Lnk adaptor suppresses radiation resistance and radiation-induced B-cell malignancies by inhibiting IL-11 signaling

Igal Louria-Hayon*, Catherine Frelin, Julie Ruston, Gerald Gish, Jing Jin, Michael M. Kofler, Jean Philippe Lambert, Hibret A. Adissu, Michael Milyavsky, Robert Herrington, Mark D. Minden, John E. Dick, Anne Claude Gingras, Norman N. Iscove, Tony Pawson

*Corresponding author for this work

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

The Lnk (Sh2b3) adaptor protein dampens the response of hematopoietic stemcells and progenitors (HSPCs) to a variety of cytokines by inhibiting JAK2 signaling. As a consequence, Lnk-/- mice develop hematopoietic hyperplasia,which progresses to a phenotype resembling the nonacute phase of myeloproliferative neoplasm. In addition, Lnk mutations have been identified in human myeloproliferative neoplasms and acute leukemia. We find that Lnk suppresses the development of radiation-induced acute B-cell malignancies in mice. Lnk-deficient HSPCs recover more effectively from irradiation than their wild-type counterparts, and this resistance of Lnk-/- HSPCs to radiation underlies the subsequent emergence of leukemia. A search for the mechanism responsible for radiation resistance identified the cytokine IL-11 as being critical for the ability of Lnk-/- HSPCs to recover from irradiation and subsequently become leukemic. In IL-11 signaling, wild-type Lnk suppresses tyrosine phosphorylation of the Src homology region 2 domain-containing phosphatase-2/protein tyrosine phosphatase nonreceptor type 11 and its association with the growth factor receptor-bound protein 2, as well as activation of the Erk MAP kinase pathway. Indeed, Src homology region 2 domain-containing phosphatase-2 has a binding motif for the Lnk Src Homology 2 domain that is phosphorylated in response to IL-11 stimulation. IL-11 therefore drives a pathway that enhances HSPC radioresistance and radiation- induced B-cell malignancies, but is normally attenuated by the inhibitory adaptor Lnk.

Original languageEnglish (US)
Pages (from-to)20599-20604
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number51
DOIs
Publication statusPublished - Dec 17 2013

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Keywords

  • Cancer
  • Gp130
  • Lymphoma
  • Survival

ASJC Scopus subject areas

  • General

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