Journal
ONCOTARGET
Volume 5, Issue 24, Pages 12675-12693Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.2564
Keywords
-
Categories
Funding
- Abraham J. and Phyllis Katz Foundation
- Loper family foundation and Developmental research from the Leukemia SPORE [P50-CA100632]
- Graduate School of Biomedical sciences
- MDACC
- UTHSC
- CCSG [CA16672]
Ask authors/readers for more resources
Mesoderm Inducer in Xenopus Like1 (MIXL1), a paired-type homeobox transcription factor induced by TGF-beta 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-beta 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)
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available