Genetic loss of SH2B3 in acute lymphoblastic leukemia

Arianne Perez-Garcia, Alberto Ambesi-Impiombato, Michael Hadler, Isaura Rigo, Charles A. LeDuc, Kara Kelly, Chaim Jalas, Elisabeth Paietta, Janis Racevskis, Jacob M. Rowe, Martin S. Tallman, Maddalena Paganin, Giuseppe Basso, Wei Tong, Wendy K. Chung, Adolfo A. Ferrando*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

84 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2425-2432
Number of pages8
Issue number14
StatePublished - 2013

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology


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