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| Figure 5: The pathogenesis of MLL. Left: HOX transcription factors are of monumental importance for controlling hematopoiesis as many control hematopoietic differentiation. HOX expression must be terminated for maturation of leukocytes to occur. Therefore, ectopic expression blocks maturation, causing a population of self-renewing, dedifferentiated precursor cells to expand. Top right: After posttranscriptional proteolytic processing, amino- and carboxyl-terminal residues of MLL are incorporated into a macromolecular complex with histone methyltransferase and histone acetyltransferase function. Fusion proteins as a result of chromosomal translocations can disrupt normal gene expression, causing an excess production of HOX gene products. Bottom right: MLL complex proteins during normal and malignant hematopoiesis. MLL interacts with a variety of protein complexes in hematopoietic stem and progenitor cells to promote transcription of critical target genes like HOXA9 and MEIS1. During hematopoietic differentiation, MLL is not recruited to target genes in part due to decreased transcription of PAFc. Insufficient recruitment of MLL leads to decreased expression of target genes. Chromosomal translocations involving MLL generate MLL fusion proteins that recruit transcriptional activation complexes dependent on the fusion partner. MLL translocation partners can form transcriptional activation complexes. These complexes involve the recruitment of pTEFb, which is required to phosphorylate the RNA Pol II C terminal domain, subsequently promoting transcriptional elongation. The H3K79 methyltransferase DOT1l is also recruited by MLL fusion proteins which further perpetuate transcriptional activation. Image to the left and top right are courtesy of [54]. Image to the bottom right is courtesy of [55]. |
