期刊
NATURE GENETICS
卷 45, 期 3, 页码 242-252出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2532
关键词
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资金
- The Henry Schueler 419 Foundation
- Partnership for Cures
- St. Baldrick's Foundation
- US National Cancer Institute (NCI) [RC4CA156329]
- US National Institutes of Health (NIH) [CA21765, U01 GM92666]
- American Association for Cancer Research (AACR) Gertrude B. Elion Cancer Research Award
- American Lebanese and Syrian Associated Charities (ALSAC) of SJCRH
- NCI [CA98543, CA98413, CA114766, 5R25CA023944]
- Swedish Research Council
- Frank A. Campini Foundation
- Team Connor Foundation
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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