Lnk constrains myeloproliferative diseases in mice.
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.
Bersenev
Alexey
A
Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
Wu
Chao
C
Balcerek
Joanna
J
Jing
Jiang
J
Kundu
Mondira
M
Blobel
Gerd A
GA
Chikwava
Kudakwashe R
KR
Tong
Wei
W
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*
D016207:Cytokines; D010770:Phosphotransferases; D053614:Janus Kinase 2
J Clin Invest. 2008 Aug;118(8):2832-44
18618018
Cold Spring Harb Symp Quant Biol. 2005;70:177-85
16869752
J Exp Med. 2002 Jun 17;195(12):1599-611
12070287
Blood. 2003 Jul 1;102(1):94-101
12623852
Cell Cycle. 2007 Mar 1;6(5):550-66
17351342
Blood. 2009 Dec 10;114(25):5191-200
19855080
Nat Rev Cancer. 2007 Nov;7(11):823-33
17957188
Annu Rev Cell Dev Biol. 1996;12:91-128
8970723
Cancer Cell. 2004 Dec;6(6):587-96
15607963
Nature. 2005 Apr 28;434(7037):1144-8
15793561
J Leukoc Biol. 2009 Jun;85(6):957-65
19293402
Curr Opin Hematol. 1995 Jan;2(1):22-8
9371968
EMBO J. 1998 Sep 15;17(18):5321-33
9736611
Sci STKE. 2003 Jul 15;2003(191):RE12
12865499
Blood. 2006 Sep 1;108(5):1652-60
16670266
Immunity. 2000 Nov;13(5):599-609
11114373
Genes Dev. 2006 Aug 1;20(15):2018-23
16882979
Nature. 2009 Aug 13;460(7257):904-8
19620960
Cell. 1995 Mar 10;80(5):729-38
7889566
Blood. 2006 Jun 1;107(11):4274-81
16478879
Blood. 2007 Nov 1;110(9):3360-4
17693582
J Exp Med. 2004 Sep 6;200(5):569-80
15337790
Genes Dev. 2008 Apr 15;22(8):992-7
18413713
J Cell Sci. 2000 Aug;113 ( Pt 16):2813-9
10910765
Science. 1997 Nov 14;278(5341):1309-12
9360930
Curr Opin Hematol. 2006 Jan;13(1):1-6
16319680
Cancer Cell. 2005 Apr;7(4):387-97
15837627
Oncogene. 2007 Oct 15;26(47):6766-76
17934484
J Exp Med. 2005 Jun 6;201(11):1771-80
15939792
Dev Cell. 2005 Jun;8(6):907-14
15935779
Exp Hematol. 2009 May;37(5):585-592.e2
19375649
EMBO J. 1997 Jul 16;16(14):4226-37
9250666
Nat Genet. 2006 Nov;38(11):1269-77
17041602
Cell. 2006 Apr 21;125(2):229-31
16630811
Blood. 2009 Oct 29;114(18):3899-908
19710504
Blood. 1997 Oct 1;90(7):2535-40
9326218
Blood. 2005 Jun 15;105(12):4604-12
15705783
Sci STKE. 2001 Jun 05;2001(85):pe1
11752654
Curr Opin Pharmacol. 2003 Aug;3(4):435-42
12901954
Proc Natl Acad Sci U S A. 2007 Feb 13;104(7):2349-54
17284614
Blood. 1951 Apr;6(4):372-5
14820991
Cancer Cell. 2002 Feb;1(1):63-74
12086889
N Engl J Med. 2005 Apr 28;352(17):1779-90
15858187