Details

Autor(en) / Beteiligte

• Kameda, Takuro
• Shide, Kotaro
• Yamaji, Takumi
• Kamiunten, Ayako
• Sekine, Masaaki
• Taniguchi, Yasuhiro
• Hidaka, Tomonori
• Kubuki, Yoko
• Shimoda, Haruko
• Marutsuka, Kousuke
• Sashida, Goro
• Aoyama, Kazumasa
• Yoshimitsu, Makoto
• Harada, Taku
• Abe, Hiroo
• Miike, Tadashi
• Iwakiri, Hisayoshi
• Tahara, Yoshihiro
• Sueta, Mitsue
• Yamamoto, Shojiro
• Hasuike, Satoru
• Nagata, Kenji
• Iwama, Atsushi
• Kitanaka, Akira
• Shimoda, Kazuya

Titel

Loss of TET2 has dual roles in murine myeloproliferative neoplasms: disease sustainer and disease accelerator

Ist Teil von

• Blood, 2015-01, Vol.125 (2), p.304-315

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2015

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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. •Loss of TET2 accelerates the degree of malignancy of MPNs in combination with JAK2V617F.•Loss of TET2 sustains MPNs in combination with JAK2V617F.