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Non-Hodgkin Lymphoma
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
Waldenström’s macroglobulinemia (WM) has a key driver mutation, MYD88L265P, in >95% of the patients; other important mutations are CXCR4 (40%), ARID1A (17%) and CD79B (15%). Copy number alterations (CNAs) resulting in gene losses occur in PRDM2 (93%), BTG1 (87%), HIVEP2 (77%), MLKN1 (77%), PLEKHG1 (70%), LYN (60%), ARID1B (50%) and FOXP1 (37%). The most common cytogenetic deletions are in chromosome 6q, which mostly overlaps with the CNAs, and comprise of losses in PLEKHG1, HIVEP2, ARID1B and BCLAF1. Mutations in MYD88, which is associated with Toll-like receptor (TLR) and interleukin-1 receptor signalling, mediating IRAK1 and IRAK4, is involved in the NFĸB signalling by direct interaction with BTK.
Enhancing prognostication and personalizing treatment of extranodal marginal zone lymphoma
Published in Expert Review of Hematology, 2023
Juan Pablo Alderuccio, Izidore S. Lossos
Compared to other B-cell lymphomas, determining mutational profile in EMZL has been problematic due to frequently small pathological sample sizes limiting comprehensive genomic interrogation. Several studies attempted to assess mutations present in this disease with most studies including a relatively small number of specimens. There are four main recurrent chromosomal translocations implicating specific genes and pathways in the pathogenesis of EMZL: BCL10::IGH at t(1;14)(p22;q32), API2:MLT at t(11;18)(q21;21), MALT1:IGH at t(14;18)(q32;q21), and FOXP1:IGH at t(3;14)(p14.1;32) [38–43]. Across all extranodal sites, the most common mutations occur in TNFAP3 (29%), CREBBP (22%), KMT2C (19%), TET2 (17%), SPEN (17%), and KMT2D (15%) genes [10,34]. However, during the 2022 American Society of Hematology annual meeting, our group presented the largest whole-exome sequencing analysis in EMZL (n = 225) describing mutations in IGLL5 (22%) as the most common alteration across all extranodal sites [44]. We also observed mutations in PRDM2 (11%) and NCOR1 (10%) which were not previously reported. This analysis described a significant enrichment of aberrations in genes involved in NOTCH signaling, DNA repair, cancer-associated sustaining of proliferative signaling, cancer-associated histone methylation, and positive regulation of transcription. EMZL demonstrates distinct genomic alterations according to the primary extranodal site of disease but commonly affects signaling pathways central to the homeostasis of normal marginal zone B cells including NF-ĸB, BCR, NOTCH, MEF2B, and NFAT [9,36]. Genomic profile does not seem to be associated with stage of disease [10,45].
The relationship between histone posttranslational modification and DNA damage signaling and repair
Published in International Journal of Radiation Biology, 2019
Ajit K Sharma, Michael J. Hendzel
H3K9me3 also serve as a docking site for a repressive complex containing the histone methyltransferase SUV39H1, KAP1 and HP1 at DSBs (Ayrapetov et al. 2014). Recruitment of SUV39H1 to damaged DNA mediates the local spreading of H3K9me3 surrounding DSBs, which further activates TIP60 and TIP60-mediated activation of ATM by acetylation. Activated ATM then phosphorylates KAP1 to release the repressive complex i.e. SUV39H1-KAP1-HP1 complex from damaged chromatin (Ayrapetov et al. 2014). Overall these results reveal that H3K9me3 regulates the DDR by recruiting Tip60 at DSBs site in order to activate ATM and thus H3K9me3 play key role in early sensing of the damage DNAs. Histone H3K9 methylation is also important in the establishment of heterochromatin, where it is required for the recruitment of HP1 proteins. As discussed earlier, this heterochromatin barrier is disassembled for efficient repair of heterochromatin-associated breaks in an ATM-dependent manner. Further macroH2A1 and PRDM2 accumulated at double-strand break, along with an enrichment of the PRDM2 mediated H3K9me2 (Khurana et al. 2014). Loss of either macroH2A1 or PRDM2 impairs the retention of BRCA1, but not 53BP1, at DSBs and reduces DNA end resection in human cells (Khurana et al. 2014). In addition to the involvement of H3K9me3 methyltransferases in the DDR, histone demethylases like KDM4B and KDM4D are also known to be recruited to damaged sites in human cells (Young et al. 2013; Khoury-Haddad et al. 2014). We found that KDM4B recruitment was dependent on poly (ADP-ribose) polymerase 1 activity and led to a transient reduction of H3K9me2 and H3K9me3 following 2 Gy of γ-irradiation (Young et al. 2013). KDM4D was also found to be directly PARylated by PARP1 in response to DNA damage induced by etoposide and camptothecin (Khoury-Haddad et al. 2014).