Mixed-Lineage Leukemia Fusions and Chromatin in Leukemia

Abstract

Recent studies have shown the importance of chromatin-modifying complexes in the maintenance of developmental gene expression and human disease. The mixed lineage leukemia gene (MLL1) encodes a chromatin-modifying protein and was discovered as a result of the cloning of translocations involved in human leukemias. MLL1 is a histone lysine 4 (H3K4) methyltransferase that supports transcription of genes that are important for normal development including homeotic (Hox) genes. MLL1 rearrangements result in expression of fusion proteins without H3K4 methylation activity but may gain the ability to recruit other chromatin-associated complexes such as the H3K79 methyltransferase DOT1L and the super elongation complex. Therefore, chromosomal translocations involving MLL1 appear to directly perturb the regulation of multiple chromatin-associated complexes to allow inappropriate expression of developmentally regulated genes and thus drive leukemia development. IDENTIFICATION AND STRUCTURE OF MLL FUSIONS

KMT2A (MLL) fusions in aggressive sarcomas in young adults

“…The KMT2A fusion occurs in 5–10% of all acute leukaemia cases. At present, >70 fusion partners of KMT2A have been reported, with AF4 , AF9 , AF10 and ENL accounting for >70% of cases . The fusion is present in up to 80% of infantile acute lymphoblastic leukaemia cases, and in approximately 35–50% of paediatric acute myeloid leukaemia cases.…”

“…Wild‐type KMT2A is proteolytically processed into two fragments, KMT2A‐N and KMT2A‐C, with opposite transcriptional properties . The currently suggested effects of the KMT2A fusion oncoprotein in leukaemia include the induction of histone H3 lysine 79 methylation by DOT1L, stimulation of transcriptional elongation, and suppression of polycomb complexes . The leukaemic KMT2A fusion protein activates HOXA cluster genes, such as HOXA5 – HOXA10 , and the heterodimerising partners of HOX proteins, such as MEIS1 and PBX3 .…”

“…At present, >70 fusion partners of KMT2A have been reported, with AF4, AF9, AF10 and ENL accounting for >70% of cases. [5][6][7] The fusion is present in up to 80% of infantile acute lymphoblastic leukaemia cases, and in approximately 35-50% of paediatric acute myeloid leukaemia cases. KMT2A fusion also occurs in association with therapy-induced leukaemias, such as those arising after etoposide therapy for unrelated malignancies.…”

“…5,7 The leukaemic KMT2A fusion protein activates HOXA cluster genes, such as HOXA5-HOXA10, and the heterodimerising partners of HOX proteins, such as MEIS1 and PBX3. 5,7 However, some of these mechanisms cannot be extrapolated to sarcomas, in which KMT2A in the chimeric proteins lacks the critical domain required for the above functions ( Figure 3C). Importantly, the KMT2A fusions reported herein had the 3 0 part of KMT2A fused to the partner genes (YAP1 and VIM), which is different from previously identified fusions in leukaemia, in which the 5 0 part of KMT2A fuses with partner genes.…”

Epigenetic Basis of Cellular Senescence and Its Implications in Aging

“…For instance, many of the HMG proteins are overexpressed and support transcriptional reprogramming in different cancer cell types, and are associated with a poor prognosis [ 68 , 81 , 82 ]. The MLL1 protein undergoes chromosomal translocations and aberrantly upregulates genes related to development and the cell cycle, promoting tumorigenesis of several leukemias [ 83 , 84 ]. The BRD4 protein plays several roles in cancer by upregulating oncogenes, such as c-myc, and genes related to proliferation, apoptosis suppression, and inflammation [ 85 , 86 ].…”