Acute Lymphoblastic Leukemia (ALL) With Low-Hypodiploid/Near-Triploid Karyotype Is a Specific Clinical Entity Characterized By a High TP53 Mutation Frequency
Authors: Patterer Verena , Zenger Melanie , Schnittger Susanne , Weissmann Sandra , Poetzinger Franziska , Kohlmann Alexander , Bellos Frauke , Kern Wolfgang , Haferlach Torsten , Haferlach Claudia 
Published: October 2019

Abstract

Background
B-lineage acute lymphoblastic leukemia (ALL) called B lymphoblastic leukemia/lymphoma by the WHO classification 2008 is subdivided into 5 subgroups defined by a specific translocation (t(9;22)(q34;q11); t(v;11q23); t(12;21)(p13;q22); t(5;14)(q31;q32); t(1;19)(q23;p13.1)). Two additional categories are defined on the basis of chromosome number: ALL with hyperdiploidy and hypodiploid ALL. The former group comprises a well defined genetic subset with blasts containing >50 and usually >66 chromosomes. In contrast, the hypodiploid subgroup is very heterogeneous and comprises ALL with a chromosome number of >46 chromosomes to near-haploid.

Aim
To characterize this rare subset of ALL with low hypodiploidy in detail with respect to cytogenetic abnormalities, molecular mutations and clinical outcome.

Patients and Methods
Out of a total cohort of 878 ALL patients analyzed between 2005 and 2013 we selected a subset of 26 cases harbouring a hypodiploid clone with 1) a chromosome number of ≤40 or 2) a near triploid clone with 56-78 chromosomes that had arisen from a low hypodiploid clone by duplication of the chromosome set. Data on karyotype, array CGH and FISH for rearrangement of BCR-ABL1, ETV6 and MLL was available in all cases. Further, cases were investigated for mutations in NRAS, KRAS, TP53, NOTCH1, FBXW7 and intragenic deletions of IKZF1. For 17 cases data on the immunophenotype was available. Clinical follow-up data was available for 19 pts.

Results
12/17 pts showed a common B ALL-phenotype, 5 pts were classified as Pro-B-ALL. All cases were negative for t(12;21)(p13;q22)/ETV6-RUNX1, t(9;22)(q34;q11)/BCR-ABL1 and translocations involving the MLL gene. The pattern of chromosomal losses was non-random. One chromosome 3 and 7 was lost in all 26 cases. Other frequently deleted chromosomes were chromosomes 15 (n=24), 17 (n=25), 13, 16 (lost in 23 cases each), 9 (n=18), 4 (n=17), 12 and 20 (lost in 16 cases each), which were all deleted in more than 50% of the cases, confirming a very specific pattern of chromosome losses. Less frequently lost were chromosomes 2 (n=12), 8 (n=11), 14 (n=10), 5 (n=8) and 18 (n=7). Rarely lost were chromosomes 6, 11 (lost in 5 cases each), 1, 10, 19, 22 (lost in 4 cases each) and the sex chromosomes X or Y in 3 cases each. Only chromosome 21 was retained in all cases. In 14 cases with doubling of the low-hypodiploid karyotype we observed the same typical pattern of gains and losses with two copies of typically lost chromosomes and four copies of typically retained chromosomes. In 11/14 pts we detected additional losses of chromosomes resulting in trisomies, most frequently of chromosomes 2 (n=7), 5 and 14 (n=6), respectively. Structural abnormalities in addition to chromosome losses were found in 85% of pts by chromosome banding analysis, none of these was recurrent. The only recurrent submicroscopic deletion detected by aCGH was a 9p deletion encompassing the CDKN2A/B locus (n=7), which was homozygous in 4 pts. As 14 additional pts showed a monosomy 9, only 5 pts did not show a deletion of at least one CDKN2A/B copy. We discovered no mutations in FBXW7, NOTCH1 and KRAS and only one mutation in NRAS. Further, no intragenic deletion of IKZF1 was detected. However, and most interestingly, 24 out of 26 pts (92.3%) showed a mutation within the TP53 gene. In 23/24 pts with TP53 mutation and in both pts with TP53wt chromosome 17 was monosomic. Further, both patients with TP53wt and monosomy 17 showed a remarkably low chromosome number of 25 and 28 chromosomes compared to TP53mut pts who showed at least 32 chromosomes. Outcome was poor: 2-year-overall survival rate of pts treated with intensive chemotherapy (n=19) was only 20%.

Conclusions
ALL with low hypodiploidy is characterized by a typical pattern of chromosome losses including loss of chromosomes 7, 3, 15, 17, 13 and 16, a very high TP53 mutation frequency and poor outcome. A duplication of the low-hypodiploid karyotype occurs frequently and results in a near triploid karyotype based on the definition by merely counting chromosomes but in fact is a very low tetraploid chromosome set. Our data suggests the introduction of a novel WHO entity within the B lymphoblastic leukaemia/lymphoma group showing low-hypodiploid/very low-tetraploid karyotype and concomitant TP53 mutation. The poor outcome of this specific ALL subset might be related to the high TP53 mutation frequency in combination with loss of the second TP53 allele due to monosomy 17.

Disclosures:
Patterer: MLL Munich Leukemia Laboratory: Employment. Zenger:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Weissmann:MLL Munich Leukemia Laboratory: Employment. Poetzinger:MLL Munich Leukemia Laboratory: Employment. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Bellos:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.