Fig. 5 | Signal Transduction and Targeted Therapy

Fig. 5

From: Interplay between cofactors and transcription factors in hematopoiesis and hematological malignancies

Fig. 5

HMT/HDT-based regulatory mechanisms in TCs are implicated in the pathogenesis and treatment of malignant hematopoiesis. HMTs and HDTs are recurrently mutated or aberrantly expressed in a variety of hematological malignancies. Their intrinsic activities on histone and nonhistone proteins within transcriptional complexes are critical for epigenetic control in normal and malignant hematopoiesis and are amenable to drug intervention or involved in drug therapeutic effects. a Left panel in mixed lineage leukemia (MLL)-AF9 fusion leukemia. MLL-AF9 recruits DOT1L, a histone 3 lysine 79 methyltransferase (H3K79me1/me2/me3), which leads to hematopoietic transformation via H3K79 dimethylation that causes aberrant transcription of genes such as HOXA9 and MEIS1. PRDM16 (a histone H3K4 methyltransferase), an antagonist to DOT1L, activates Gfi1b-mediated gene transcription, which in turn downregulates the HOXA gene cluster. However, PRDM16 expression is always silenced by DNA methylation in MLL-AF9 leukemia. Right panel, similar to DOT1L, the H3K9me2/me1 demethylase JMJD1C contributes to MLL-AF9 leukemia maintenance by affecting MYB, MYC, and HOXA9-MEIS1 gene expression programs, suggesting that individual genes can be regulated by different kinds of HMTs and/or HDT-containing TCs. b Growth factor independence 1 (GFI1) is critical to the initiation of the endothelial-to-hematopoietic transition (EHT) due to its recruitment of the LSD1–CoREST repressive complex to epigenetically silence the endothelial program and allow the emergence of HSCs. Disruption or separation of the GFI1–LSD1 repressive complex by LSD1 inhibitors is considered to induce differentiation in certain subtypes of AML. c UTX, a coactivator of TAL1, is essential to leukemia maintenance in TAL1-positive cells due to its promotion of an open chromatin configuration at target gene sites by H3K27me3 demethylation. A therapy based on UTX inhibition is efficient at inducing cell death through downregulation of the TAL1 leukemic gene expression program. d UTX is a critical mediator of RA-induced differentiation in leukemic cells. RA treatment leads to the coordinated removal of repressive marks, the displacement of polycomb group proteins, and the deposition of activating marks. RA promotes the activation of RAR target genes by recruiting NCoA6, UTX, and ASH2L, concomitant with the demethylation of H3K27 and trimethylation of H3K4

Back to article page