2014
DOI: 10.18632/oncotarget.2564
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A role for BMP-induced homeobox geneMIXL1in acute myelogenous leukemia and identification of type I BMP receptor as a potential target for therapy

Abstract: Mesoderm Inducer in Xenopus Like1 (MIXL1), a paired-type homeobox transcription factor induced by TGF-β family of ligands is required for early embryonic specification of mesoderm and endoderm. Retrovirally transduced Mixl1 is reported to induce acute myelogenous leukemia (AML) with a high penetrance. But the mechanistic underpinnings of MIXL1 mediated leukemogenesis are unknown. Here, we establish the protooncogene c-REL to be a transcriptional target of MIXL1 by genome wide chromatin immune precipitation. Ac… Show more

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Cited by 21 publications
(30 citation statements)
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References 89 publications
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“…We found that AML-conditioned medium mediates Smad1 and -5 activation in MSCs. Recent reports indicate that BMPs are highly expressed in plasma samples from AML patients compared with those from healthy individuals (14,15,34), supporting our findings. Although it is not entirely clear which BMP proteins are involved, BMP6 and BMP9 have been shown to have the highest osteogenic activity among their family members (BMP1-15) (11) because of their association with Wnt signaling (12).…”
Section: Discussionsupporting
confidence: 91%
See 1 more Smart Citation
“…We found that AML-conditioned medium mediates Smad1 and -5 activation in MSCs. Recent reports indicate that BMPs are highly expressed in plasma samples from AML patients compared with those from healthy individuals (14,15,34), supporting our findings. Although it is not entirely clear which BMP proteins are involved, BMP6 and BMP9 have been shown to have the highest osteogenic activity among their family members (BMP1-15) (11) because of their association with Wnt signaling (12).…”
Section: Discussionsupporting
confidence: 91%
“…BMPs exert their biological effects by signaling through two type I serine/threonine kinase receptors, RIA and RIB, which are transduced by Smad1, -4, and -5 transcription factors. Previous reports suggest that elevated BMP-mediated signaling in AML patients promotes expression of antiapoptotic genes (14) and promotes AML cell growth (15). However, it is not clear how elevated BMP signaling affects the surrounding stroma in the AML-BM.…”
Section: Introductionmentioning
confidence: 99%
“…21 In human cord blood and adults, BMP4 regulates SCs and their niche [22][23][24] such as progenitor differentiation into megakaryocytes, 25 whereas BMP2 favors erythropoietic commitment. 26 Deregulation of the BMP pathway at the intrinsic and extrinsic levels has been reported in hematological malignancies 19,27 and is involved in the cancer SC phenotype in solid tumors, 17,[28][29][30][31] suggesting that it represents a general feature of transformed SC events that could contribute to tumor heterogeneity. In CP-CML patients at diagnosis, the BMP pathway is deregulated with soluble BMPs, secreted in the tumor niche that maintains a fraction of BMPR1b 1 LSCs and amplifies leukemic progenitors, participating in disease progression.…”
Section: Introductionmentioning
confidence: 99%
“…Although exact details of mechanisms are yet to be fully elucidated, recent studies indicate that alterations in the BMP pathway act in a paracrine fashion to enhance proliferation and survival of primitive leukemic stem cells and more mature myeloid progenitors [42,43]. In addition, BMP signalling appears to have oncogenic properties for promyelocytic leukaemia and acute myelogenous leukaemia, presumably via similar effects on leukemic stem cells [44,45]. Taken together, emerging evidence suggest that BMP inhibition may represent a novel approach for leukaemia treatment by targeting leukemic stem cells, perhaps in conjunction with existing targeted therapies.…”
Section: Role Of Bmp Signalling In Cancer Pathogenesismentioning
confidence: 99%