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Familial Monosomy 7 Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
MLL3 (7q36.1) encodes a protein with histone methyltransferase activity that targets lysine 4 of histone 3 (H3K4)., and acts as a haploinsufficient tumor suppressor. Loss-of-function mutations in MLL3 often co-occur with N-RAS, K-RAS, and PTPN11 activation, NF1 deletion, and TP53 inactivation in MDS and AML.
RNA-seq analysis identifies transcriptomic profiles associated with anal cancer recurrence among people living with HIV
Published in Annals of Medicine, 2023
Yuanfan Ye, Kevin J. Maroney, Howard W. Wiener, Olga A. Mamaeva, Anna D. Junkins, Greer A. Burkholder, Staci L. Sudenga, Mohd Khushman, Sameer Al Diffalha, Anju Bansal, Sadeep Shrestha
Chemoradiation therapy (CRT), the standard treatment for SCCA [10–12], has shown a superior treatment rate compared to other treatments. However, 10–26% of patients do not have a complete response to CRT, and about 24% of patients may relapse [13–16]. Further, treatment outcomes for PLWH are not as well described as for individuals living without HIV. Given the limited number of SCCA cases, a conventional clinical trial is limited and molecular approaches have been explored. Yanik et al. [17] indicated that there were no differences with immune-related expression profiles or check-point molecule expression (e.g. PD-L1) in SCCA by HIV status. However, Yanik’s study combined tumor tissues from treated and untreated individuals and importantly only select candidate immune-related genes were examined in 3 PLWH and 4 patients without HIV. A multi-platform profiling analysis of SCCA tissues by Smaglo et al. suggested over-expression of proteins involved in resistance to chemotherapeutic drugs such as excision repair cross-complementing gene 1 (ERCC1) and multi-drug resistance-associated protein 1 (MRP1) that offered therapeutic investigation [18]. Other genomic profiling studies suggested no unique patterns between primary SCCA and recurrent SCCA [19]; mutations in PIK3CA, FBXW7, MLL2, and MLL3 appeared to be common among primary and metastatic SCCA [20–23]. However, to date there are no biological signatures that determine CRT response in SCCA patients.
Mantle cell lymphoma: insights into therapeutic targets at the preclinical level
Published in Expert Opinion on Therapeutic Targets, 2020
Epigenetic deregulation is a hallmark of MCL. Recurrent mutations of several established epigenetic regulators can be found in MCL patients including MLL2/KMT2D, MLL3/KMT2C, MEF2B, SMARCA4, NSD2, ARID1 [10,14]. Histone deacetylase inhibitors (HDACs) regulate expression of key molecules involved in pathogenesis and drug resistance of MCL including SOX11, proapoptotic BCL2 molecules or VEGF [149,150]. HDAC inhibitors provide an alternative strategy for combinatorial therapy of MCL [151]. Single-agent HDACs demonstrated only modest activity in MCL. Cladribine, an inhibitor of DNA methylation, is used in some centers in front-line or salvage therapy of MCL. The combination of cladribine, rituximab, and vorinostat has been recently tested in newly diagnosed MCL [152]. The combinations of HDAC inhibitors and ibrutinib appeared particularly promising in the preclinical settings. The efficacy of abexinostat and pevonedistat in combination with ibrutinib is currently being evaluated in several early phase clinical trials (NCT03939182, NCT03479268) [153]. A dual HDAC and PI3K inhibitor fimepinostat showed preclinical anti-lymphoma efficacy in MCL [154].
Novel agents for mantle cell lymphoma: molecular rational and clinical data
Published in Expert Opinion on Investigational Drugs, 2020
Clémentine Sarkozy, Vincent Ribrag
ATM, CCND1, TP53, and RB1 are also among the most recurrently mutated genes in MCL [6,16,17] (Table 1). ATM and RB1 mutations tend to co-occur in the same cases, reflecting the importance of DNA damage response pathway additionally to cell-cycle control alterations, whereas TP53 and ATM tend to be mutually exclusive [18]. Abnormalities within epigenetic modifiers such as MLL3, MLL2, WHSC1, MEF2B, SMARCA4, and SALL3, cell adhesion development regulation (NOTCH1/2, ANK2 …), the anti-apoptotic protein BIRC3 are also recurrently present in MCL. In few patients, a pattern of clonal heterogeneity at diagnosis based on a slightly distinct profile at two different sites of biopsy has been reported by Bea et al. [17]. Noteworthy, Zhang et al. [16] showed that epigenetically defined regions of open chromatin of the MCL COO (i.e. naïve B cell) are highly related to MCL gene expression and that mutations in the most recurrent genes were associated with open chromatin in their corresponding COO. These data indicate that epigenetic based therapy might be efficient or at least present synergistic effect with another targeted agent in MCL.