Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=28126925
&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
MUC1-mediated induction of myeloid-derived suppressor cells in patients with
acute myeloid leukemia
#MMPMID28126925
Pyzer AR
; Stroopinsky D
; Rajabi H
; Washington A
; Tagde A
; Coll M
; Fung J
; Bryant MP
; Cole L
; Palmer K
; Somaiya P
; Karp Leaf R
; Nahas M
; Apel A
; Jain S
; McMasters M
; Mendez L
; Levine J
; Joyce R
; Arnason J
; Pandolfi PP
; Kufe D
; Rosenblatt J
; Avigan D
Blood
2017[Mar]; 129
(13
): 1791-1801
PMID28126925
show ga
Myeloid-derived suppressor cells (MDSCs) play a critical role in promoting immune
tolerance and disease growth. The mechanism by which tumor cells evoke the
expansion of MDSCs in acute myeloid leukemia (AML) has not been well described.
We have demonstrated that patients with AML exhibit increased presence of MDSCs
in their peripheral blood, in comparison with normal controls. Cytogenetic
studies demonstrated that MDSCs in patients with AML may be derived from leukemic
or apparently normal progenitors. Engraftment of C57BL/6 mice with TIB-49 AML led
to an expansion of CD11b(+) Gr1(+) MDSCs in bone marrow and spleen. Coculture of
the AML cell lines MOLM-4, THP-1 or primary AML cells with donor peripheral blood
mononuclear cells elicited a cell contact-dependent expansion of MDSCs. MDSCs
were suppressive of autologous T-cell responses as evidenced by reduced T-cell
proliferation and a switch from a Th1 to a Th2 phenotype. We hypothesized that
the expansion of MDSCs in AML is accomplished by tumor-derived extracellular
vesicles (EVs). Using tracking studies, we demonstrated that AML EVs are taken-up
myeloid progenitor cells, resulting in the selective proliferation of MDSCs in
comparison with functionally competent antigen-presenting cells. The MUC1
oncoprotein was subsequently identified as the critical driver of EV-mediated
MDSC expansion. MUC1 induces increased expression of c-myc in EVs that induces
proliferation in the target MDSC population via downstream effects on cell cycle
proteins. Moreover, we demonstrate that the microRNA miR34a acts as the
regulatory mechanism by which MUC1 drives c-myc expression in AML cells and EVs.
free
free
free
