B-lymphoblastic leukaemia/lymphoma with hypodiploidy

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Haematolymphoid Tumours (WHO Classification, 5th ed.)

Primary Author(s)*

Miguel Gonzalez Mancera, MD

WHO Classification of Disease

Structure Disease
Book Haematolymphoid Tumours (5th ed.)
Category B-cell lymphoid proliferations and lymphomas
Family Precursor B-cell neoplasms
Type B-lymphoblastic leukaemias/lymphomas
Subtype(s) B-lymphoblastic leukaemia/lymphoma with hypodiploidy

Related Terminology

Acceptable N/A
Not Recommended N/A

Gene Rearrangements

No recurrent gene rearrangements have been described[1].

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
N/A N/A N/A N/A N/A N/A N/A N/A

Individual Region Genomic Gain/Loss/LOH

Hypodiploid B-ALL is characterized by widespread genomic losses consistent with the hypodiploid karyotype[1].

Chr # Gain, Loss, Amp, LOH Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size] Relevant Gene(s) Diagnostic, Prognostic, and Therapeutic Significance - D, P, T Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
Please refer to section "Characteristic Chromosomal or Other Global Mutational Patterns" below.

Characteristic Chromosomal or Other Global Mutational Patterns

This entity is defined by the presence of neoplastic lymphoblasts containing less than 46 chromosomes, and can be subdivided into near-haploid B-ALL/LBL with hypodiploidy (24–31 chromosomes); low-hypodiploid B-ALL/LBL with hypodiploidy (32–39 chromosomes); and high-hypodiploid B-ALL/LBL with hypodiploidy (40–43 chromosomes)[1][2]. Of note, near-diploid cases (44–45 chromosomes) are not included in the hypodiploid category in clinical therapy–directed classification schemes because they do not share the poor prognosis observed[3]. In a study, for patients with 44 chromosomes, monosomy 7, the presence of a dicentric chromosome, or both predicted a worse event-free survival (EFS) but similar overall survival (OS)[4].

Chromosomal Pattern Molecular Pathogenesis 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
Near-haploid (NH) with hypodiploidy (24–31 chromosomes) Near haploidy may be the primary event with loss of chromosomes, followed by a secondary event of doubling of chromosomes indicating uniparental isodisomy (UPID), microdeletions if any may occur after the secondary event[5]. The chromosomal loss alone may be enough for leukemogenesis and the unconserved random chromosomes may contain specific genes that increase the oncogenic potential of leukemic cells[6][7]. Rare (0.5%)[8] D: Hypodiploidy demonstrated by karyotyping and/or FISH; flow cytometry DNA index analysis and/or single nucleotide polymorphism (SNP) array analysis to identify masked hypodiploidy.

P: Poor prognosis[4][9]. 5-year EFS 25–40%[8].

No (NCCN) NH observed in pediatric population with virtually no adult cases reported.

Nonrandom retention of X chromosome plus chromosomes 8, 14, 18, and 21 frequently observed. Most common targets of aneuploidy are chromosomes 1–7, 9, 11–13, 15–17, 19–20 and 22[10][11][12][13][14]. Near-haploid and low-hypodiploid B-ALL/LBL may undergo doubling, resulting in a pseudohyperdiploid or near-triploid clone containing up to 78 chromosomes, and can present as a diagnostic challenge. If the original hypodiploid clone is not present, the hypodiploidy is regarded as masked, and the case may be mistaken for high-hyperdiploid B-ALL/LBL, resulting in an inappropriate prognostication[9][15][16]. The two subtypes may be differentiated by SNP array analysis, demonstrating copy-neutral loss of heterozygosity for doubled monosomic chromosomes. The DNA index assessed by flow cytometry may also be helpful if distinct peaks representing the hypodiploid and doubled clones are both detectable[17].

Low-hypodiploid (LH) with hypodiploidy (32–39 chromosomes) More than 90% of low-hypodiploid patients have been identified with TP53 mutations, which occur in virtually all low-hypodiploid B-ALL cases due to the very recurrent loss of chromosome 17[13][18][19]. p53 is one of the most prominent tumor suppressors. Its activation as a transcription factor stimulates downstream pathways leading to protective cellular processes, including cell-cycle arrest, apoptosis, and senescence, to prevent the propagation of genetically altered cells[20]. Rare in children, recurrent in adolescents, young adults, and adults P: Associated with poor prognosis. EFS 30–50%[8][9]. No (NCCN) LH B-ALL/LBL is rare in children (< 1%); however, frequency increases with age, accounting for 5% of B-ALL/LBL cases in adolescents and young adults, and > 10% of cases in adults. Nonrandom retention of two copies of chromosomes from the following: the sex chromosomes plus chromosomes 1,6, 8, 10, 14, 18, and19. Chromosome 21 is almost always retained in two copies.

The most common targets of aneuploidy are chromosomes 2–4, 7, 9, 12–13, 15–17 and 20[14].

High-hypodiploid B-ALL/LBL with hypodiploidy (40–43 chromosomes) Genetic alterations involve CDKN2A and TP53[18]. Rare, occurring in approximately 4% of diagnosed cases of hypodiploidy in both children and adults, but with a predominance of the younger group[12][21]. P: Associated with poor prognosis. EFS 75%[3]. No (NCCN) Chromosome abnormalities include whole chromosome loss, specifically one sex chromosome and often chromosomes 7, 9, and/or 13. Also detected are structural anomalies especially dicentric chromosomes involving chromosomes 7, 9 or 12.

Gene Mutations (SNV/INDEL)

Holmfeldt et al sequenced 124 cases of low-hypodiploid B-ALL and showed that more than two-thirds (70.6%) of near-haploid ALL cases harbored genetic alterations known or predicted to result in activation of RTK or Ras signaling, including deletion, amplification and/or sequence mutation of NF1, NRAS, KRAS, MAPK1, FLT3 or PTPN11[10].  

Gene Genetic Alteration Tumor Suppressor Gene, Oncogene, Other 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
TP53
 Missense mutations most common (exons 7, 8, 6, and 5).

Frameshift mutations less frequent (exons 4 and 7)[13]. Typically loss of function (LOF) mutations.

Tumor supressor gene Common (>90%) D: may indicate need for genetic counseling for Li-Fraumeni syndrome in pediatric population

P: poor outcome

No (NCCN) These alterations correlate with low-hypodiploid ALL (32–39 chromosomes) and poorer clinical outcomes[10]. Approximately 50% of children with low-hypodiploid B-ALL/LBL carry germline TP53 variants associated with Li–Fraumeni syndrome. Accordingly, genetic counseling is recommended for children with low-hypodiploid B-ALL carrying TP53 mutations, and their relatives[22]. In contrast to childhood cases, TP53 mutations in low-hypodiploid adult B-ALL are somatic, are not found in healthy hematopoietic cells, and not detectable in remission samples[10][13].
RB1 Focal deletion and mutation[10][23] Tumor supressor gene Common No established significance No (NCCN) Associated with low-hypodiploid B-ALL.
NF1 Mutations and focal deletions. In 68% of the cases, the NF1 deletions were intragenic involving exons 15 through 35. Because of aneuploidy, the NF1 alterations were biallelic in 76.7% of near-haploid cases.[10] Tumor supressor gene Mutations: Recurrent

Focal deletions: Common[10]

No established significance No (NCCN) Involved in RTK/RAS cellular pathway, and associated primarily with near-haploid B-ALL[10][23].
FLT3 Mutation[10] Oncogene Recurrent No established significance No (NCCN)
NRAS Mutation[10] Oncogene Recurrent No established significance No (NCCN)
KRAS Mutation[10] Oncogene Rare No established significance No (NCCN)
MAPK1 Mutation[10] Oncogene Rare No established significance No (NCCN)
PTPN11 Mutation[10] Oncoogene Rare No established significance No (NCCN)
CDKN2A/B Focal deletion[10] Tumor supressor Common No established significance No (NCCN) Associated with near-haploid B-ALL and low-hypodiploid B-ALL.
IKZF2 Focal deletion. Alterations of IKZF2 and IKZF3 were biallelic as a result of aneuploidy[10]. Tumor supressor Common No established significance No (NCCN) Associated with low-hypodiploid B-ALL.
IKZF3


Focal deletion and one frameshift mutation[10] Tumor supressor Recurrent No established significance No (NCCN) Associated with near-haploid B-ALL.
PAG1 Focal deletion[10]. Most PAG1 deletions were homozygous and involved the upstream region and first exon, leading to a complete loss of PAG1 expression. Tumor supressor Recurrent No established significance No (NCCN) Associated with near-haploid B-ALL. It was identified as a putative RAS signaling inhibitor and have a negative regulatory function in proximal B-cell receptor signaling[10].

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

Epigenomic Alterations

In near haploid 19% of the cases had focal deletions of histone gene cluster at 6p22, however, non-hypodiploid ALL had 8%, lower frequency of these deletions[10]. Of the 25 next generation sequenced haploid cases 16 (64%) cases had twenty-six histone modifier gene mutations and of the 15 low hypodiploid ALL cases 9 (60%) cases had 9 mutations; the most common mutation (32%) of the near haploid cases was transcriptional co-activator and histone acetyltransferase CREBBP[10].

Genes and Main Pathways Involved

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
NF1, NRAS, KRAS, MAPK1, FLT3 or PTPN11; Activating mutations[10] RTK or Ras signaling Constitutive activation of mitogenic and anti-apoptotic pathways, driving uncontrolled cell proliferation, survival, and malignant transformation.
CDKN2A/B, TP53, RB1; Loss of function mutations[10] Cell cycle and apoptosis Propagation of genetically altered cells.
IKZF1, IKZF2, IKZF3, PAX5, EBF1, VPREB1[23] B-cell development Altered lymphoid development and differentiation.
PAG1[23] BCR signaling Altered regulatory function in proximal B cell–receptor signaling.
ETV6[23] Hematopoiesis Not fully elucidated in this entity
ARPP21[23] Calmodulin signaling Not fully elucidated in this entity
SLX4IP[23] Telomere length maintenance Not fully elucidated in this entity
CUL5[23] Ubiquitin pathway Not fully elucidated in this entity
FAM53B[23] Wnt signaling Not fully elucidated in this entity
PDS5B[23] Cohesis complex Not fully elucidated in this entity
ANKRD11, DMD[23] Cell adhesion Not fully elucidated in this entity

Genetic Diagnostic Testing Methods

Karyotype, flow cytometry DNA index, FISH, and SNP arrays are all useful in establishing the diagnosis[1].

When using FISH or karyotype, approximately 16% to 30% of the ALL cases yield no or inadequate cytogenetic results due to inadequate specimens and absent or few mitotic cells.

Among those with a cytogenetic result, 15% to 25% have a normal karyotype[24]. High-resolution SNP array can detect IKZF1 deletions and other cryptic copy number aberrations as well as CN-LOH that are not detectable by chromosome analysis[25].

Familial Forms

In Low hypodiploid (LH), several studies have not only identified a high percentage of pediatric patients with TP53 mutations, but close to half displayed germline mutations, suggesting that LH ALL is a manifestation of Li-Fraumeni syndrome in children[10][19][22].

Adults also showed a high incidence of TP53 mutations, but these mutations appear to be somatic in origin. In Near Haploid (NH), mutations of genes of receptor tyrosine kinase (RTK) pathway, Ras signaling, IKZF3 (17q21.1) and histone clusters, but mutations of IZFK2, RB1, or TP53 were rare.

Additional Information

Genetic abnormalities involving TP53, RB1 and IKZF2 are hallmarks of low hypodiploid ALL, where as near haploid ALL has RTK, RAS and IKZF3 alterations[10].

Links

N/A

References

  1. ↑ 1.0 1.1 1.2 1.3 WHO Classification of Tumours: Haematolymphoid Tumours [Internet; Beta Version Ahead of Print](5th ed.), International Agency for Research on Cancer (2022)
  2. ↑ Harrison, Christine J.; Moorman, Anthony V.; Broadfield, Zoë J.; Cheung, Kan L.; Harris, Rachel L.; Reza Jalali, G.; Robinson, Hazel M.; Barber, Kerry E.; Richards, Sue M. (2004). "Three distinct subgroups of hypodiploidy in acute lymphoblastic leukaemia". British Journal of Haematology. 125 (5): 552–559. doi:10.1111/j.1365-2141.2004.04948.x. ISSN 0007-1048. PMID 15147369.
  3. ↑ 3.0 3.1 Pui, Ching-Hon; Rebora, Paola; Schrappe, Martin; Attarbaschi, Andishe; Baruchel, Andre; Basso, Giuseppe; Cavé, Hélène; Elitzur, Sarah; Koh, Katsuyoshi (2019-04-01). "Outcome of Children With Hypodiploid Acute Lymphoblastic Leukemia: A Retrospective Multinational Study". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 37 (10): 770–779. doi:10.1200/JCO.18.00822. ISSN 1527-7755. PMC 7051863. PMID 30657737.
  4. ↑ 4.0 4.1 Nachman, James B.; Heerema, Nyla A.; Sather, Harland; Camitta, Bruce; Forestier, Erik; Harrison, Christine J.; Dastugue, Nicole; Schrappe, Martin; Pui, Ching-Hon (2007). "Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia". Blood. 110 (4): 1112–1115. doi:10.1182/blood-2006-07-038299. ISSN 0006-4971. PMC 1939895. PMID 17473063.
  5. ↑ Safavi, S.; Forestier, E.; Golovleva, I.; Barbany, G.; Nord, K. H.; Moorman, A. V.; Harrison, C. J.; Johansson, B.; Paulsson, K. (2013). "Loss of chromosomes is the primary event in near-haploid and low-hypodiploid acute lymphoblastic leukemia". Leukemia. 27 (1): 248–250. doi:10.1038/leu.2012.227. ISSN 1476-5551. PMID 22889820.
  6. ↑ Harrison, Christine J.; Moorman, Anthony V.; Barber, Kerry E.; Broadfield, Zoë J.; Cheung, Kan L.; Harris, Rachel L.; Jalali, G. Reza; Robinson, Hazel M.; Strefford, Jonathan C. (2005-05). "Interphase molecular cytogenetic screening for chromosomal abnormalities of prognostic significance in childhood acute lymphoblastic leukaemia: a UK Cancer Cytogenetics Group Study". British Journal of Haematology. 129 (4): 520–530. doi:10.1111/j.1365-2141.2005.05497.x. ISSN 0007-1048. PMID 15877734. {{cite journal}}: Check date values in: |date= (help)
  7. ↑ Raimondi, Susana C.; Zhou, Yinmei; Mathew, Susan; Shurtleff, Sheila A.; Sandlund, John T.; Rivera, Gaston K.; Behm, Frederick G.; Pui, Ching-Hon (2003-12-15). "Reassessment of the prognostic significance of hypodiploidy in pediatric patients with acute lymphoblastic leukemia". Cancer. 98 (12): 2715–2722. doi:10.1002/cncr.11841. ISSN 0008-543X. PMID 14669294.
  8. ↑ 8.0 8.1 8.2 Panuciak, Kinga; Nowicka, Emilia; Mastalerczyk, Angelika; Zawitkowska, Joanna; Niedźwiecki, Maciej; Lejman, Monika (2023-05-15). "Overview on Aneuploidy in Childhood B-Cell Acute Lymphoblastic Leukemia". International Journal of Molecular Sciences. 24 (10): 8764. doi:10.3390/ijms24108764. ISSN 1422-0067. PMC 10218510. PMID 37240110.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  9. ↑ 9.0 9.1 9.2 Safavi, Setareh; Paulsson, Kajsa (2017). "Near-haploid and low-hypodiploid acute lymphoblastic leukemia: two distinct subtypes with consistently poor prognosis". Blood. 129 (4): 420–423. doi:10.1182/blood-2016-10-743765. ISSN 1528-0020. PMID 27903530.
  10. ↑ 10.00 10.01 10.02 10.03 10.04 10.05 10.06 10.07 10.08 10.09 10.10 10.11 10.12 10.13 10.14 10.15 10.16 10.17 10.18 10.19 10.20 10.21 10.22 10.23 Holmfeldt, Linda; Wei, Lei; Diaz-Flores, Ernesto; Walsh, Michael; Zhang, Jinghui; Ding, Li; Payne-Turner, Debbie; Churchman, Michelle; Andersson, Anna (2013). "The genomic landscape of hypodiploid acute lymphoblastic leukemia". Nature Genetics. 45 (3): 242–252. doi:10.1038/ng.2532. ISSN 1546-1718. PMC 3919793. PMID 23334668.
  11. ↑ Creasey, Thomas; Enshaei, Amir; Nebral, Karin; Schwab, Claire; Watts, Kathryn; Cuthbert, Gavin; Vora, Ajay; Moppett, John; Harrison, Christine J. (2021-09). "Single nucleotide polymorphism array-based signature of low hypodiploidy in acute lymphoblastic leukemia". Genes, Chromosomes & Cancer. 60 (9): 604–615. doi:10.1002/gcc.22956. ISSN 1098-2264. PMC 8600946. PMID 33938069. {{cite journal}}: Check date values in: |date= (help)
  12. ↑ 12.0 12.1 Harrison, Christine J.; Moorman, Anthony V.; Broadfield, Zoë J.; Cheung, Kan L.; Harris, Rachel L.; Reza Jalali, G.; Robinson, Hazel M.; Barber, Kerry E.; Richards, Sue M. (2004-06). "Three distinct subgroups of hypodiploidy in acute lymphoblastic leukaemia". British Journal of Haematology. 125 (5): 552–559. doi:10.1111/j.1365-2141.2004.04948.x. ISSN 0007-1048. PMID 15147369. {{cite journal}}: Check date values in: |date= (help)
  13. ↑ 13.0 13.1 13.2 13.3 Mühlbacher, Verena; Zenger, Melanie; Schnittger, Susanne; Weissmann, Sandra; Kunze, Franziska; Kohlmann, Alexander; Bellos, Frauke; Kern, Wolfgang; Haferlach, Torsten (2014). "Acute lymphoblastic leukemia with low hypodiploid/near triploid karyotype is a specific clinical entity and exhibits a very high TP53 mutation frequency of 93%". Genes, Chromosomes & Cancer. 53 (6): 524–536. doi:10.1002/gcc.22163. ISSN 1098-2264. PMID 24619868.
  14. ↑ 14.0 14.1 Holmfeldt, Linda; Wei, Lei; Diaz-Flores, Ernesto; Walsh, Michael; Zhang, Jinghui; Ding, Li; Payne-Turner, Debbie; Churchman, Michelle; Andersson, Anna (2013-03). "The genomic landscape of hypodiploid acute lymphoblastic leukemia". Nature Genetics. 45 (3): 242–252. doi:10.1038/ng.2532. ISSN 1546-1718. PMC 3919793. PMID 23334668. {{cite journal}}: Check date values in: |date= (help)
  15. ↑ Carroll, Andrew J.; Shago, Mary; Mikhail, Fady M.; Raimondi, Susana C.; Hirsch, Betsy A.; Loh, Mignon L.; Raetz, Elizabeth A.; Borowitz, Michael J.; Wood, Brent L. (2019-10). "Masked hypodiploidy: Hypodiploid acute lymphoblastic leukemia (ALL) mimicking hyperdiploid ALL in children: A report from the Children's Oncology Group". Cancer Genetics. 238: 62–68. doi:10.1016/j.cancergen.2019.07.009. ISSN 2210-7762. PMC 6768693. PMID 31425927. {{cite journal}}: Check date values in: |date= (help)
  16. ↑ Creasey, Thomas; Enshaei, Amir; Nebral, Karin; Schwab, Claire; Watts, Kathryn; Cuthbert, Gavin; Vora, Ajay; Moppett, John; Harrison, Christine J. (2021-09). "Single nucleotide polymorphism array-based signature of low hypodiploidy in acute lymphoblastic leukemia". Genes, Chromosomes & Cancer. 60 (9): 604–615. doi:10.1002/gcc.22956. ISSN 1098-2264. PMC 8600946. PMID 33938069. {{cite journal}}: Check date values in: |date= (help)
  17. ↑ Yu, Chih-Hsiang; Lin, Tze-Kang; Jou, Shiann-Tarng; Lin, Chien-Yu; Lin, Kai-Hsin; Lu, Meng-Yao; Chen, Shu-Huey; Cheng, Chao-Neng; Wu, Kang-Hsi (2020-07-13). "MLPA and DNA index improve the molecular diagnosis of childhood B-cell acute lymphoblastic leukemia". Scientific Reports. 10 (1): 11501. doi:10.1038/s41598-020-68311-9. ISSN 2045-2322. PMC 7359332. PMID 32661308.
  18. ↑ 18.0 18.1 Safavi, Setareh; Olsson, Linda; Biloglav, Andrea; Veerla, Srinivas; Blendberg, Molly; Tayebwa, Johnbosco; Behrendtz, Mikael; Castor, Anders; Hansson, Markus (2015). "Genetic and epigenetic characterization of hypodiploid acute lymphoblastic leukemia". Oncotarget. 6 (40): 42793–42802. doi:10.18632/oncotarget.6000. ISSN 1949-2553. PMC 4767471. PMID 26544893.
  19. ↑ 19.0 19.1 Stengel, Anna; Schnittger, Susanne; Weissmann, Sandra; Kuznia, Sabrina; Kern, Wolfgang; Kohlmann, Alexander; Haferlach, Torsten; Haferlach, Claudia (2014-07-10). "TP53 mutations occur in 15.7% of ALL and are associated with MYC-rearrangement, low hypodiploidy, and a poor prognosis". Blood. 124 (2): 251–258. doi:10.1182/blood-2014-02-558833. ISSN 1528-0020. PMID 24829203.
  20. ↑ Vogelstein, B.; Lane, D.; Levine, A. J. (2000-11-16). "Surfing the p53 network". Nature. 408 (6810): 307–310. doi:10.1038/35042675. ISSN 0028-0836. PMID 11099028.
  21. ↑ Moorman, Anthony V. (2016). "New and emerging prognostic and predictive genetic biomarkers in B-cell precursor acute lymphoblastic leukemia". Haematologica. 101 (4): 407–416. doi:10.3324/haematol.2015.141101. ISSN 1592-8721. PMC 5004393. PMID 27033238.
  22. ↑ 22.0 22.1 Comeaux, Evan Q.; Mullighan, Charles G. (2017-03-01). "TP53 Mutations in Hypodiploid Acute Lymphoblastic Leukemia". Cold Spring Harbor Perspectives in Medicine. 7 (3): a026286. doi:10.1101/cshperspect.a026286. ISSN 2157-1422. PMC 5334249. PMID 28003275.{{cite journal}}: CS1 maint: article number as page number (link)
  23. ↑ 23.00 23.01 23.02 23.03 23.04 23.05 23.06 23.07 23.08 23.09 23.10 Molina, Oscar; Bataller, Alex; Thampi, Namitha; Ribera, Jordi; Granada, Isabel; Velasco, Pablo; Fuster, José Luis; Menéndez, Pablo (2021-12-22). "Near-Haploidy and Low-Hypodiploidy in B-Cell Acute Lymphoblastic Leukemia: When Less Is Too Much". Cancers. 14 (1): 32. doi:10.3390/cancers14010032. ISSN 2072-6694. PMC 8750410. PMID 35008193.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  24. ↑ Moorman, Anthony V.; Ensor, Hannah M.; Richards, Sue M.; Chilton, Lucy; Schwab, Claire; Kinsey, Sally E.; Vora, Ajay; Mitchell, Chris D.; Harrison, Christine J. (2010-05). "Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial". The Lancet. Oncology. 11 (5): 429–438. doi:10.1016/S1470-2045(10)70066-8. ISSN 1474-5488. PMID 20409752. {{cite journal}}: Check date values in: |date= (help)
  25. ↑ Wang, Yunhong; Miller, Sue; Roulston, Diane; Bixby, Dale; Shao, Lina (2016). "Genome-Wide Single-Nucleotide Polymorphism Array Analysis Improves Prognostication of Acute Lymphoblastic Leukemia/Lymphoma". The Journal of molecular diagnostics: JMD. 18 (4): 595–603. doi:10.1016/j.jmoldx.2016.03.004. ISSN 1943-7811. PMID 27161658.


Notes

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[[Copy Number and cn-LOH Abnormalities in ALL]

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