The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole-genome and exome sequencing of 40 cases, identified two subtypes that differ in the severity of aneuploidy, transcriptional profiles and submicroscopic genetic alterations. Near-haploid ALL with 24–31 chromosomes harbor alterations targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (encoding AIOLOS; 13%). In contrast, low-hypodiploid ALL with 32–39 chromosomes are characterized by alterations in TP53 (91.2%) that are commonly present in nontumor cells, IKZF2 (encoding HELIOS; 53%) and RB1 (41%). Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.
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We thank J. Morris, E. Walker and A. Merriman for performing SNP and gene expression microarrays and G. Zambetti and P. Brindle for insightful discussions of TP53 and CREBBP mutational data, respectively. We also thank H. Mulder, R. Collins, M. Barbato, E. Stonerock, E. Pinto and M. Ellis for technical assistance, the Tissue Resources Core facility and the Flow Cytometry and Cell Sorting Core facility of the St. Jude Children's Research Hospital (SJCRH). This work was supported by The Henry Schueler 41&9 Foundation in conjunction with Partnership for Cures, the St. Baldrick's Foundation, US National Cancer Institute (NCI) grant RC4CA156329, US National Institutes of Health (NIH) grants CA21765 and U01 GM92666, the American Association for Cancer Research (AACR) Gertrude B. Elion Cancer Research Award and the American Lebanese and Syrian Associated Charities (ALSAC) of SJCRH. Support was also provided by NCI grants to the Children's Oncology Group, including CA98543, CA98413 and CA114766. L.H. was supported by the Swedish Research Council. S.P.H. is the Ergen Family Chair in Pediatric Cancer. M.L.L. is a Clinical Scholar in the Leukemia Lymphoma Society and supported by the Frank A. Campini Foundation. C.G.M. is a Pew Scholar in the Biomedical Sciences and a St. Baldrick's Scholar. M.L.L. and E.D.-F. were supported by the Team Connor Foundation, and S.N.P. was supported by 5R25CA023944 from NCI. This paper is dedicated to Henry 'Hank' Schueler who died from complications of hypodiploid ALL and whose Foundation is dedicated to finding a cure for hypodiploid ALL in his memory and to James B. Nachman who was instrumental in the genesis of this project and who recently passed away.
The authors declare no competing financial interests.
Supplementary Note and Supplementary Tables 3–6, 9, 13, 16–20, 23, 24 and 27–34 and Supplementary Figures 1–22 (PDF 5157 kb)
Pediatric hypodiploid ALL cohort (XLSX 36 kb)
Adult ALL cohort (XLSX 29 kb)
Mutations identified by next-generation sequencing (XLSX 123 kb)
Structural variations identified by whole genome sequencing (XLSX 19 kb)
Regions of copy number alterations and copy-neutral loss-of-heterozygosity in hypodiploid ALL (XLSX 357 kb)
Mutations identified by Sanger sequencing in the hypodiploid ALL cohort (XLSX 26 kb)
Copy number alterations and mutations (XLSX 29 kb)
Differential expression analysis – NH versus masked NH (XLSX 5372 kb)
Differential expression analysis – LH versus masked LH (XLSX 5395 kb)
Differential expression analysis – NH versus LH (XLSX 7710 kb)
Gene set enrichment analysis (GSEA) – NH versus LH (XLSX 176 kb)
Single nucleotide variations identified by mRNA seq of NALM-16 (XLSX 17 kb)
Primer sequences used for targeted gene resequencing and NF1 deletion mapping (XLSX 30 kb)
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Holmfeldt, L., Wei, L., Diaz-Flores, E. et al. The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet 45, 242–252 (2013). https://doi.org/10.1038/ng.2532
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