1. 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
- Author
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Raymond, Aaron, Liu, Bin, Liang, Hong, Wei, Ciamaio, Guindani, Michele, Lu, Yue, Liang, Shoudan, St. John, Lisa S, Molldrem, Jeff, and Nagarajan, Lalitha
- Subjects
Hematology ,Human Genome ,Pediatric ,Rare Diseases ,Stem Cell Research ,Childhood Leukemia ,Genetics ,Pediatric Cancer ,Cancer ,Biotechnology ,Stem Cell Research - Nonembryonic - Non-Human ,Stem Cell Research - Nonembryonic - Human ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,Bone Morphogenetic Protein 4 ,Bone Morphogenetic Protein Receptors ,Type I ,Cell Differentiation ,Cell Line ,Tumor ,Genes ,Homeobox ,Genes ,rel ,HEK293 Cells ,HL-60 Cells ,Homeodomain Proteins ,Humans ,K562 Cells ,Leukemia ,Myeloid ,Acute ,Mice ,Molecular Targeted Therapy ,U937 Cells ,Oncology and Carcinogenesis - 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).
- Published
- 2014