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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Nat+Med
2017 ; 23
(11
): 1369-1376
Nephropedia Template TP
gab.com Text
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English Wikipedia
The N(6)-methyladenosine (m(6)A)-forming enzyme METTL3 controls myeloid
differentiation of normal hematopoietic and leukemia cells
#MMPMID28920958
Vu LP
; Pickering BF
; Cheng Y
; Zaccara S
; Nguyen D
; Minuesa G
; Chou T
; Chow A
; Saletore Y
; MacKay M
; Schulman J
; Famulare C
; Patel M
; Klimek VM
; Garrett-Bakelman FE
; Melnick A
; Carroll M
; Mason CE
; Jaffrey SR
; Kharas MG
Nat Med
2017[Nov]; 23
(11
): 1369-1376
PMID28920958
show ga
N(6)-methyladenosine (m(6)A) is an abundant nucleotide modification in mRNA that
is required for the differentiation of mouse embryonic stem cells. However, it
remains unknown whether the m(6)A modification controls the differentiation of
normal and/or malignant myeloid hematopoietic cells. Here we show that
shRNA-mediated depletion of the m(6)A-forming enzyme METTL3 in human
hematopoietic stem/progenitor cells (HSPCs) promotes cell differentiation,
coupled with reduced cell proliferation. Conversely, overexpression of wild-type
METTL3, but not of a catalytically inactive form of METTL3, inhibits cell
differentiation and increases cell growth. METTL3 mRNA and protein are expressed
more abundantly in acute myeloid leukemia (AML) cells than in healthy HSPCs or
other types of tumor cells. Furthermore, METTL3 depletion in human myeloid
leukemia cell lines induces cell differentiation and apoptosis and delays
leukemia progression in recipient mice in vivo. Single-nucleotide-resolution
mapping of m(6)A coupled with ribosome profiling reveals that m(6)A promotes the
translation of c-MYC, BCL2 and PTEN mRNAs in the human acute myeloid leukemia
MOLM-13 cell line. Moreover, loss of METTL3 leads to increased levels of
phosphorylated AKT, which contributes to the differentiation-promoting effects of
METTL3 depletion. Overall, these results provide a rationale for the therapeutic
targeting of METTL3 in myeloid leukemia.