Loss of TET2 has dual roles in murine myeloproliferative neoplasms: disease sustainer and disease accelerator.
Acquired mutations of JAK2 and TET2 are frequent in myeloproliferative neoplasms (MPNs). We examined the individual and cooperative effects of these mutations on MPN development. Recipients of JAK2V617F cells developed primary myelofibrosis-like features; the addition of loss of TET2 worsened this JAK2V617F-induced disease, causing prolonged leukocytosis, splenomegaly, extramedullary hematopoiesis, and modestly shorter survival. Double-mutant (JAK2V617F plus loss of TET2) myeloid cells were more likely to be in a proliferative state than JAK2V617F single-mutant myeloid cells. In a serial competitive transplantation assay, JAK2V617F cells resulted in decreased chimerism in the second recipients, which did not develop MPNs. In marked contrast, cooperation between JAK2V617F and loss of TET2 developed and maintained MPNs in the second recipients by compensating for impaired hematopoietic stem cell (HSC) functioning. In-vitro sequential colony formation assays also supported the observation that JAK2V617F did not maintain HSC functioning over the long-term, but concurrent loss of TET2 mutation restored it. Transcriptional profiling revealed that loss of TET2 affected the expression of many HSC signature genes. We conclude that loss of TET2 has two different roles in MPNs: disease accelerator and disease initiator and sustainer in combination with JAK2V617F.
Department of Gastroenterology and Hematology, and.
Takuro
T
Kameda
Department of Gastroenterology and Hematology, and.
Kotaro
K
Shide
Department of Gastroenterology and Hematology, and.
Takumi
T
Yamaji
Department of Gastroenterology and Hematology, and.
Ayako
A
Kamiunten
Department of Gastroenterology and Hematology, and.
Masaaki
M
Sekine
Department of Gastroenterology and Hematology, and.
Yasuhiro
Y
Taniguchi
Department of Gastroenterology and Hematology, and.
Tomonori
T
Hidaka
Department of Gastroenterology and Hematology, and.
Yoko
Y
Kubuki
Department of Gastroenterology and Hematology, and.
Haruko
H
Shimoda
Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan;
Kousuke
K
Marutsuka
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan; and.
Goro
G
Sashida
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan; and.
Kazumasa
K
Aoyama
Division of Hematology and Immunology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Makoto
M
Yoshimitsu
Department of Gastroenterology and Hematology, and.
Taku
T
Harada
Department of Gastroenterology and Hematology, and.
Hiroo
H
Abe
Department of Gastroenterology and Hematology, and.
Tadashi
T
Miike
Department of Gastroenterology and Hematology, and.
Hisayoshi
H
Iwakiri
Department of Gastroenterology and Hematology, and.
Yoshihiro
Y
Tahara
Department of Gastroenterology and Hematology, and.
Mitsue
M
Sueta
Department of Gastroenterology and Hematology, and.
Shojiro
S
Yamamoto
Department of Gastroenterology and Hematology, and.
Satoru
S
Hasuike
Department of Gastroenterology and Hematology, and.
Kenji
K
Nagata
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan; and.
Atsushi
A
Iwama
Department of Gastroenterology and Hematology, and.
Akira
A
Kitanaka
Department of Gastroenterology and Hematology, and.
Kazuya
K
Shimoda
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics*; D049308:Dioxygenases; D005434:Flow Cytometry; D053614:Janus Kinase 2 / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009196:Myeloproliferative Disorders / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics*
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D049308:Dioxygenases; C551914:Tet2 protein, mouse; D053614:Janus Kinase 2