Differential regulation of the c-Myc/Lin28 axis discriminates subclasses of rearranged MLL leukemia

// Lili Chen 1 , Yuqing Sun 1 , Jingya Wang 1 , Hui Jiang 2 and Andrew G. Muntean 1 1 Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA 2 Department of Biostatistics, School of Public Health,University of Michigan, Ann Arbor, MI, USA Correspondence to: Andrew G. Muntean, email: // Keywords : acute myeloid leukemia, MLL, c-Myc, Lin28, let-7 Received : March 07, 2016 Accepted : March 14, 2016 Published : March 19, 2016 Abstract MLL rearrangements occur in myeloid and lymphoid leukemias and are generally associated with a poor prognosis, however this varies depending on the fusion partner. We modeled acute myeloid leukemia (AML) in mice using various MLL fusion proteins (MLL-FPs) and observed significantly different survival outcomes. To better understand the differences between these leukemias, we examined the genome wide expression profiles of leukemic cells transformed with different MLL-FPs. RNA-sequencing and pathway analysis identified the c-Myc transcriptional program as one of the top distinguishing features. c-Myc protein levels were highly correlative with AML disease latency in mice. Functionally, overexpression of c-Myc resulted in a more aggressive proliferation rate in MLL-FP cell lines. While all MLL-FP transformed cells displayed sensitivity to BET inhibitors, high c-Myc expressing cells showed greater resistance to Brd4 inhibition. The Myc target Lin28B was also differentially expressed in MLL-FP cell lines in agreement with c-Myc expression. Examination of Lin28B miRNAs targets revealed that let-7g was significantly increased in leukemic cells associated with the longest disease latency and forced let-7g expression induced differentiation of leukemic blasts. Thus, differential regulation of the c-Myc/Lin28/ let-7g program by different MLL-FPs is functionally related to disease latency and BET inhibitor resistance in MLL leukemias.