The genomic landscape of hypodiploid acute lymphoblastic leukemia

Nat Genet. 2013 Mar;45(3):242-52. doi: 10.1038/ng.2532. Epub 2013 Jan 20.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aneuploidy*
  • Animals
  • Base Sequence
  • Cell Line, Tumor
  • Chromosome Aberrations*
  • Gene Expression Regulation, Neoplastic
  • Haploidy
  • Humans
  • Ikaros Transcription Factor / genetics
  • Ikaros Transcription Factor / metabolism
  • Mice
  • Molecular Sequence Data
  • Mutation*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Retinoblastoma Protein / genetics
  • Retinoblastoma Protein / metabolism
  • Signal Transduction
  • Transplantation, Heterologous
  • Treatment Outcome
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • IKZF2 protein, human
  • Retinoblastoma Protein
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Ikaros Transcription Factor
  • Phosphatidylinositol 3-Kinases

Associated data

  • GEO/GSE27237
  • GEO/GSE38463