Genetic loss of SH2B3 in acute lymphoblastic leukemia
Year: 2013
Type: article
Abstract: 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.
Source: Blood
Institutions: Columbia University, Columbia University Irving Medical Center, Albert Einstein College of Medicine, Technion – Israel Institute of Technology, Shaare Zedek Medical Center, Bikur Cholim Hospital, Memorial Sloan Kettering Cancer Center, University of Padua, Children's Hospital of Philadelphia
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1980822528