These data implicate the miR-17∼92 cluster as part of a regulatory mechanism necessary to maintain MEIS1/HOXA9 -mediated transformation in MLLleukemia, indicating that targeting multiple non-homologous miRNAs may be utilized as a novel therapeutic regimen.
In conclusion, our results show that in contrast to its classical role antagonizing trithorax function, the polycomb group protein EZH2 collaborates with trithorax-associated menin to block MLL-AF9 leukemia cell differentiation, uncovering a novel mechanism for suppression of C/EBPα and leukemia cell differentiation, through menin-mediated upregulation of EZH2.
Furthermore, HOTAIR knockdown reduced infiltration of leukemic blasts, decreased frequency of LSC, and prolonged overall survival in MLL-AF9-induced murine leukemia, suggesting that HOTAIR is required for the maintenance of AML.
The frequency and clinical correlations of MLL gene amplification in leukemia will need careful follow-up, since the frequently cryptic amplification described in these cases may not generally provoke confirmatory FISH studies.
In this review, we will discuss the role of MLL and its fusion partners in normal HSPCs and hematopoiesis, including the links between chromatin effectors, epigenetic landscapes, and leukemia development, and summarize current approaches to therapeutic targeting of <i>MLL</i>-r leukemias.
MLL aberrations are detected in around 5-10% of acute myeloid and lymphatic leukemias and an additional 5% of acute myeloid leukemias show a partial internal MLL duplication (PTD).
This reviews discusses (i) the current situation in MLL-rearranged leukaemia, (ii) the molecular and genetic tools to functionally investigate the many different MLL fusions, (iii) the latency of disease development, (iv) a novel cancer mechanism that has been recently uncovered when different MLL fusion protein complexes were characterized, (v) mutated signalling pathways in MLL-rearranged leukaemia and (vi) presents new ideas on how a given MLL fusion protein may modulate existing signalling pathways in leukaemic cells.
These results suggest that TRL-01 is a useful cell line for studying not only the leukemia-related biology of MLL-ENL but also the intercellular association between leukemia and stroma.
Aberrant fusion proteins involving the MLL histone methyltransferase (HMT) lead to recruitment of DOT1L, to a multi-protein complex resulting in aberrant methylation of histone H3 lysine 79 at MLL target genes, and ultimately enhanced expression of critical genes for hematopoietic differentiation, including HOXA9 and MEIS1, and as such defines the established mechanism for leukemogenesis in MLL-rearrangement (MLL-r) leukemias.
IKK/NF-κB signaling is required for wild-type and fusion MLL protein retention and maintenance of associated histone modifications, providing a molecular rationale for enhanced efficacy in therapeutic targeting of this pathway in MLLleukemias.
MLL translocations t(4;11) and t(11;19) characterized extensively hypermethylated leukemias, whereas t(9;11)-positive infant ALL and infant ALL carrying wild-type MLL genes epigenetically resembled normal bone marrow.
EHZF expression is observed in most acute myelogenous leukaemias and is particularly high in those with rearrangements of the MLL gene, where EHZF may contribute to the leukaemic phenotype.
The histone H3 lysine 4 (H3K4) presenter WDR5 forms protein complexes with H3K4 methyltransferases MLL1-MLL4 and binding partner proteins including RBBP5, ASH2L, and DPY30, and plays a key role in histone H3K4 trimethylation, chromatin remodeling, transcriptional activation of target genes, normal biology, and diseases such as MLL-rearranged leukemia.