RESUMO
The MLL1 histone methyltransferase gene undergoes many distinct chromosomal rearrangements to yield poor-prognosis leukemia. The remaining wild-type allele is most commonly, but not always, retained. To what extent the wild-type allele contributes to leukemogenesis is unclear. Here we show, using rigorous, independent animal models, that endogenous MLL1 is dispensable for MLL-rearranged leukemia. Potential redundancy was addressed by co-deleting the closest paralog, Mll2. Surprisingly, Mll2 deletion alone had a significant impact on survival of MLL-AF9-transformed cells, and additional Mll1 loss further reduced viability and proliferation. We show that MLL1/MLL2 collaboration is not through redundancy, but regulation of distinct pathways. These findings highlight the relevance of MLL2 as a drug target in MLL-rearranged leukemia and suggest its broader significance in AML.
Assuntos
Proteínas de Ligação a DNA/genética , Rearranjo Gênico , Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Neoplasias/genética , Animais , Proliferação de Células/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/fisiologia , Deleção de Genes , Regulação Neoplásica da Expressão Gênica , Histona-Lisina N-Metiltransferase/metabolismo , Histona-Lisina N-Metiltransferase/fisiologia , Humanos , Camundongos , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteína de Leucina Linfoide-Mieloide/fisiologia , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/fisiologia , Proteínas Recombinantes de Fusão/genéticaRESUMO
Accumulating recent evidence supports the notion that many enzymes that modify histones are fundamental players in normal hematopoiesis as well as hematologic malignancies, and represent an important new class of drug targets. Histone H3 lysine 4 (H3K4) methylation plays several distinct roles in gene expression and is modulated by specific methyltransferases and demethylases. Recent progress has been made clarifying the unique biological roles of the enzymes that carry out H3K4 methylation, yet a detailed understanding of H3K4 methylation states in various genomic contexts and the diverse functions of the enzymes that perform these methylation events is incomplete, but developing rapidly. In this review, we summarize and discuss the general mechanisms of H3K4 methylation, and how the six main enzymes from the SET/MLL family (responsible for H3K4me1/me2/me3) function in hematopoiesis and in hematologic malignancies.