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Gene regulation changes driven by wild type and cancer-associated mutant variants of Myc as B-cells convert to Lymphoma-like cells

ABSTRACT: cMyc plays a major role in lymphoma development. In addition, missense mutations including T58A and T58I the substitution mutations augment cMyc activity during lymphoma development. In this study, we characterized lymphoma-associated gene expression changes as increasing levels of wild type or mutant cMyc proteins progressively drive conversion of B-cells to lymphoma-like cells. To this end we established a cell system in which primary mouse B-cells were transduced with constructs that over-express the anti-apoptotic proteins, BMI1 and BCLXL and allow variable expression of cMyc (wild type, T58A or T58I) from a doxycycline-regulated promoter. Increased cMyc expression is associated with cell cycle entry, increased cell size and increased cell proliferation. Generally, gene programs required for cell growth and proliferation are induced while specific functions associated with B-cells are repressed. Mutant cMyc proteins cause differential effects, relative to each other and to wild type cMyc, that are focused on particular aspects of the cMyc-induced program.

ORGANISM(S): Mus musculus

PROVIDER: GSE122602 | GEO | 2021/11/15

REPOSITORIES: GEO

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Project description:This study was designed to identify highly recurrent genetic alterations typical of SÃ©zary syndrome (Sz), an aggressive cutaneous T-cell lymphoma/leukemia, possibly revealing pathogenetic mechanisms and novel therapeutic targets. High-resolution array-based comparative genomic hybridization was done on malignant T cells from 20 patients. Expression levels of selected biologically relevant genes residing within loci with frequent copy number alteration were measured using quantitative PCR. Combined binary ratio labeling-fluorescence in situ hybridization karyotyping was done on malignant cells from five patients. Minimal common regions with copy number alteration occurring in at least 35% of patients harbored 15 bona fide oncogenes and 3 tumor suppressor genes. Based on the function of the identified oncogenes and tumor suppressor genes, at least three molecular mechanisms are relevant in the pathogenesis of Sz. First, gain of cMYC and loss of cMYC antagonists (MXI1 and MNT) were observed in 75% and 40% to 55% of patients, respectively, which were frequently associated with deregulated gene expression. The presence of cMYC/MAX protein heterodimers in SÃ©zary cells was confirmed using a proximity ligation assay. Second, a region containing TP53 and genome maintenance genes (RPA1/HIC1) was lost in the majority of patients. Third, the interleukin 2 (IL-2) pathway was affected by gain of STAT3/STAT5 and IL-2 (receptor) genes in 75% and 30%, respectively, and loss of TCF8 and DUSP5 in at least 45% of patients. In sum, the Sz genome is characterized by gross chromosomal instability with highly recurrent gains and losses. Prominent among deregulated genes are those encoding cMYC, cMYC-regulating proteins, mediators of MYC-induced apoptosis, and IL-2 signaling pathway components. [Cancer Res 2008;68(8):2689â98] Keywords: aCGH, COBRA, FISH, PLA In this multicenter study, we aimed to obtain a detailed catalogue of numerical and structural chromosomal abnormalities in a group of 20 well-defined Sz patients using high-resolution array-based CGH in combination with combined binary ratio labeling (COBRA), fluorescence in situ hybridization (FISH), and in situ proximity ligation assays (PLA).

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Gene regulation changes driven by wild type and cancer-associated mutant variants of Myc as B-cells convert to Lymphoma-like cells

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