Clustered PHD domains in mixed lineage leukaemia proteins are attracted by acetylation-rich active promoters and enhancers

Histone lysine methyltransferase (KMT2) proteins form the core of COMPASS and COMPASS-like complexes that mediate transcriptional memory by methylating H3K4 at promoters and enhancers. KMT2A-D proteins, alternatively called mixed lineage leukaemia proteins (MLL1-4), contain highly conserved unique triplet and quartet of plant homeodomains (PHDs). Here, we show that clustered PHDs, expressed in isolation in HeLa cells, localize to well-defined loci of acetylation-rich active promoters and enhancers. Binding sites overlap with targets of full-length KMT2A (MLL1) and the COMPASS-like subunit WDR5, RbBP5 and with cell cycle and cancer-related genes. COSMIC data identify frequent variations in the PHDs of KMT2 proteins, particularly KMT2C, in a wide spectrum of malignancies. Changes are enriched at conserved positions within the PHDs, indicating that they cause loss-of-function mutations. Taken together, the biochemical and cancer data suggest that the PHDs contribute to KMT2A-D targeting to active promoters and enhancers.

Mature B cell acute lymphoblastic leukaemia with KMT2A-MLLT3 transcripts in children: three case reports and literature reviews

Background Mature B cell acute lymphoblastic leukaemia (BAL) is characterised by French–American–British (FAB)-L3 morphology and the presence of surface immunoglobulin (sIgM) light chain restriction. BAL is also considered as the leukaemic phase of Burkitt lymphoma (BL), in which t (8; 14) (q24; q32) or its variants are related to the myelocytomatosis oncogene (MYC) rearrangement (MYCr) is usually present. However, BAL with lysine methyltransferase 2A (KMT2A, previously called Mixed lineage leukaemia, MLL) gene rearrangement (KMT2Ar, previously called MLLr) is rare. Results Three BAL patients with KMT2Ar were enrolled between January 2017 and November 2019, accounting for 1.37% of the B-ALL population in our hospital. We also reviewed 24 previously reported cases of BAL and KMT2Ar and analysed the features, treatment, and prognosis. Total 13 males and 14 females were enrolled in our research, and the average age at diagnosis was 19.5 ± 4.95 months old. In these 27 patients, renal, central nervous system (CNS) and skin involvement were existent in 6, 4 and 3 patients, respectively; 26 patients (26/27) showed non-ALL-L3 morphology, while one patient is ALL-L3; overexpression of CD19 was detected in most cases, negative or suspicious expression of CD20 was found in 64% of patients. KMT2Ar was reported, but MYCr was not observed. 25 patients (25/27) achieved complete remission after chemotherapy or Stem cell transplantation. The patients were sensitive to chemotherapy, prospective event-free survival (pEFS) of BAL patients with KMT2Ar who received allogeneic haematopoietic stem cell transplantation (allo-HSCT) was higher than that in patients who received chemotherapy alone (83.33% vs 41.91%). Conclusion BAL patients with KMT2Ar had unique manifestations, including younger age at diagnosis and overexpression of CD19; expression of CD20 was rare, and MYCr was undetectable. The pEFS was higher in patients undergoing allo-HSCT than in patients undergoing chemotherapy alone.

The MLL1 trimeric catalytic complex is a dynamic conformational ensemble stabilized by multiple weak interactions

Histone H3K4 methylation is an epigenetic mark associated with actively transcribed genes. This modification is catalyzed by the mixed lineage leukaemia (MLL) family of histone methyltransferases including MLL1, MLL2, MLL3, MLL4, SET1A and SET1B. The catalytic activity of this family is dependent on interactions with additional conserved proteins, but the structural basis for subunit assembly and the mechanism of regulation is not well understood. We used a hybrid methods approach to study the assembly and biochemical function of the minimally active MLL1 complex (MLL1, WDR5 and RbBP5). A combination of small angle X-ray scattering, cross-linking mass spectrometry, nuclear magnetic resonance spectroscopy and computational modeling were used to generate a dynamic ensemble model in which subunits are assembled via multiple weak interaction sites. We identified a new interaction site between the MLL1 SET domain and the WD40 β-propeller domain of RbBP5, and demonstrate the susceptibility of the catalytic function of the complex to disruption of individual interaction sites.

MLL1 minimal catalytic complex is a dynamic conformational ensemble susceptible to pharmacological allosteric disruption

ABSTRACTHistone H3K4 methylation is an epigenetic mark associated with actively transcribed genes. This modification is catalyzed by the mixed lineage leukaemia (MLL) family of histone methyltransferases including MLL1, MLL2, MLL3, MLL4, SET1A and SET1B. Catalytic activity of MLL proteins is dependent on interactions with additional conserved proteins but the structural basis for subunit assembly and the mechanism of regulation is not well understood. We used a hybrid methods approach to study the assembly and biochemical function of the minimally active MLL1 complex (MLL1, WDR5 and RbBP5). A combination of small angle X-ray scattering (SAXS), cross-linking mass spectrometry (XL-MS), NMR spectroscopy, and computational modeling were used to generate a dynamic ensemble model in which subunits are assembled via multiple weak interaction sites. We identified a new interaction site between the MLL1 SET domain and the WD40 repeat domain of RbBP5, and demonstrate the susceptibility of the catalytic function of the complex to disruption of individual interaction sites.

Mixed lineage leukaemia histone methylases 1 collaborate with ERα to regulate HOXA10 expression in AML

We find that E2 could elevate HOXA10 expression. We examine HOXA10 regulated by MLL1 with an epigenetic way. MLL1 bind to HOXA10 promoter through formatting complex with mainly ERα.