title: Lnk constrains myeloproliferative diseases in mice.
abstract: Hematopoietic stem and progenitor cell (HSPC) expansion is regulated by intrinsic signaling pathways activated by cytokines. The intracellular kinase JAK2 plays an essential role in cytokine signaling, and activating mutations in JAK2 are found in a number of hematologic malignancies. We previously demonstrated that lymphocyte adaptor protein (Lnk, also known as Sh2b3) binds JAK2 and attenuates its activity, thereby limiting HSPC expansion. Here we show that loss of Lnk accelerates and exacerbates oncogenic JAK2-induced myeloproliferative diseases (MPDs) in mice. Specifically, Lnk deficiency enhanced cytokine-independent JAK/STAT signaling and augmented the ability of oncogenic JAK2 to expand myeloid progenitors in vitro and in vivo. An activated form of JAK2, unable to bind Lnk, caused greater myeloid expansion than activated JAK2 alone and accelerated myelofibrosis, indicating that Lnk directly inhibits oncogenic JAK2 in constraining MPD development. In addition, Lnk deficiency cooperated with the BCR/ABL oncogene, the product of which does not directly interact with or depend on JAK2 or Lnk, in chronic myeloid leukemia (CML) development, suggesting that Lnk also acts through endogenous pathways to constrain HSPCs. Consistent with this idea, aged Lnk-/- mice spontaneously developed a CML-like MPD. Taken together, our data establish Lnk as a bona fide suppressor of MPD in mice and raise the possibility that Lnk dysfunction contributes to the development of hematologic malignancies in humans.
authors.affiliation: Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Alexey
authors.initials: A
authors.lastname: Bersenev
authors.forename: Chao
authors.initials: C
authors.lastname: Wu
authors.forename: Joanna
authors.initials: J
authors.lastname: Balcerek
authors.forename: Jiang
authors.initials: J
authors.lastname: Jing
authors.forename: Mondira
authors.initials: M
authors.lastname: Kundu
authors.forename: Gerd A
authors.initials: GA
authors.lastname: Blobel
authors.forename: Kudakwashe R
authors.initials: KR
authors.lastname: Chikwava
authors.forename: Wei
authors.initials: W
authors.lastname: Tong
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics*; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D016207:Cytokines; D010770:Phosphotransferases; D053614:Janus Kinase 2
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