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 M. Paietta, Janis Racevskis, Jacob M. Rowe, Martin S. Tallman, Maddalena Paganin, Giuseppe Basso, Wei Tong, Wendy K. Chung, Adolfo A. Ferrando

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)2425-2432
Number of pages8
JournalBlood
Volume122
Issue number14
DOIs
StatePublished - Oct 3 2013

Fingerprint

Precursor Cell Lymphoblastic Leukemia-Lymphoma
Proteins
Autoimmunity
Mutation
Janus Kinase 3
Janus Kinases
Cell proliferation
Transcription
Genetic Predisposition to Disease
Hematopoietic Stem Cells
Stem cells
Transducers
Tumors
Leukemia
Homeostasis
Genes
Cell Proliferation
Lymphocytes
Cytokines
Neoplasms

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Perez-Garcia, A., Ambesi-Impiombato, A., Hadler, M., Rigo, I., LeDuc, C. A., Kelly, K., ... Ferrando, A. A. (2013). Genetic loss of SH2B3 in acute lymphoblastic leukemia. Blood, 122(14), 2425-2432. https://doi.org/10.1182/blood-2013-05-500850

Genetic loss of SH2B3 in acute lymphoblastic leukemia. / Perez-Garcia, Arianne; Ambesi-Impiombato, Alberto; Hadler, Michael; Rigo, Isaura; LeDuc, Charles A.; Kelly, Kara; Jalas, Chaim; Paietta, Elisabeth M.; Racevskis, Janis; Rowe, Jacob M.; Tallman, Martin S.; Paganin, Maddalena; Basso, Giuseppe; Tong, Wei; Chung, Wendy K.; Ferrando, Adolfo A.

In: Blood, Vol. 122, No. 14, 03.10.2013, p. 2425-2432.

Research output: Contribution to journalArticle

Perez-Garcia, A, Ambesi-Impiombato, A, Hadler, M, Rigo, I, LeDuc, CA, Kelly, K, Jalas, C, Paietta, EM, Racevskis, J, Rowe, JM, Tallman, MS, Paganin, M, Basso, G, Tong, W, Chung, WK & Ferrando, AA 2013, 'Genetic loss of SH2B3 in acute lymphoblastic leukemia.', Blood, vol. 122, no. 14, pp. 2425-2432. https://doi.org/10.1182/blood-2013-05-500850
Perez-Garcia A, Ambesi-Impiombato A, Hadler M, Rigo I, LeDuc CA, Kelly K et al. Genetic loss of SH2B3 in acute lymphoblastic leukemia. Blood. 2013 Oct 3;122(14):2425-2432. https://doi.org/10.1182/blood-2013-05-500850
Perez-Garcia, Arianne ; Ambesi-Impiombato, Alberto ; Hadler, Michael ; Rigo, Isaura ; LeDuc, Charles A. ; Kelly, Kara ; Jalas, Chaim ; Paietta, Elisabeth M. ; Racevskis, Janis ; Rowe, Jacob M. ; Tallman, Martin S. ; Paganin, Maddalena ; Basso, Giuseppe ; Tong, Wei ; Chung, Wendy K. ; Ferrando, Adolfo A. / Genetic loss of SH2B3 in acute lymphoblastic leukemia. In: Blood. 2013 ; Vol. 122, No. 14. pp. 2425-2432.
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AU - Kelly, Kara

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