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

9 Citations (Scopus)

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
StatePublished - Dec 17 2013

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Interleukin-11
src Homology Domains
B-Lymphocytes
SH2 Domain-Containing Protein Tyrosine Phosphatases
Radiation
GRB2 Adaptor Protein
Neoplasms
Leukemia
Cytokines
Protein Tyrosine Phosphatases
Hyperplasia
Tyrosine
Phosphotransferases
Phosphorylation
Phenotype
Mutation
Proteins

Keywords

  • Cancer
  • Gp130
  • Lymphoma
  • Survival

ASJC Scopus subject areas

  • General

Cite this

Louria-Hayon, Igal ; Frelin, Catherine ; Ruston, Julie ; Gish, Gerald ; Jin, Jing ; Kofler, Michael M. ; Lambert, Jean Philippe ; Adissu, Hibret A. ; Milyavsky, Michael ; Herrington, Robert ; Minden, Mark D. ; Dick, John E. ; Gingras, Anne Claude ; Iscove, Norman N. ; Pawson, Tony. / Lnk adaptor suppresses radiation resistance and radiation-induced B-cell malignancies by inhibiting IL-11 signaling. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 51. pp. 20599-20604.
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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.",
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author = "Igal Louria-Hayon and Catherine Frelin and Julie Ruston and Gerald Gish and Jing Jin and Kofler, {Michael M.} and Lambert, {Jean Philippe} and Adissu, {Hibret A.} and Michael Milyavsky and Robert Herrington and Minden, {Mark D.} and Dick, {John E.} and Gingras, {Anne Claude} and Iscove, {Norman N.} and Tony Pawson",
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Louria-Hayon, I, Frelin, C, Ruston, J, Gish, G, Jin, J, Kofler, MM, Lambert, JP, Adissu, HA, Milyavsky, M, Herrington, R, Minden, MD, Dick, JE, Gingras, AC, Iscove, NN & Pawson, T 2013, 'Lnk adaptor suppresses radiation resistance and radiation-induced B-cell malignancies by inhibiting IL-11 signaling', Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 51, pp. 20599-20604. https://doi.org/10.1073/pnas.1319665110

Lnk adaptor suppresses radiation resistance and radiation-induced B-cell malignancies by inhibiting IL-11 signaling. / Louria-Hayon, Igal; Frelin, Catherine; Ruston, Julie; Gish, Gerald; Jin, Jing; Kofler, Michael M.; Lambert, Jean Philippe; Adissu, Hibret A.; Milyavsky, Michael; Herrington, Robert; Minden, Mark D.; Dick, John E.; Gingras, Anne Claude; Iscove, Norman N.; Pawson, Tony.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 51, 17.12.2013, p. 20599-20604.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Lnk adaptor suppresses radiation resistance and radiation-induced B-cell malignancies by inhibiting IL-11 signaling

AU - Louria-Hayon, Igal

AU - Frelin, Catherine

AU - Ruston, Julie

AU - Gish, Gerald

AU - Jin, Jing

AU - Kofler, Michael M.

AU - Lambert, Jean Philippe

AU - Adissu, Hibret A.

AU - Milyavsky, Michael

AU - Herrington, Robert

AU - Minden, Mark D.

AU - Dick, John E.

AU - Gingras, Anne Claude

AU - Iscove, Norman N.

AU - Pawson, Tony

PY - 2013/12/17

Y1 - 2013/12/17

N2 - 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.

AB - 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.

KW - Cancer

KW - Gp130

KW - Lymphoma

KW - Survival

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DO - 10.1073/pnas.1319665110

M3 - Article

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SP - 20599

EP - 20604

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 51

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