title: Differential regulation of the c-Myc/Lin28 axis discriminates subclasses of rearranged MLL leukemia.
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.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Jingya
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biostatistics, School of Public Health,University of Michigan, Ann Arbor, MI, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Muntean
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics*; D015321:Gene Rearrangement; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism
chemical_list: C488352:Lin-28 protein, mouse; C489428:Myc protein, mouse; D015514:Oncogene Proteins, Fusion; D016271:Proto-Oncogene Proteins c-myc; D016601:RNA-Binding Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse
keywords: Lin28; MLL; acute myeloid leukemia; c-Myc; let-7