The genomic landscape of hypodiploid acute lymphoblastic leukemia

Holmfeldt, L; Wei, L; Diaz-Flores, E; Walsh, M; Zhang, JH; Ding, L; Payne-Turner, D; Churchman, M; Andersson, A; Chen, SC; McCastlain, K; Becksfort, J; Ma, J; Wu, G; Patel, SN; Heatley, SL; Phillips, LA; Song, GC; Easton, J; Parker, M; Chen, X; Rusch, M; Boggs, K; Vadodaria, B; Hedlund, E; Drenberg, C; Baker, S; Pei, DQ; Cheng, C; Huether, R; Lu, C; Fulton, RS; Fulton, LL; Tabib, Y; Dooling, DJ; Ochoa, K; Minden, M; Lewis, ID; To, LB; Marlton, P; Roberts, AW; Raca, G; Stock, W; Neale, G; Drexler, HG; Dickins, RA; Ellison, DW; Shurtleff, SA; Pui, CH; Ribeiro, RC; Devidas, M; Carroll, AJ; Heerema, NA; Wood, B; Borowitz, MJ; Gastier-Foster, JM; Raimondi, SC; Mardis, ER; Wilson, RK; Downing, JR; Hunger, SP; Loh, ML; Mullighan, CG

Author(s): Holmfeldt, L; Wei, L; Diaz-Flores, E; Walsh, M; Zhang, JH; Ding, L; Payne-Turner, D; Churchman, M; Andersson, A; Chen, SC; McCastlain, K; Becksfort, J; Ma, J; Wu, G; Patel, SN; Heatley, SL; Phillips, LA; Song, GC; Easton, J; Parker, M; Chen, X; Rusch, M; Boggs, K; Vadodaria, B; Hedlund, E; Drenberg, C; Baker, S; Pei, DQ; Cheng, C; Huether, R; Lu, C; Fulton, RS; Fulton, LL; Tabib, Y; Dooling, DJ; Ochoa, K; Minden, M; Lewis, ID; To, LB; Marlton, P; Roberts, AW; Raca, G; Stock, W; Neale, G; Drexler, HG; Dickins, RA; Ellison, DW; Shurtleff, SA; Pui, CH; Ribeiro, RC; Devidas, M; Carroll, AJ; Heerema, NA; Wood, B; Borowitz, MJ; Gastier-Foster, JM; Raimondi, SC; Mardis, ER; Wilson, RK; Downing, JR; Hunger, SP; Loh, ML; Mullighan, CG;
Details: Publication Year 2013-03,Volume 45,Issue #3,Page 242-252
Journal Title: NATURE GENETICS
Publication Type: Journal Article
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.
Publisher: NATURE PUBLISHING GROUP
Keywords: JUVENILE MYELOMONOCYTIC LEUKEMIA; NEUROFIBROMATOSIS TYPE-1 GENE; REGULATORY T-CELLS; TRANSMEMBRANE ADAPTER; HEMATOLOGIC MALIGNANCIES; P53 MUTATIONS; HUMAN CANCERS; MUTANT P53; IKAROS; CHILDHOOD
Research Division(s): Molecular Medicine; Cancer And Haematology
Link To PubMed Central Version: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3919793/
Publisher's Version: https://doi.org/10.1038/ng.2532

Creation Date: 2013-03-01 12:00:00