The genomic landscape of hypodiploid acute lymphoblastic leukemia

Linda Holmfeldt, Lei Wei, Ernesto Diaz-Flores, Michael 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 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, L. Bik To, Paula Marlton, Andrew W. Roberts, Gordana Raca, Wendy Stock, Geoffrey Neale, Hans G. Drexler, Ross A. 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, James R. Downing, Stephen P. Hunger, Mignon L. Loh, Charles G. Mullighan

Research output: Contribution to journalArticle

348 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
Issue number3
DOIs
Publication statusPublished - 1 Mar 2013

ASJC Scopus subject areas

  • Genetics

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