NOTCH1, SF3B1, MDM2 and MYD88 mutations in patients with chronic lymphocytic leukemia

Abstract

Mutations in certain genes have been suggested to be associated with the pathogenesis of chronic lymphocytic leukemia (CLL), which is the most common leukemia in adults. In a case-control study, 100 patients with CLL and 105 healthy individuals were investigated for Notch homolog 1, translocation-associated (Drosophila) (NOTCH1) c.7544-7545delCT, recombinant splicing factor 3B subunit 1 (SF3B1) c.2098A>G, mouse double minute 2 homolog (MDM2) 40-bp insertion/deletion and myeloid differentiation primary response 88 (MYD88) L265P mutations by using allele specific-polymerase chain reaction (AS-PCR), a designed AS-PCR, PCR and PCR-restriction fragment length polymorphism methods, respectively. The presence of NOTCH1 and SF3B1 mutations were confirmed by genomic DNA sequencing. The NOTCH1 mutation was detected in 10% of patients and not detected in the control group. A higher frequency of NOTCH1 mutation was detected in patients with stage III CLL (62.5%) compared with stages 0-II CLL (37.5%) (odds ratio, 4.69-fold; 95% confidence interval, 1.0-21.9; P=0.049). The SF3B1 mutation was observed in 12% of the patients compared with 1.9% of the controls (P=0.012). The presence of MDM2 polymorphism was not associated with the risk or the stage of the disease. In addition, the MYD88 L265P mutation was not detected in the patients or the controls. The current study established the frequency of NOTCH1, SF3B1, MDM2 and MYD88 mutations in patients with CLL from the Kurdish population of Western Iran. In summary, a high frequency of NOTCH1 and SF3B1 mutations were identified in patients with CLL compared with healthy individuals, and the NOTCH1 mutation was associated with a high stage of the disease.

The 40bp Indel Polymorphism rs150550023 in the MDM2 Promoter is Associated with Intriguing Shifts in Gene Expression in the p53-MDM2 Regulatory Hub

“…Here we report a comprehensive analysis of the rs150550023 Indel polymorphism located in the constitutive promoter P1 of the human MDM2 gene, including the first investigation of rs150550023 association with the age at onset and prognosis of any cancer, and with the mRNA expression of MDM2 and other relevant genes in tumor tissue. We did not find an association of rs150550023 with breast cancer risk, in agreement with most previous studies and meta-analyses [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ]. The reports of a nonsignificantly elevated vs. a nonsignificantly reduced risk associated with the Del-allele (like in the present study) are divided roughly equally.…”

“…One study has used reporter assays in HeLa, HepG2, and JEG-3 human cell lines to indicate a role of rs150550023 in promoter P1 activity [ 15 ]. All tumor entities combined, fewer than 20 original studies and three meta-analyses have investigated the association of rs150550023 with cancer risk [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ]. Most of these studies did not find an association, except in specific patient subpopulations, whereas associations with indicators other than cancer risk have hardly been studied for rs150550023.…”

CtIP -mediated alternative mRNA splicing finetunes the DNA damage response

“…However, considering the involvement of CtIP, described here, and BRCA1 (Savage et al, 2014) in RNA splicing, maybe the cancer connection should be revisited on the light of those novel roles. Conversely, recent studies have detected recurrent mutations in components of the spliceosome in myelodysplastic syndromes (Pollyea et al, 2019; Shiozawa et al, 2018), renal cell carcinoma (Verma and Das, 2018; Yang et al, 2017), chronic lymphocytic leukaemia (Agrawal et al, 2017; Maleki et al, 2019), lung adenocarcinoma (Kim et al, 2018; Mao et al, 2019), breast cancer (Gokmen-Polar et al, 2019; Zhao et al, 2019) or pancreatic cancer (Tian et al, 2015; Zhou et al, 2017). Moreover, alterations in expression of splicing factors, including SF3B, can derive in various types of cancers (Alsafadi et al, 2016; Goswami et al, 2014; Maguire et al, 2015; Zheng et al, 2018).…”

A Different View for an Old Disease: NEDDylation and Other Ubiquitin-Like Post-Translational Modifications in Chronic Lymphocytic Leukemia

“…Constitutive activation of NOTCH is considered one of the main drivers of CLL, since it has been found in at least, but not only, the 4-13% of CLL cases carrying NOTCH1 mutations ( 2 , 56 , 57 ). Somehow surprisingly, no alteration in the modifications of proteins directly involved in this pathway were found in CLL.…”