A role for BMP-induced homeobox geneMIXL1in acute myelogenous leukemia and identification of type I BMP receptor as a potential target for therapy

// Aaron Raymond 1, 2 , Bin Liu 1, 3 , Hong Liang 1 , Caimiao Wei 4 , Michele Guindani 4 , Yue Lu 5, 6 , Shoudan Liang 7 , Lisa S. St. John 8 , Jeff Molldrem 8 , Lalitha Nagarajan 1, 2, 3, 5, 9, 10 1 Department of Genetics, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 2 Graduate Program in Genes and Development, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 3 Center for Cancer Genetics and Genomics, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 4 Department of Biostatistics, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 5 Dept. of Leukemia, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 6 Dept. of Molecular Carcinogenesis, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 7 Dept. of Bioinformatics and Computational Biology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 8 Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 9 Graduate Program in Human Molecular Genetics, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 10 Center for Stem cell and Developmental biology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Correspondence to: Lalitha Nagarajan, e-mail: lnagaraj@mdanderson.org 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)