Constitutive JAK3 activation induces lymphoproliferative syndromes in murine bone marrow transplantation models.
The tyrosine kinase JAK3 plays a well-established role during normal lymphocyte development and is constitutively phosphorylated in several lymphoid malignancies. However, its contribution to lymphomagenesis remains elusive. In this study, we used the newly identified activating JAK3A572V mutation to elucidate the effect of constitutive JAK3 signaling on murine lymphopoiesis. In a bone marrow transplantation model, JAK3A572V induces an aggressive, fatal, and transplantable lymphoproliferative disorder characterized by the expansion of CD8(+)TCRalphabeta(+)CD44(+)CD122(+)Ly-6C(+) T cells that closely resemble an effector/memory T-cell subtype. Compared with wild-type counterparts, these cells show increased proliferative capacities in response to polyclonal stimulation, enhanced survival rates with elevated expression of Bcl-2, and increased production of interferon-gamma (IFNgamma) and tumor necrosis factor-alpha (TNFalpha), correlating with enhanced cytotoxic abilities against allogeneic target cells. Of interest, the JAK3A572V disease is epidermotropic and produces intraepidermal microabscesses. Taken together, these clinical features are reminiscent of those observed in an uncommon but aggressive subset of CD8(+) human cutaneous T-cell lymphomas (CTCLs). However, we also observed a CD4(+) CTCL-like phenotype when cells are transplanted in an MHC-I-deficient background. These data demonstrate that constitutive JAK3 activation disrupts T-cell homeostasis and induces lymphoproliferative diseases in mice.
Cornejo
Melanie G
MG
Division of Hematology, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Kharas
Michael G
MG
Werneck
Miriam B
MB
Le Bras
Séverine
S
Moore
Sandra A
SA
Ball
Brian
B
Beylot-Barry
Marie
M
Rodig
Scott J
SJ
Aster
Jon C
JC
Lee
Benjamin H
BH
Cantor
Harvey
H
Merlio
Jean-Philippe
JP
Gilliland
D Gary
DG
Mercher
Thomas
T
D000818:Animals; D000950:Antigens, Ly / Q000032:analysis; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000473:pathology*; D004790:Enzyme Induction; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D053646:Interleukin-2 Receptor beta Subunit / Q000032:analysis; D053616:Janus Kinase 3 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016410:Lymphoma, T-Cell, Cutaneous / Q000473:pathology; D038041:Lymphopoiesis / Q000235:genetics / Q000502:physiology*; D008232:Lymphoproliferative Disorders / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D017354:Point Mutation; D011828:Radiation Chimera; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012867:Skin / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000473:pathology*
D000950:Antigens, Ly; C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; C508022:Il2rb protein, mouse; D053646:Interleukin-2 Receptor beta Subunit; C494192:Ly-6C antigen, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011993:Recombinant Fusion Proteins; C507933:JAK3 protein, human; D053616:Janus Kinase 3