Lnk constrains myeloproliferative diseases in mice
Alexey Bersenev, Chao Wu, Joanna Balcerek, Jiang Jing, Mondira Kundu, Gerd A. Blobel, Kudakwashe R. Chikwava, Wei Tong
Alexey Bersenev, Chao Wu, Joanna Balcerek, Jiang Jing, Mondira Kundu, Gerd A. Blobel, Kudakwashe R. Chikwava, Wei Tong
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Research Article Hematology

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

Alexey Bersenev, Chao Wu, Joanna Balcerek, Jiang Jing, Mondira Kundu, Gerd A. Blobel, Kudakwashe R. Chikwava, Wei Tong

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Figure 1

Lnk deficiency exacerbates MPD development initiated by TEL/JAK2 in mice.

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Lnk deficiency exacerbates MPD development initiated by TEL/JAK2 in mice...
(A) WT and Lnk–/– BM cells were infected with retroviruses encoding either MIG vector alone or TEL/JAK2, and 1 million total BM cells were transplanted into each irradiated host animal. Kaplan-Meier survival analysis of transplanted mice is shown. P < 0.05, long-rank test comparing WT;TEL/JAK2 and Lnk–/–;TEL/JAK2 groups. n = 5. (B) Lnk deficiency exacerbates CML development initiated by TEL/JAK2 in mice when defined numbers of purified progenitors were transplanted into the hosts. Magnetic bead–enriched Lin– progenitor cells from WT and Lnk–/– mice were infected with retroviruses, and equal numbers of WT and Lnk–/– progenitors were transplanted into irradiated host animals. Kaplan-Meier survival analysis of 3 transplants with different progenitor numbers (left, 50,000 progenitor cells; middle, 30,000 progenitor cells; right, 10,000 progenitor cells) is shown. n = 5 in each group of each transplant.