Click here to close Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly. We suggest using a current version of Chrome, FireFox, or Safari.
XB-ART-50411
Oncotarget December 30, 2014; 5 (24): 12675-93.

A role for BMP-induced homeobox gene MIXL1 in acute myelogenous leukemia and identification of type I BMP receptor as a potential target for therapy.

Raymond A , Liu B , Liang H , Wei C , Guindani M , Lu Y , Liang S , St John LS , Molldrem J , Nagarajan L .


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. Accordingly, expression of c-REL and its downstream targets BCL2L1 and BCL2A2 are elevated in MIXL1 expressing cells. Notably, MIXL1 regulates c-REL through a zinc finger binding motif, potentially by a MIXL1-Zinc finger protein transcriptional complex. Furthermore, MIXL1 expression is detected in the cancer genome atlas (TCGA) AML samples in a pattern mutually exclusive from that of HOXA9, CDX2 and HLX suggesting the existence of a core, yet distinct HOX transcriptional program. Finally, we demonstrate MIXL1 to be induced by BMP4 and not TGF-β in primary human hematopoietic stem and progenitor cells. Consequently, MIXL1 expressing AML cells are preferentially sensitive to the BMPR1 kinase inhibitor LDN-193189. These findings support the existence of a novel MIXL1-c REL mediated survival axis in AML that can be targeted by BMPR1 inhibitors. (MIXL1- human gene, Mixl1- mouse ortholog, MIXL1- protein).

PubMed ID: 25544748
PMC ID: PMC4350356
Article link: Oncotarget
Grant support: [+]
Genes referenced: actl6a bcl2l1 bmp4 bmpr2 cdx2 dnmt3a eif1 flt3 hlx hoxa9 idh1 jak3 mzf1 npm1 rel runx1 runx3 slc39a13 smad1 smad4.1 smad4.2 smyd5 tp53 zp3.2

Disease Ontology terms: acute myeloid leukemia
OMIMs: LEUKEMIA, ACUTE MYELOID; AML

Article Images: [+] show captions
References:
Alfa, 2006, Pubmed [+]


Xenbase: The Xenopus laevis and X. tropicalis resource.
Version: 4.12.3


Major funding for Xenbase is provided by grant P41 HD064556