title: Genetic loss of SH2B3 in acute lymphoblastic leukemia.
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.
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY;
authors.forename: Arianne
authors.initials: A
authors.lastname: Perez-Garcia
authors.forename: Alberto
authors.initials: A
authors.lastname: Ambesi-Impiombato
authors.forename: Michael
authors.initials: M
authors.lastname: Hadler
authors.forename: Isaura
authors.initials: I
authors.lastname: Rigo
authors.forename: Charles A
authors.initials: CA
authors.lastname: LeDuc
authors.forename: Kara
authors.initials: K
authors.lastname: Kelly
authors.forename: Chaim
authors.initials: C
authors.lastname: Jalas
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Paietta
authors.forename: Janis
authors.initials: J
authors.lastname: Racevskis
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Rowe
authors.forename: Martin S
authors.initials: MS
authors.lastname: Tallman
authors.forename: Maddalena
authors.initials: M
authors.lastname: Paganin
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.forename: Wei
authors.initials: W
authors.lastname: Tong
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.forename: Adolfo A
authors.initials: AA
authors.lastname: Ferrando
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics; D001483:Base Sequence; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000235:genetics; D005260:Female; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D035781:Siblings
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C490778:SH2B3 protein, human
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