Identification of MLL-fusion/MYC⊣miR-26⊣TET1 signaling circuit in MLL-rearranged leukemia.

Expression of functionally important genes is often tightly regulated at both transcriptional and post-transcriptional levels. We reported previously that TET1, the founding member of the TET methylcytosine dioxygenase family, plays an essential oncogenic role in MLL-rearranged acute myeloid leukemia (AML), where it is overexpressed owing to MLL-fusion-mediated direct up-regulation at the transcriptional level. Here we show that the overexpression of TET1 in MLL-rearranged AML also relies on the down-regulation of miR-26a, which directly negatively regulates TET1 expression at the post-transcriptional level. Through inhibiting expression of TET1 and its downstream targets, forced expression of miR-26a significantly suppresses the growth/viability of human MLL-rearranged AML cells, and substantially inhibits MLL-fusion-mediated mouse hematopoietic cell transformation and leukemogenesis. Moreover, c-Myc, an oncogenic transcription factor up-regulated in MLL-rearranged AML, mediates the suppression of miR-26a expression at the transcriptional level. Collectively, our data reveal a previously unappreciated signaling pathway involving the MLL-fusion/MYC⊣miR-26a⊣TET1 signaling circuit, in which miR-26a functions as an essential tumor-suppressor mediator and its transcriptional repression is required for the overexpression and oncogenic function of TET1 in MLL-rearranged AML. Thus, restoration of miR-26a expression/function holds therapeutic potential to treat MLL-rearranged AML.

Huang H ，Jiang X ，Wang J ，Li Y ，Song CX ，Chen P ，Li S ，Gurbuxani S ，Arnovitz S ，Wang Y ，Weng H ，Neilly MB ，He C ，Li Z ，Chen J ... -  《-》

MiR-495 is a tumor-suppressor microRNA down-regulated in MLL-rearranged leukemia.

Jiang X ，Huang H ，Li Z ，He C ，Li Y ，Chen P ，Gurbuxani S ，Arnovitz S ，Hong GM ，Price C ，Ren H ，Kunjamma RB ，Neilly MB ，Salat J ，Wunderlich M ，Slany RK ，Zhang Y ，Larson RA ，Le Beau MM ，Mulloy JC ，Rowley JD ，Chen J ... -  《-》

TET1 plays an essential oncogenic role in MLL-rearranged leukemia.

Huang H ，Jiang X ，Li Z ，Li Y ，Song CX ，He C ，Sun M ，Chen P ，Gurbuxani S ，Wang J ，Hong GM ，Elkahloun AG ，Arnovitz S ，Wang J ，Szulwach K ，Lin L ，Street C ，Wunderlich M ，Dawlaty M ，Neilly MB ，Jaenisch R ，Yang FC ，Mulloy JC ，Jin P ，Liu PP ，Rowley JD ，Xu M ，He C ，Chen J ... -  《-》

Differential regulation of the c-Myc/Lin28 axis discriminates subclasses of rearranged MLL leukemia.

Chen L ，Sun Y ，Wang J ，Jiang H ，Muntean AG ... -  《Oncotarget》

ZNF521 sustains the differentiation block in MLL-rearranged acute myeloid leukemia.

Germano G ，Morello G ，Aveic S ，Pinazza M ，Minuzzo S ，Frasson C ，Persano L ，Bonvini P ，Viola G ，Bresolin S ，Tregnago C ，Paganin M ，Pigazzi M ，Indraccolo S ，Basso G ... -  《Oncotarget》