 positive AML. This may be due to a very rapid clonal evolution, resulting in resistance in a much higher proportion of patients and in a significantly shorter time than in CML<ref name=":2" />.


<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
</blockquote>
==Individual Region Genomic Gain/Loss/LOH==
==Individual Region Genomic Gain/Loss/LOH==


Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable.'') </span>


Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.'') </span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
!Chr #!!'''Gain, Loss, Amp, LOH'''!!'''Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]'''!!'''Relevant Gene(s)'''
!Diagnostic Significance (Yes, No or Unknown)
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T'''
!Prognostic Significance (Yes, No or Unknown)
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
!Therapeutic Significance (Yes, No or Unknown)
!'''Clinical Relevance Details/Other Notes'''
!Notes
|-
|-
|EXAMPLE
|<span class="blue-text">EXAMPLE:</span>
 
7
7
|EXAMPLE Loss
|<span class="blue-text">EXAMPLE:</span> Loss
|EXAMPLE
|<span class="blue-text">EXAMPLE:</span>
 
chr7:1- 159,335,973 [hg38]
|EXAMPLE
 
chr7
chr7
|Yes
|<span class="blue-text">EXAMPLE:</span>
|Yes
Unknown
|No
|<span class="blue-text">EXAMPLE:</span> D, P
|EXAMPLE
|<span class="blue-text">EXAMPLE:</span> No
 
|<span class="blue-text">EXAMPLE:</span>
Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).
Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add references).
|-
|-
|EXAMPLE
|<span class="blue-text">EXAMPLE:</span>
 
8
8
|EXAMPLE Gain
|<span class="blue-text">EXAMPLE:</span> Gain
|EXAMPLE
|<span class="blue-text">EXAMPLE:</span>
 
chr8:1-145,138,636 [hg38]
|EXAMPLE
 
chr8
chr8
|No
|<span class="blue-text">EXAMPLE:</span>
|No
Unknown
|No
|<span class="blue-text">EXAMPLE:</span> D, P
|EXAMPLE
|
 
|<span class="blue-text">EXAMPLE:</span>
Common recurrent secondary finding for t(8;21) (add reference).
Common recurrent secondary finding for t(8;21) (add references).
|-
|<span class="blue-text">EXAMPLE:</span>
17
|<span class="blue-text">EXAMPLE:</span> Amp
|<span class="blue-text">EXAMPLE:</span>
17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]
|<span class="blue-text">EXAMPLE:</span>
''ERBB2''
|<span class="blue-text">EXAMPLE:</span> D, P, T
|
|<span class="blue-text">EXAMPLE:</span>
Amplification of ''ERBB2'' is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.
|-
|
|
|
|
|
|
|
|}
|}


<blockquote class='blockedit'>{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}
<blockquote class="blockedit">{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}</blockquote>


AML with BCR-ABL1 carries unique genome imbalances. Nacheva et al., used array comparative genomic hybridisation (CGH) to perform a comparative study between several BCR-ABL1 positive entities. BCR-ABL1 positive AML displays characteristic of lymphoid disease (found in BCR-ABL1 positive ALL and CML): deletions of ''IKZF1'' and/or ''CDKN2A/B'' genes were recurrent findings in BCR-ABL1 positive AML as well as cryptic deletions within the immunoglobulin ''IGH'' and T cell receptor gene (''TRG alpha'') complexes<ref>{{Cite journal|last=Nacheva|first=Ellie P.|last2=Grace|first2=Colin D.|last3=Brazma|first3=Diana|last4=Gancheva|first4=Katya|last5=Howard-Reeves|first5=Julie|last6=Rai|first6=Lena|last7=Gale|first7=Rosemary E.|last8=Linch|first8=David C.|last9=Hills|first9=Robert K.|date=2013|title=Does BCR/ABL1 positive acute myeloid leukaemia exist?|url=https://www.ncbi.nlm.nih.gov/pubmed/23521501|journal=British Journal of Haematology|volume=161|issue=4|pages=541–550|doi=10.1111/bjh.12301|issn=1365-2141|pmid=23521501}}</ref>. Importantly, these aberrations were found to be absent in CML-MBC and hence they are potentially a helpful diagnostic tool for difficult cases.
AML with BCR-ABL1 carries unique genome imbalances. Nacheva et al., used array comparative genomic hybridisation (CGH) to perform a comparative study between several BCR-ABL1 positive entities. BCR-ABL1 positive AML displays characteristic of lymphoid disease (found in BCR-ABL1 positive ALL and CML): deletions of ''IKZF1'' and/or ''CDKN2A/B'' genes were recurrent findings in BCR-ABL1 positive AML as well as cryptic deletions within the immunoglobulin ''IGH'' and T cell receptor gene (''TRG alpha'') complexes<ref>{{Cite journal|last=Nacheva|first=Ellie P.|last2=Grace|first2=Colin D.|last3=Brazma|first3=Diana|last4=Gancheva|first4=Katya|last5=Howard-Reeves|first5=Julie|last6=Rai|first6=Lena|last7=Gale|first7=Rosemary E.|last8=Linch|first8=David C.|last9=Hills|first9=Robert K.|date=2013|title=Does BCR/ABL1 positive acute myeloid leukaemia exist?|url=https://www.ncbi.nlm.nih.gov/pubmed/23521501|journal=British Journal of Haematology|volume=161|issue=4|pages=541–550|doi=10.1111/bjh.12301|issn=1365-2141|pmid=23521501}}</ref>. Importantly, these aberrations were found to be absent in CML-MBC and hence they are potentially a helpful diagnostic tool for difficult cases.


Most cases will have monosomy 7, trisomy 8 or complex karyotypes in addition to the t(9;22)(q34.1;q11.2)<ref name=":0" />.
Most cases will have monosomy 7, trisomy 8 or complex karyotypes in addition to the t(9;22)(q34.1;q11.2)<ref name=":0">Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. Revised 4th Edition. IARC Press: Lyon, France, p140.</ref>.


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<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
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</blockquote>
</blockquote>
==Characteristic Chromosomal Patterns==
==Characteristic Chromosomal or Other Global Mutational Patterns==


Put your text here <span style="color:#0070C0">(''EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis'')</span>


Put your text here and fill in the table <span style="color:#0070C0">(I''nstructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.'')</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
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!Chromosomal Pattern
!Chromosomal Pattern
!Diagnostic Significance (Yes, No or Unknown)
!Molecular Pathogenesis
!Prognostic Significance (Yes, No or Unknown)
!'''Prevalence -'''
!Therapeutic Significance (Yes, No or Unknown)
'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
!Notes
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T'''
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
!'''Clinical Relevance Details/Other Notes'''
|-
|-
|EXAMPLE
|<span class="blue-text">EXAMPLE:</span>
 
Co-deletion of 1p and 18q
Co-deletion of 1p and 18q
|Yes
|<span class="blue-text">EXAMPLE:</span> See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|No
|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
|No
|<span class="blue-text">EXAMPLE:</span> D, P
|EXAMPLE:
|
 
|
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|-
|<span class="blue-text">EXAMPLE:</span>
Microsatellite instability - hypermutated
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|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
|<span class="blue-text">EXAMPLE:</span> P, T
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In AML, BCR-ABL1 has been described together with different class II aberrations such as CBFB-MYH11, RUNX1- RUNX1T1 and PML-RARA<ref name=":2" />. In AML, BCR-ABL1 seems to cooperate with several AML-specific aberrations such as inv(16), t(8;21) and myelodysplasia-related cytogenetic aberrations<ref name=":2" /><ref>{{Cite journal|last=Bacher|first=Ulrike|last2=Haferlach|first2=Torsten|last3=Alpermann|first3=Tamara|last4=Zenger|first4=Melanie|last5=Hochhaus|first5=Andreas|last6=Beelen|first6=Dietrich W.|last7=Uppenkamp|first7=Michael|last8=Rummel|first8=Mathias|last9=Kern|first9=Wolfgang|date=2011|title=Subclones with the t(9;22)/BCR-ABL1 rearrangement occur in AML and seem to cooperate with distinct genetic alterations|url=https://www.ncbi.nlm.nih.gov/pubmed/21275954|journal=British Journal of Haematology|volume=152|issue=6|pages=713–720|doi=10.1111/j.1365-2141.2010.08472.x|issn=1365-2141|pmid=21275954}}</ref>. (For diagnostic purpose, note that inv(16) is not restricted to AML and can also be found in CML-MBC).
In AML, BCR-ABL1 has been described together with different class II aberrations such as CBFB-MYH11, RUNX1- RUNX1T1 and PML-RARA<ref name=":2" />. In AML, BCR-ABL1 seems to cooperate with several AML-specific aberrations such as inv(16), t(8;21) and myelodysplasia-related cytogenetic aberrations<ref name=":2" /><ref>{{Cite journal|last=Bacher|first=Ulrike|last2=Haferlach|first2=Torsten|last3=Alpermann|first3=Tamara|last4=Zenger|first4=Melanie|last5=Hochhaus|first5=Andreas|last6=Beelen|first6=Dietrich W.|last7=Uppenkamp|first7=Michael|last8=Rummel|first8=Mathias|last9=Kern|first9=Wolfgang|date=2011|title=Subclones with the t(9;22)/BCR-ABL1 rearrangement occur in AML and seem to cooperate with distinct genetic alterations|url=https://www.ncbi.nlm.nih.gov/pubmed/21275954|journal=British Journal of Haematology|volume=152|issue=6|pages=713–720|doi=10.1111/j.1365-2141.2010.08472.x|issn=1365-2141|pmid=21275954}}</ref>. (For diagnostic purpose, note that inv(16) is not restricted to AML and can also be found in CML-MBC).


<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
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</blockquote>
</blockquote>
==Gene Mutations (SNV/INDEL)==
==Gene Mutations (SNV/INDEL)==


Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity.'') </span>


Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.'') </span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
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!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC /  TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
!Gene!!'''Genetic Alteration'''!!'''Tumor Suppressor Gene, Oncogene, Other'''!!'''Prevalence -'''
!'''Diagnostic Significance (Yes, No or Unknown)'''
'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
!Prognostic Significance (Yes, No or Unknown)
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  '''
!Therapeutic Significance (Yes, No or Unknown)
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
!Notes
!'''Clinical Relevance Details/Other Notes'''
|-
|-
|EXAMPLE: TP53; Variable LOF mutations
|<span class="blue-text">EXAMPLE:</span>''EGFR''


EXAMPLE:
<br />
 
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
EGFR; Exon 20 mutations
|<span class="blue-text">EXAMPLE:</span> Oncogene
 
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
EXAMPLE: BRAF; Activating mutations
|<span class="blue-text">EXAMPLE:</span> T
|EXAMPLE: TSG
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
|EXAMPLE: 20% (COSMIC)
|<span class="blue-text">EXAMPLE:</span> Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
 
|-
EXAMPLE: 30% (add Reference)
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
|EXAMPLE: IDH1 R123H
<br />
|EXAMPLE: EGFR amplification
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
|<span class="blue-text">EXAMPLE:</span> P
|
|<span class="blue-text">EXAMPLE:</span> >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
|-
|<span class="blue-text">EXAMPLE:</span> ''BRAF''; Activating mutations
|<span class="blue-text">EXAMPLE:</span> Activating mutations
|<span class="blue-text">EXAMPLE:</span> Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
|<span class="blue-text">EXAMPLE:</span> T
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|EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).
|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
<br />
|}
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
 


<blockquote class='blockedit'>{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}
<blockquote class="blockedit">{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}</blockquote>


Coinciding molecular events such as ''NPM1'' mutations have been reported<ref name=":1" />.
Coinciding molecular events such as ''NPM1'' mutations have been reported<ref name=":1" />.
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<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
</blockquote>
==Epigenomic Alterations==
==Epigenomic Alterations==
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==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==


Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table.'')</span>
 
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Please include references throughout the table. Do not delete the table.)''</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|-
|EXAMPLE: BRAF and MAP2K1; Activating mutations
|<span class="blue-text">EXAMPLE:</span> ''BRAF'' and ''MAP2K1''; Activating mutations
|EXAMPLE: MAPK signaling
|<span class="blue-text">EXAMPLE:</span> MAPK signaling
|EXAMPLE: Increased cell growth and proliferation
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
|-
|-
|EXAMPLE: CDKN2A; Inactivating mutations
|<span class="blue-text">EXAMPLE:</span> ''CDKN2A''; Inactivating mutations
|EXAMPLE: Cell cycle regulation
|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
|EXAMPLE: Unregulated cell division
|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
|-
|-
|EXAMPLE:  KMT2C and ARID1A; Inactivating mutations
|<span class="blue-text">EXAMPLE:</span> ''KMT2C'' and ''ARID1A''; Inactivating mutations
|EXAMPLE:  Histone modification, chromatin remodeling
|<span class="blue-text">EXAMPLE:</span> Histone modification, chromatin remodeling
|EXAMPLE:  Abnormal gene expression program
|<span class="blue-text">EXAMPLE:</span> Abnormal gene expression program
|-
|
|
|
|}
|}


<blockquote class='blockedit'>{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}
<blockquote class="blockedit">{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}</blockquote>


The ''BCR'' gene product has serine/threonine kinase activity and is a GTPase-activating protein for p21rac<ref>{{Cite journal|last=Maru|first=Y.|last2=Witte|first2=O. N.|date=1991|title=The BCR gene encodes a novel serine/threonine kinase activity within a single exon|url=https://www.ncbi.nlm.nih.gov/pubmed/1657398|journal=Cell|volume=67|issue=3|pages=459–468|doi=10.1016/0092-8674(91)90521-y|issn=0092-8674|pmid=1657398}}</ref>. The ''ABL1'' gene is a proto-oncogene that encodes a protein tyrosine kinase involved in a variety of cellular processes, including cell division, adhesion, differentiation, and response to stress. The activity of this protein is negatively regulated by its SH3 domain, whereby deletion of the region encoding this domain results in an oncogene<ref>{{Cite journal|last=Wang|first=Jean Y. J.|date=2014|title=The capable ABL: what is its biological function?|url=https://www.ncbi.nlm.nih.gov/pubmed/24421390|journal=Molecular and Cellular Biology|volume=34|issue=7|pages=1188–1197|doi=10.1128/MCB.01454-13|issn=1098-5549|pmc=3993570|pmid=24421390}}</ref>. The t(9,22)(q34;q11) leads to the formation of a Philadelphia chromosome and generates an active chimeric BCR-ABL1 tyrosine kinase. The fusion gene is created by juxtaposing the ''ABL1'' gene on chromosome 9 (region q34) to a part of ''BCR'' (breakpoint cluster region) gene on chromosome 22 (region q11). This is a reciprocal translocation, creating an elongated chromosome 9 (der 9), and a truncated chromosome 22 (the Philadelphia chromosome, 22q-), the oncogenic BCR-ABL1 being found on the shorter derivative 22 chromosome<ref>{{Cite journal|last=Kurzrock|first=Razelle|last2=Kantarjian|first2=Hagop M.|last3=Druker|first3=Brian J.|last4=Talpaz|first4=Moshe|date=2003|title=Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics|url=https://www.ncbi.nlm.nih.gov/pubmed/12755554|journal=Annals of Internal Medicine|volume=138|issue=10|pages=819–830|doi=10.7326/0003-4819-138-10-200305200-00010|issn=1539-3704|pmid=12755554}}</ref><ref>{{Cite journal|last=Melo|first=J. V.|date=1996|title=The diversity of BCR-ABL fusion proteins and their relationship to leukemia phenotype|url=https://www.ncbi.nlm.nih.gov/pubmed/8839828|journal=Blood|volume=88|issue=7|pages=2375–2384|issn=0006-4971|pmid=8839828}}</ref>. This gene encodes for a BCR-ABL1 fusion protein, a tyrosine kinase. Tyrosine kinase activities are typically regulated in an auto-inhibitory manner, but the BCR-ABL1 fusion gene codes for a protein that is continuously activated, causing unregulated cell division. This is a result of the replacement of the myristoylated cap region which causes a conformational change rendering the kinase domain inactive, with a truncated portion of the BCR protein<ref>{{Cite journal|last=Nagar|first=Bhushan|last2=Hantschel|first2=Oliver|last3=Young|first3=Matthew A.|last4=Scheffzek|first4=Klaus|last5=Veach|first5=Darren|last6=Bornmann|first6=William|last7=Clarkson|first7=Bayard|last8=Superti-Furga|first8=Giulio|last9=Kuriyan|first9=John|date=2003|title=Structural basis for the autoinhibition of c-Abl tyrosine kinase|url=https://www.ncbi.nlm.nih.gov/pubmed/12654251|journal=Cell|volume=112|issue=6|pages=859–871|doi=10.1016/s0092-8674(03)00194-6|issn=0092-8674|pmid=12654251}}</ref>. The enzyme is responsible for the uncontrolled growth of leukemic cells which survive better than normal blood cells. As a result of BCR/ABL1 variable splicing (fusion RNA and hybrid proteins), two transcripts p190 and p210 are found for BCR-ABL1 positive AML.
The ''BCR'' gene product has serine/threonine kinase activity and is a GTPase-activating protein for p21rac<ref>{{Cite journal|last=Maru|first=Y.|last2=Witte|first2=O. N.|date=1991|title=The BCR gene encodes a novel serine/threonine kinase activity within a single exon|url=https://www.ncbi.nlm.nih.gov/pubmed/1657398|journal=Cell|volume=67|issue=3|pages=459–468|doi=10.1016/0092-8674(91)90521-y|issn=0092-8674|pmid=1657398}}</ref>. The ''ABL1'' gene is a proto-oncogene that encodes a protein tyrosine kinase involved in a variety of cellular processes, including cell division, adhesion, differentiation, and response to stress. The activity of this protein is negatively regulated by its SH3 domain, whereby deletion of the region encoding this domain results in an oncogene<ref>{{Cite journal|last=Wang|first=Jean Y. J.|date=2014|title=The capable ABL: what is its biological function?|url=https://www.ncbi.nlm.nih.gov/pubmed/24421390|journal=Molecular and Cellular Biology|volume=34|issue=7|pages=1188–1197|doi=10.1128/MCB.01454-13|issn=1098-5549|pmc=3993570|pmid=24421390}}</ref>. The t(9,22)(q34;q11) leads to the formation of a Philadelphia chromosome and generates an active chimeric BCR-ABL1 tyrosine kinase. The fusion gene is created by juxtaposing the ''ABL1'' gene on chromosome 9 (region q34) to a part of ''BCR'' (breakpoint cluster region) gene on chromosome 22 (region q11). This is a reciprocal translocation, creating an elongated chromosome 9 (der 9), and a truncated chromosome 22 (the Philadelphia chromosome, 22q-), the oncogenic BCR-ABL1 being found on the shorter derivative 22 chromosome<ref>{{Cite journal|last=Kurzrock|first=Razelle|last2=Kantarjian|first2=Hagop M.|last3=Druker|first3=Brian J.|last4=Talpaz|first4=Moshe|date=2003|title=Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics|url=https://www.ncbi.nlm.nih.gov/pubmed/12755554|journal=Annals of Internal Medicine|volume=138|issue=10|pages=819–830|doi=10.7326/0003-4819-138-10-200305200-00010|issn=1539-3704|pmid=12755554}}</ref><ref>{{Cite journal|last=Melo|first=J. V.|date=1996|title=The diversity of BCR-ABL fusion proteins and their relationship to leukemia phenotype|url=https://www.ncbi.nlm.nih.gov/pubmed/8839828|journal=Blood|volume=88|issue=7|pages=2375–2384|issn=0006-4971|pmid=8839828}}</ref>. This gene encodes for a BCR-ABL1 fusion protein, a tyrosine kinase. Tyrosine kinase activities are typically regulated in an auto-inhibitory manner, but the BCR-ABL1 fusion gene codes for a protein that is continuously activated, causing unregulated cell division. This is a result of the replacement of the myristoylated cap region which causes a conformational change rendering the kinase domain inactive, with a truncated portion of the BCR protein<ref>{{Cite journal|last=Nagar|first=Bhushan|last2=Hantschel|first2=Oliver|last3=Young|first3=Matthew A.|last4=Scheffzek|first4=Klaus|last5=Veach|first5=Darren|last6=Bornmann|first6=William|last7=Clarkson|first7=Bayard|last8=Superti-Furga|first8=Giulio|last9=Kuriyan|first9=John|date=2003|title=Structural basis for the autoinhibition of c-Abl tyrosine kinase|url=https://www.ncbi.nlm.nih.gov/pubmed/12654251|journal=Cell|volume=112|issue=6|pages=859–871|doi=10.1016/s0092-8674(03)00194-6|issn=0092-8674|pmid=12654251}}</ref>. The enzyme is responsible for the uncontrolled growth of leukemic cells which survive better than normal blood cells. As a result of BCR/ABL1 variable splicing (fusion RNA and hybrid proteins), two transcripts p190 and p210 are found for BCR-ABL1 positive AML.
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[[File:BCR-ABL1 translocation image.jpg|Figure 1. Philadelphia chromosome. A piece of chromosome 9 and a piece of chrosomome 22 break off and trade places. The BCR-ABL1 gene is formed on chromosome 22 where the piece of chromosome 9 attaches. The changed chromosome 22 is called Philadelphia chromosome. Image from National Cancer Institute website https://www.cancer.gov/publications/dictionaries/cancer-terms/def/bcr-abl-fusion-gene|frame|center]]
[[File:BCR-ABL1 translocation image.jpg|Figure 1. Philadelphia chromosome. A piece of chromosome 9 and a piece of chrosomome 22 break off and trade places. The BCR-ABL1 gene is formed on chromosome 22 where the piece of chromosome 9 attaches. The changed chromosome 22 is called Philadelphia chromosome. Image from National Cancer Institute website https://www.cancer.gov/publications/dictionaries/cancer-terms/def/bcr-abl-fusion-gene|frame|center]]


<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
</blockquote>
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==
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==References==
==References==
(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted.''</span> <span style="color:#0070C0">''If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">) </span> <references />
(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">)</span> <references />


'''
<br />


==Notes==
==Notes==
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the [[Leadership|''<u>Associate Editor</u>'']] or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.
 
Prior Author(s): 
 
Kay Weng Choy MBBS, Monash Medical Centre 
 
       
<nowiki>*</nowiki>''Citation of this Page'': “Acute myeloid leukaemia with BCR::ABL1 fusion”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_BCR::ABL1_fusion</nowiki>.
<nowiki>*</nowiki>''Citation of this Page'': “Acute myeloid leukaemia with BCR::ABL1 fusion”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_BCR::ABL1_fusion</nowiki>.
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases A]]
[[Category:HAEM5]]
[[Category:DISEASE]]
[[Category:Diseases A]]
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