HAEM5:B-lymphoblastic leukaemia/lymphoma with hypodiploidy: Difference between revisions

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

Please refer to section "Characteristic Chromosomal or Other Global Mutational Patterns" below.

This entity is defined by the presence of neoplastic lymphoblasts containing less than 46 chromosomes<ref name=":0">Borowitz MJ, et al., (2017). B-Lymphoblastic leukaemia/lymphoma 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. IARC Press: Lyon, France, p206.</ref>, 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)<ref name=":13" />. 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<ref name=":14" />. In a study, for patients with 44 chromosomes, monosomy 7, the presence of a dicentric chromosome, or both predicted a worse EFS but similar OS<ref name=":3">{{Cite journal|last=Nachman|first=James B.|last2=Heerema|first2=Nyla A.|last3=Sather|first3=Harland|last4=Camitta|first4=Bruce|last5=Forestier|first5=Erik|last6=Harrison|first6=Christine J.|last7=Dastugue|first7=Nicole|last8=Schrappe|first8=Martin|last9=Pui|first9=Ching-Hon|date=2007|title=Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/17473063|journal=Blood|volume=110|issue=4|pages=1112–1115|doi=10.1182/blood-2006-07-038299|issn=0006-4971|pmc=1939895|pmid=17473063}}</ref>.

|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<ref name=":15">{{Cite journal|last=Harrison|first=Christine J.|last2=Moorman|first2=Anthony V.|last3=Barber|first3=Kerry E.|last4=Broadfield|first4=Zoë J.|last5=Cheung|first5=Kan L.|last6=Harris|first6=Rachel L.|last7=Jalali|first7=G. Reza|last8=Robinson|first8=Hazel M.|last9=Strefford|first9=Jonathan C.|date=2005-05|title=Interphase molecular cytogenetic screening for chromosomal abnormalities of prognostic significance in childhood acute lymphoblastic leukaemia: a UK Cancer Cytogenetics Group Study|url=https://pubmed.ncbi.nlm.nih.gov/15877734|journal=British Journal of Haematology|volume=129|issue=4|pages=520–530|doi=10.1111/j.1365-2141.2005.05497.x|issn=0007-1048|pmid=15877734}}</ref><ref>{{Cite journal|last=Raimondi|first=Susana C.|last2=Zhou|first2=Yinmei|last3=Mathew|first3=Susan|last4=Shurtleff|first4=Sheila A.|last5=Sandlund|first5=John T.|last6=Rivera|first6=Gaston K.|last7=Behm|first7=Frederick G.|last8=Pui|first8=Ching-Hon|date=2003-12-15|title=Reassessment of the prognostic significance of hypodiploidy in pediatric patients with acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/14669294|journal=Cancer|volume=98|issue=12|pages=2715–2722|doi=10.1002/cncr.11841|issn=0008-543X|pmid=14669294}}</ref>.

P: Associated with poor prognosis<ref name=":3" />. 5-year EFS 25–40%<ref name=":8">{{Cite journal|last=Panuciak|first=Kinga|last2=Nowicka|first2=Emilia|last3=Mastalerczyk|first3=Angelika|last4=Zawitkowska|first4=Joanna|last5=Niedźwiecki|first5=Maciej|last6=Lejman|first6=Monika|date=2023-05-15|title=Overview on Aneuploidy in Childhood B-Cell Acute Lymphoblastic Leukemia|url=https://pubmed.ncbi.nlm.nih.gov/37240110|journal=International Journal of Molecular Sciences|volume=24|issue=10|pages=8764|doi=10.3390/ijms24108764|issn=1422-0067|pmc=10218510|pmid=37240110}}</ref>.

|It has been observed in the pediatric population with virtually no adult cases reported. Nonrandom retention of the X chromosome plus chromosomes 8, 14, 18, and 21 are frequently observed. The most common targets of aneuploidy are chromosomes 1–7, 9, 11–13, 15–17, 19–20 and 22<ref name=":2" /><ref>{{Cite journal|last=Creasey|first=Thomas|last2=Enshaei|first2=Amir|last3=Nebral|first3=Karin|last4=Schwab|first4=Claire|last5=Watts|first5=Kathryn|last6=Cuthbert|first6=Gavin|last7=Vora|first7=Ajay|last8=Moppett|first8=John|last9=Harrison|first9=Christine J.|date=2021-09|title=Single nucleotide polymorphism array-based signature of low hypodiploidy in acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/33938069|journal=Genes, Chromosomes & Cancer|volume=60|issue=9|pages=604–615|doi=10.1002/gcc.22956|issn=1098-2264|pmc=8600946|pmid=33938069}}</ref><ref name=":11">{{Cite journal|last=Harrison|first=Christine J.|last2=Moorman|first2=Anthony V.|last3=Broadfield|first3=Zoë J.|last4=Cheung|first4=Kan L.|last5=Harris|first5=Rachel L.|last6=Reza Jalali|first6=G.|last7=Robinson|first7=Hazel M.|last8=Barber|first8=Kerry E.|last9=Richards|first9=Sue M.|date=2004-06|title=Three distinct subgroups of hypodiploidy in acute lymphoblastic leukaemia|url=https://pubmed.ncbi.nlm.nih.gov/15147369|journal=British Journal of Haematology|volume=125|issue=5|pages=552–559|doi=10.1111/j.1365-2141.2004.04948.x|issn=0007-1048|pmid=15147369}}</ref><ref name=":6" /><ref name=":7">{{Cite journal|last=Holmfeldt|first=Linda|last2=Wei|first2=Lei|last3=Diaz-Flores|first3=Ernesto|last4=Walsh|first4=Michael|last5=Zhang|first5=Jinghui|last6=Ding|first6=Li|last7=Payne-Turner|first7=Debbie|last8=Churchman|first8=Michelle|last9=Andersson|first9=Anna|date=2013-03|title=The genomic landscape of hypodiploid acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/23334668|journal=Nature Genetics|volume=45|issue=3|pages=242–252|doi=10.1038/ng.2532|issn=1546-1718|pmc=3919793|pmid=23334668}}</ref>.

Near-haploid and low-hypodiploid B-ALL/LBL may undergo doubling, resulting in a pseudohyperdiploid or near-triploid clone containing up to 78 chromosomes. 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<ref>{{Cite journal|last=Carroll|first=Andrew J.|last2=Shago|first2=Mary|last3=Mikhail|first3=Fady M.|last4=Raimondi|first4=Susana C.|last5=Hirsch|first5=Betsy A.|last6=Loh|first6=Mignon L.|last7=Raetz|first7=Elizabeth A.|last8=Borowitz|first8=Michael J.|last9=Wood|first9=Brent L.|date=2019-10|title=Masked hypodiploidy: Hypodiploid acute lymphoblastic leukemia (ALL) mimicking hyperdiploid ALL in children: A report from the Children's Oncology Group|url=https://pubmed.ncbi.nlm.nih.gov/31425927|journal=Cancer Genetics|volume=238|pages=62–68|doi=10.1016/j.cancergen.2019.07.009|issn=2210-7762|pmc=6768693|pmid=31425927}}</ref><ref>{{Cite journal|last=Creasey|first=Thomas|last2=Enshaei|first2=Amir|last3=Nebral|first3=Karin|last4=Schwab|first4=Claire|last5=Watts|first5=Kathryn|last6=Cuthbert|first6=Gavin|last7=Vora|first7=Ajay|last8=Moppett|first8=John|last9=Harrison|first9=Christine J.|date=2021-09|title=Single nucleotide polymorphism array-based signature of low hypodiploidy in acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/33938069|journal=Genes, Chromosomes & Cancer|volume=60|issue=9|pages=604–615|doi=10.1002/gcc.22956|issn=1098-2264|pmc=8600946|pmid=33938069}}</ref>. 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<ref>{{Cite journal|last=Yu|first=Chih-Hsiang|last2=Lin|first2=Tze-Kang|last3=Jou|first3=Shiann-Tarng|last4=Lin|first4=Chien-Yu|last5=Lin|first5=Kai-Hsin|last6=Lu|first6=Meng-Yao|last7=Chen|first7=Shu-Huey|last8=Cheng|first8=Chao-Neng|last9=Wu|first9=Kang-Hsi|date=2020-07-13|title=MLPA and DNA index improve the molecular diagnosis of childhood B-cell acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/32661308|journal=Scientific Reports|volume=10|issue=1|pages=11501|doi=10.1038/s41598-020-68311-9|issn=2045-2322|pmc=7359332|pmid=32661308}}</ref>.

|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<ref name=":6" /><ref name=":9" /><ref name=":10">{{Cite journal|last=Stengel|first=Anna|last2=Schnittger|first2=Susanne|last3=Weissmann|first3=Sandra|last4=Kuznia|first4=Sabrina|last5=Kern|first5=Wolfgang|last6=Kohlmann|first6=Alexander|last7=Haferlach|first7=Torsten|last8=Haferlach|first8=Claudia|date=2014-07-10|title=TP53 mutations occur in 15.7% of ALL and are associated with MYC-rearrangement, low hypodiploidy, and a poor prognosis|url=https://pubmed.ncbi.nlm.nih.gov/24829203|journal=Blood|volume=124|issue=2|pages=251–258|doi=10.1182/blood-2014-02-558833|issn=1528-0020|pmid=24829203}}</ref>. 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<ref>{{Cite journal|last=Vogelstein|first=B.|last2=Lane|first2=D.|last3=Levine|first3=A. J.|date=2000-11-16|title=Surfing the p53 network|url=https://pubmed.ncbi.nlm.nih.gov/11099028|journal=Nature|volume=408|issue=6810|pages=307–310|doi=10.1038/35042675|issn=0028-0836|pmid=11099028}}</ref>.

|P: Associated with poor prognosis. EFS 30–50%<ref name=":8" />.

|Rare, occurring in approximately 4% of diagnosed cases of hypodiploidy in both children and adults, but with a predominance of the younger group<ref name=":11" /><ref name=":12" />.

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

 

|Approximately 50% of children with low-hypodiploid B-ALL/LBL carry germline ''TP53'' variants associated with Li–Fraumeni syndrome, an autosomal dominant disorder caused by ''TP53'' mutations. These alterations correlate with low-hypodiploid ALL (32–39 chromosomes) and poorer clinical outcomes<ref name=":2" />.

|Mutations and focal deletions. In 68% of the cases, the ''NF1'' deletions were intragenic involving exons 15 through 35<ref name=":2" />.

| rowspan="6" |Involved in RTK/RAS cellular pathway, and associated primarily with near-haploid B-ALL<ref name=":2" /><ref name=":16" />.

|Mutations<ref name=":2" />

|Mutations<ref name=":2" />

|Cell cycle and apoptosis

|Focal deletion<ref name=":16" />

|Transcription

|Focal deletion<ref name=":16" />

|Transcription

|Focal deletion<ref name=":2" />

|BCR signaling

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<ref name=":2" />.

 

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''<ref name=":2" />.

|Constitutive activation of mitogenic and anti-apoptotic pathways, driving uncontrolled cell proliferation, survival, and malignant transformation

|''IKZF1, IKZF2, IKZF3, PAX5, EBF1, VPREB1''

|

|''CDKN2A/B, TP53, RB1''

|Cell cycle and apoptosis

|

|''ETV6''

|

|''ARPP21''

|

|''SLX4IP''

|

|''CUL5''

|

|''FAM53B''

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|''PDS5B''

|

|''ANKRD11, DMD''

|

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<center>

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

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<ref name=":2" /><ref name=":10" /><ref>{{Cite journal|last=Comeaux|first=Evan Q.|last2=Mullighan|first2=Charles G.|date=2017-03-01|title=TP53 Mutations in Hypodiploid Acute Lymphoblastic Leukemia|url=https://pubmed.ncbi.nlm.nih.gov/28003275|journal=Cold Spring Harbor Perspectives in Medicine|volume=7|issue=3|pages=a026286|doi=10.1101/cshperspect.a026286|issn=2157-1422|pmc=5334249|pmid=28003275}}</ref>.