The genomic landscape of hypodiploid acute lymphoblastic leukemia

Linda Holmfeldt, Lei Wei, Ernesto Diaz-Flores, Michael F Walsh, Jinghui Zhang, Li Ding, Debbie Payne-Turner, Michelle Churchman, Anna Andersson, Shann-Ching Chen, Kelly McCastlain, Jared Becksfort, Jing Ma, Gang Wu, Samir N Patel, Susan L Heatley, Letha A Phillips, Guangchun Song, John Easton, Matthew ParkerXiang Chen, Michael Rusch, Kristy Boggs, Bhavin Vadodaria, Erin Hedlund, Christina Drenberg, Sharyn D Baker, Deqing Pei, Cheng Cheng, Robert Huether, Charles Lu, Robert S Fulton, Lucinda L Fulton, Yashodhan Tabib, David J Dooling, Kerri Ochoa, Mark Minden, Ian D Lewis, Luen Bik To, Paula Marlton, Andrew W Roberts, Gordana Raca, Wendy Stock, Geoffrey Neale, Hans G Drexler, Ross Alexander Dickins, David W Ellison, Sheila A Shurtleff, Ching-Hon Pui, Raul C Ribeiro, Meenakshi Devidas, Andrew J Carroll, Nyla A Heerema, Brent Wood, Michael J Borowitz, Julie M Gastier-Foster, Susana C Raimondi, Elaine R Mardis, Richard K Wilson, Stephen P Hunger, James R Downing, Mignon Lee-Cheun Loh, Charles G Mullighan

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341 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)242 - 252
Number of pages11
JournalNature Genetics
Volume45
DOIs
Publication statusPublished - 2013
Externally publishedYes

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