TY - JOUR
T1 - Genetic loss of SH2B3 in acute lymphoblastic leukemia
AU - Perez-Garcia, Arianne
AU - Ambesi-Impiombato, Alberto
AU - Hadler, Michael
AU - Rigo, Isaura
AU - LeDuc, Charles A.
AU - Kelly, Kara
AU - Jalas, Chaim
AU - Paietta, Elisabeth
AU - Racevskis, Janis
AU - Rowe, Jacob M.
AU - Tallman, Martin S.
AU - Paganin, Maddalena
AU - Basso, Giuseppe
AU - Tong, Wei
AU - Chung, Wendy K.
AU - Ferrando, Adolfo A.
N1 - Publisher Copyright:
© 2013 by The American Society of Hematology.
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84887805156
U2 - 10.1182/blood-2013-05-500850
DO - 10.1182/blood-2013-05-500850
M3 - Article
C2 - 23908464
AN - SCOPUS:84887805156
SN - 0006-4971
VL - 122
SP - 2425
EP - 2432
JO - Blood
JF - Blood
IS - 14
ER -