Genetic loss of SH2B3 in acute lymphoblastic leukemia

Blood. 2013 Oct 3;122(14):2425-32. doi: 10.1182/blood-2013-05-500850. Epub 2013 Aug 1.


The SH2B adaptor protein 3 (SH2B3) gene encodes a negative regulator of cytokine signaling with a critical role in the homeostasis of hematopoietic stem cells and lymphoid progenitors. Here, we report the identification of germline homozygous SH2B3 mutations in 2 siblings affected with developmental delay and autoimmunity, one in whom B-precursor acute lymphoblastic leukemia (ALL) developed. Mechanistically, loss of SH2B3 increases Janus kinase-signal transducer and activator of transcription signaling, promotes lymphoid cell proliferation, and accelerates leukemia development in a mouse model of NOTCH1-induced ALL. Moreover, extended mutation analysis showed homozygous somatic mutations in SH2B3 in 2 of 167 ALLs analyzed. Overall, these results demonstrate a Knudson tumor suppressor role for SH2B3 in the pathogenesis of ALL and highlight a possible link between genetic predisposition factors in the pathogenesis of autoimmunity and leukemogenesis.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Autoimmune Diseases / genetics
  • Base Sequence
  • Blotting, Western
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • Developmental Disabilities / genetics
  • Female
  • Genotype
  • Germ-Line Mutation
  • Humans
  • Infant
  • Infant, Newborn
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Oligonucleotide Array Sequence Analysis
  • Pedigree
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Proteins / genetics*
  • Siblings


  • Adaptor Proteins, Signal Transducing
  • Intracellular Signaling Peptides and Proteins
  • Proteins
  • SH2B3 protein, human