The genomic landscape of hypodiploid acute lymphoblastic leukemia

L Holmfeldt, L Wei, E Diaz-Flores, M Walsh, J Zhang… - Nature …, 2013 - nature.com
L Holmfeldt, L Wei, E Diaz-Flores, M Walsh, J Zhang, L Ding, D Payne-Turner, M Churchman…
Nature genetics, 2013nature.com
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 …
Abstract
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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