HAEM4Backup:B-Lymphoblastic Leukemia/Lymphoma with Hypodiploidy

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Primary Author(s)*

Ashwini Yenamandra PhD FACMG

Lisa Smith PhD FACMG

Yassmine Akkari PhD FACMG

Cancer Category/Type

B lymphoblastic leukaemia/lymphoma, Acute Lymphoblastic Leukemia (B-ALL)

Cancer Sub-Classification / Subtype

Hypodiploidy

Definition / Description of Disease

Hypodiploidy is a rare entity comprising approximately 5% of all B-cell acute lymphoblastic leukemias. The majority of cases (>80%) fall within the 44-45 chromosome range. However, beyond this, there are three main groups, that although rare, are associated with a very poor clinical prognosis.

Near-haploid karyotype with 26 Chromosomes in a 4-year-old. Note: Chromosomes 8, 10 and 21 have TWO copies. Courtesy of Ashwini Yenamandra, Vanderbilt University Medical Center, Nashville, TN.
Doubling of the near-haploid cell line with 52 Chromosomes. Note: Chromosomes 8, 10 and 21 have FOUR copies. Courtesy of Ashwini Yenamandra, Vanderbilt University Medical Center, Nashville, TN.

Synonyms / Terminology

Hypodiploidy- High Hypodiploidy, Low Hypodiploidy, Near-haploidy

Epidemiology / Prevalence

Hypodiploid ALL accounts for about 5% of ALL cases. Approximately 1% of ALL cases with hypodiploidy have <45 chromosomes[1]. It is more common in children than adults and accounts for 75% of pediatric cancers[2]. Hypodiploid ALL with chromosome numbers less than 44 is associated with poor prognosis.

Clinical Features

The clinical features are generally similar to those seen in other types of B-ALL like anemia, thrombocytopenia and neutropenia. May have very high WBC count at presentation. Malignant and poorly differentiated lymphoid cells in the bone marrow, peripheral blood and extramedullary sites[3]. Symptoms may include anemia, thrombocytopenia, leukopenia, fever, weight loss, night sweats, bleeding, bruising, fatigue[3]. Splenomegaly and hepatomegaly (20%), central nervous system (CNS) in 5-8% of patients[3]. Diagnosis: 20% of blasts or more lymphoblasts in the bone marrow, or peripheral blood[3].

Sites of Involvement

Bone Marrow, Peripheral Blood, extra medullary sites.

Morphologic Features

Malignant and poorly differentiated lymphoid cells in the bone marrow, peripheral blood and extramedullary sites[3]. Symptoms may include anemia, thrombocytopenia, leukopenia, fever, weight loss, night sweats, bleeding, bruising, fatigue[3]. Splenomegaly and hepatomegaly (20%), central nervous system (CNS) in 5-8% of patients[3]. Diagnosis: 20% of blasts or more lymphoblasts in the bone marrow, or peripheral blood[3]

Immunophenotype

Put your text here and/or fill in the table

Finding Marker
Positive CD19
Positive CD10
Negative (universal) EXAMPLE CD3
Negative (subset) EXAMPLE CD4

Chromosomal Rearrangements (Gene Fusions)

N/A

Characteristic Chromosomal Aberrations / Patterns

Based on WHO classification[1], hypodiploidy is divided into:

1. Near-haploidy (NH=23-29 chromosomes) This is a very rare category, 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.

2. Low Hypodiploidy (LH=33-39 chromosomes) This category was reported in both children and 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.

3. High Hypodiploidy (HH=40-43 chromosomes) This category was observed in both children and adults. 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.

4. Near-diploid (ND=44-45 chromosomes) This category is not often included in hypodiploid.

Note: A slight variation in the range of chromosome number has been reported in the literature in the classification of NH, LH, HH and NH[1][3][4][5][6][7][8][9][10][11][12] [13][14][15][16][17][2] [1-17].

Sorting patients into these three rare groups is easy. However, detecting the presence of a masked low-hypodiploid/masked near-hypodiploid group, which is endoreduplication of the low- and near-haploid groups and associated with a very poor prognosis, is difficult. Often karyotypes in these two groups, usually ranging from 56-78 chromosomes, are mistaken for hyperdiploidy/near-triploidy, which in itself is associated with a good prognosis. The key is to look for trisomies vs tetrasomies of the chromosomes. Typically, hyperdiploidy/near-triploidy should have three copies of several chromosomes (usually the X, 4, 10, 17, and 18), and four copies of 14 and 21. However, the masked low-hypodiploid/masked near-hypodiploid groups should show tetrasomies for the sex chromosomes and chromosomes 1, 14, 18, 21, and 22 while having only two copies of chromosomes 7 and 17.

When only a 56-78 chromosome count is detected, the above mentioned criteria is helpful, but SNP-array testing can also be informative. Masked near-haploidy appears to show LOH involving the chromosomes that are not gained and true hyperdiploidy will show heterozygosity. Dicentric chromosomes reportedly originated from chromosomes 9p, 12p or 20q in near diploid karyotypes[4]. In near haploid aneuploidy of chromosomes 1 through 7, 9, 11, 13, 15-17, 19,20, 22 while in low hypodiploid aneuploidy of chromosomes 2 through 4, 7, 9, 12, 13, 15 and 17 were reported[4].

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].

In hypodiploid ALL, molecular mutations are equally as important as chromosome number, or as a result of chromosome number, molecular mutations have a driving effect. Both LH and NH have common mutations involved in the disease process. In near haploid ALL (NH) RTK and RAS (71%) signaling were a hallmark[4]. In addition, lymphoid transcription factor gene IKZF3 (13%, encoding AIOLOS) and deletions of histone cluster at 6p22 (19%) were also reported[4]. In low hypodiploid (LH) ALL mutations involved TP53 (91.2%) and IKZF2 (53%, encoding HELIOS, 2q34), and RB1 genes (41%) loci[4]. Both NH and LH had activation of RAS signaling and P13K signaling pathways and sensitive to P13K inhibitors indicating these drugs may offer a new therapeutic option[4]. Inn this group, 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. Adults also showed a high incidence of TP53 (91%) in low hypodiploid ALL mutations, but these mutations appear to be somatic in origin. In NH, mutations appear in genes involving receptor tyrosine kinase (RTK) pathway, Ras signaling, IKZF3 (17q21.1), and histone clusters, but rarely IZFK2, RB1, or TP53[4].

Copy number alterations and sequence mutations have been reported in FLT3, NF1, KRAS, NRAS, PTPN11, RTK, RAS, IKZF1, IKZF2, IKZF3, TP53, RB1, Histone, 6q22, CDKN2A, CDKN2B, PAX5, and PAG1 gene loci[4].

The most significant observation by Holmfeldt et al.,[4] is that a global difference in the gene expression profiles distinguishes subgroups of hypodiploid ALL. More than 600 genes had subtype specific enrichment on gene set enrichment analysis[4]. In addition, RAS pathway, RB1 and TP53 mutations mimic solid tumor pathways[4].

Genomic Gain/Loss/LOH

Chromosome Number Gain/Loss/Amp/LOH Region
17 Gain SOX9
9 Loss CDKN2A/CDKN2B (22-50%)

Gene Mutations (SNV/INDEL)

Gene Mutation Oncogene/Tumor Suppressor/Other Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) Prevalence (COSMIC/TCGA/Other)
TP53 R280S, Y220C and several other mutations, please see reference[4]. Tumor Suppressor Missense/Nonsense/Insertion/Splice in Low Hypodiploid about 90%

Other Mutations

RTK-RAS signaling pathways: About two-thirds of near haploid ALL (71%) had activation of RTK-RAS signaling pathways including deletion, amplification and sequence mutation of NF1, NRAS, KRAS, MAPK1, FLT3 and PTPN11[4]. NF1 mutation was reported in 44% of near haploid cases with a biallelic mutation of NF1 in 77% of the near haploid cases. In 68% of the cases, the NF1 deletions were intragenic involving exons 15 through 35[4]. The focal deletion results in deletion of GAP[4].

PAG1 mutations: Recurrent alterations of PAG1 was reported in 10.3% of near haploid ALL, PAG1 mutations are rare in other hypodiploid cases[4]. PAG1 was identified as a putative RAS signaling inhibitor and have a negative regulatory function in proximal B-cell receptor signaling[4].

TP53 mutations: High mutation rate was observed (91%) in low hypodiploid than in non-low hypodiploid (5%) B-ALL; In low hypodiploid ALL, 43% were observed in non-tumor hematopoietic cells, suggesting either an inherited or a germline de novo origin of the mutation[4].

Epigenomics (Methylation)

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[4].

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[4].

Genes and Main Pathways Involved

RTK and RAS pathway alterations as de novo germline mutations or in primitive hematopoietic progenitor cells[4].

Diagnostic Testing Methods

FLOW, Hematopathology, Cytogenetics, Fluorescence insitu Hybridization (FISH), Next Generation sequencing (NGS), Exome sequencing, Microarray.

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) is the most common cause of cancer in pediatric patients. It is characterized by recurrent genetic abnormalities of chromosome number, deletions, duplications and translocations. Hypodiploidy, a neoplasm of lymphoblasts containing less than 46 chromosomes[1]. Hypodiploid ALL has poor prognosis and near haploid with worst prognosis[1][4][6].

Patients with 44 chromosomes had a better event free survival (EFS) than patients with fewer than 44 chromosomes[6]. However, patients with 44 chromosomes and monosomy 7 or a dicentric chromosome had worse EFS[6]. Children and adults with less than 44 chromosomes had poor outcome despite contemporary therapy[6].

In near haploid cases, two-thirds had activation of RAS signaling and P13K signaling pathways; these are sensitive to P13K inhibitors indicating these drugs may offer a new therapeutic option[4].

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.

Adults also showed a high incidence of TP53 mutations, but these mutations appear to be somatic in origin. In 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.

Other 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[4].

Links

N/A

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 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.
  2. ↑ 2.0 2.1 Karen Seiter, MD; Chief Editor: Emmanuel C Besa, MD (2018). Acute lymphoblastic  leukemia (ALL). Medscape. emedicine, Medscape Article, Drugs & Diseases, Hematology.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 Terwilliger, T.; et al. (2017). "Acute lymphoblastic leukemia: a comprehensive review and 2017 update". Blood Cancer Journal. 7 (6): e577. doi:10.1038/bcj.2017.53. ISSN 2044-5385. PMC 5520400. PMID 28665419.
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 4.16 4.17 4.18 4.19 4.20 4.21 4.22 4.23 4.24 Holmfeldt, Linda; et al. (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.
  5. ↑ 5.0 5.1 Safavi, S.; et al. (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. ↑ 6.0 6.1 6.2 6.3 6.4 Nachman, James B.; et al. (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.
  7. ↑ Safavi, Setareh; et al. (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.
  8. ↑ Mehta, Parinda A.; et al. (2015). "Transplantation Outcomes for Children with Hypodiploid Acute Lymphoblastic Leukemia". Biology of Blood and Marrow Transplantation: Journal of the American Society for Blood and Marrow Transplantation. 21 (7): 1273–1277. doi:10.1016/j.bbmt.2015.04.008. ISSN 1523-6536. PMC 4465998. PMID 25865650.
  9. ↑ Mullighan, Charles G. (2012). "Molecular genetics of B-precursor acute lymphoblastic leukemia". The Journal of Clinical Investigation. 122 (10): 3407–3415. doi:10.1172/JCI61203. ISSN 1558-8238. PMC 3461902. PMID 23023711.
  10. ↑ Harrison, Christine J.; et al. (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.
  11. ↑ Wang, Yunhong; et al. (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.
  12. ↑ Safavi, Setareh; et al. (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.
  13. ↑ 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.
  14. ↑ Fang, Min; et al. (2015). "Adult Low-Hypodiploid Acute B-Lymphoblastic Leukemia With IKZF3 Deletion and TP53 Mutation: Comparison With Pediatric Patients". American Journal of Clinical Pathology. 144 (2): 263–270. doi:10.1309/AJCPW83OXPYKPEEN. ISSN 1943-7722. PMID 26185311.
  15. ↑ Mühlbacher, Verena; et al. (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.
  16. ↑ Woo, Jennifer S.; et al. (2014). "Childhood B-acute lymphoblastic leukemia: a genetic update". Experimental Hematology & Oncology. 3: 16. doi:10.1186/2162-3619-3-16. ISSN 2162-3619. PMC 4063430. PMID 24949228.
  17. ↑ Collins-Underwood, J. R.; et al. (2010). "Genomic profiling of high-risk acute lymphoblastic leukemia". Leukemia. 24 (10): 1676–1685. doi:10.1038/leu.2010.177. ISSN 1476-5551. PMID 20739952.

Notes

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