Research Papers:
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
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Abstract
Aaron Raymond1,2, Bin Liu1,3, Hong Liang1, Caimiao Wei4, Michele Guindani4, Yue Lu5,6, Shoudan Liang7, Lisa S. St. John8, Jeff Molldrem8, Lalitha Nagarajan1,2,3,5,9,10
1Department of Genetics, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
2Graduate Program in Genes and Development, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
3Center for Cancer Genetics and Genomics, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
4Department of Biostatistics, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
5Dept. of Leukemia, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
6Dept. of Molecular Carcinogenesis, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
7Dept. of Bioinformatics and Computational Biology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
8Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
9Graduate Program in Human Molecular Genetics, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
10Center for Stem cell and Developmental biology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Correspondence to:
Lalitha Nagarajan, e-mail: [email protected]
Received: May 01, 2014 Accepted: October 02, 2014 Published: December 17, 2014
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)
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