IGH/MYC Translocation Associates with BRCA2 Deficiency and Synthetic Lethality to PARP1 Inhibitors

Maifrede, Silvia; Martin, Kayla; Podszywałow-Bartnicka, Paulina; Sullivan-Reed, Katherine; Langer, Samantha; Nejati, Reza; Dasgupta, Yashodhara; Hulse, Michael; Gritsyuk, Daniel; Nieborowska‐Skorska, Margaret; Lupey-Green, Lena N.; Zhao, Huaqing; Piwocka, Katarzyna; Wasik, Mariusz A.; Tempera, Italo; Skórski, Tomasz

doi:10.1158/1541-7786.mcr-16-0468

Cited by 26 publications

(26 citation statements)

References 20 publications

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“…Tumor suppressor protein BRCA2 paly important role in DNA double-strand break repair. BRCA2 deficiency may predispose leukemia cells to synthetic lethality triggered by PARP1 inhibitors [26]. High expression of THAP1-USF1-BRCA2 correlated with patient's poor prognosis (P-value = 7.4e−3, Fig.…”

Section: Functions and Prognostic Utility Of Ffls Marked By Diverse Cmentioning

confidence: 95%

Identifying functions and prognostic biomarkers of network motifs marked by diverse chromatin states in human cell lines

Wang

Zhao

et al. 2019

Oncogene

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Epigenetic modifications play critical roles in modulating gene expression, yet their roles in regulatory networks in human cell lines remain poorly characterized. We integrated multiomics data to construct directed regulatory networks with nodes and edges labeled with chromatin states in human cell lines. We observed extensive association of diverse chromatin states and network motifs. The gene expression analysis showed that diverse chromatin states of coherent type-1 feedforward loop (C1-FFL) and incoherent type-1 feedforward loops (I1-FFL) contributed to the dynamic expression patterns of targets. Notably, diverse chromatin state compositions could help C1-or I1-FFL to control a large number of distinct biological functions in human cell lines, such as four different types of chromatin state compositions cooperating with K562-associated C1-FFLs controlling "regulation of cytokinesis," "G1/S transition of mitotic cell cycle," "DNA recombination," and "telomere maintenance," respectively. Remarkably, we identified six chromatin state-marked C1-FFL instances (HCFC1-NFYA-ABL1, THAP1-USF1-BRCA2, ZNF263-USF1-UBA52, MYC-ATF1-UBA52, ELK1-EGR1-CCT4, and YY1-EGR1-INO80C) could act as prognostic biomarkers of acute myelogenous leukemia though influencing cancer-related biological functions, such as cell proliferation, telomere maintenance, and DNA recombination. Our results will provide novel insight for better understanding of chromatin state-mediated gene regulation and facilitate the identification of novel diagnostic and therapeutic biomarkers of human cancers.These authors contributed equally:

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Section: Functions and Prognostic Utility Of Ffls Marked By Diverse Cmentioning

confidence: 95%

Identifying functions and prognostic biomarkers of network motifs marked by diverse chromatin states in human cell lines

Wang

Zhao

et al. 2019

Oncogene

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“…Homologous recombination repair is crucial for the repair of DNA double strand breaks and for the maintenance of chromosomal stability. Reduced expression level of BRCA2, a crucial player in homologous recombination repair pathway, probably explains the spontaneous and Ara-C induced accumulation of DNA double strand breaks [146]. The above example illustrates that the oncogenic fusion event(s) triggered by DNA damaging agents such as IR may compromise transcription and repair activities leading to initiation and progression of carcinogenic events in normal cells.…”

Section: Interphase Fish For Detecting Chromosome Positioning and Brementioning

confidence: 97%

Applications of Fluorescence in Situ Hybridization in Radiation Cytogenetic Biodosimetry and Population Monitoring

Balajee¹

2018

obm genet

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The technique of in situ hybridization (ISH) using radioactively labeled DNA probes was first described in the late 1960s and early 1970s. The first use of fluorescence in situ hybridization (FISH) was reported in 1980s where RNA labeled with a fluorophore at the 3' end was used to detect specific DNA sequences. Since then, the technique has undergone various modifications for detecting single genes, chromosomes and whole genomes on various targets such as interphase nucleus, prematurely condensed chromosomes, metaphase chromosomes, fresh and paraffinized tissue sections. Although FISH is quite frequently used in clinical diagnostics, its use has recently been extended to the field of radiation biodosimetry where both stable (translocations) and unstable aberrations (dicentrics and rings) are detected with high resolution for estimating the absorbed radiation dose in humans after incidental, accidental or occupational exposure to ionizing radiation. This review summarizes the diverse applications of FISH in radiation biodosimetry that range from radiation dose estimation to prediction of deterministic (i.e. acute radiation syndrome severity) and stochastic (i.e. genetic mutations and cancer) effects in the affected human population.

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“…Yet other studies exploited the concept of synthetic lethality toward identification of effective therapeutic targets in tumors addicted to deregulated MYC expression/activity, based on either reverse‐genetic screens or select targeting (eg, ), or pharmacologic intervention with inhibitory compounds against various cellular proteins, including kinases, BET Bromodomains (eg, ), Histone deacetylases (HDACs), PARP, glycolytic enzymes, and others …”

Section: Targeting Myc Addictionmentioning

confidence: 99%

MYC in Germinal Center‐derived lymphomas: Mechanisms and therapeutic opportunities

Bisso

Sabò

Amati

2019

Immunological Reviews

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Summary The rearrangement of immunoglobulin loci during the germinal center reaction is associated with an increased risk of chromosomal translocations that activate oncogenes such as MYC, BCL2 or BCL6, thus contributing to the development of B‐cell lymphomas. MYC and BCL2 activation are initiating events in Burkitt's (BL) and Follicular Lymphoma (FL), respectively, but can occur at later stages in other subtypes such as Diffuse Large‐B Cell Lymphoma (DLBCL). MYC can also be activated during the progression of FL to the transformed stage. Thus, either DLBCL or FL can give rise to aggressive double‐hit lymphomas (DHL) with concurrent activation of MYC and BCL2. Research over the last three decades has improved our understanding of the functions of these oncogenes and the basis for their cooperative action in lymphomagenesis. MYC, in particular, is a transcription factor that contributes to cell activation, growth and proliferation, while concomitantly sensitizing cells to apoptosis, the latter being blocked by BCL2. Here, we review our current knowledge about the role of MYC in germinal center B‐cells and lymphomas, discuss MYC‐induced dependencies that can sensitize cancer cells to select pharmacological inhibitors, and illustrate their therapeutic potential in aggressive lymphomas—and in particular in DHL, in combination with BCL2 inhibitors.

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IGH/MYC Translocation Associates with BRCA2 Deficiency and Synthetic Lethality to PARP1 Inhibitors

Cited by 26 publications

References 20 publications

Identifying functions and prognostic biomarkers of network motifs marked by diverse chromatin states in human cell lines

Identifying functions and prognostic biomarkers of network motifs marked by diverse chromatin states in human cell lines

Applications of Fluorescence in Situ Hybridization in Radiation Cytogenetic Biodosimetry and Population Monitoring

MYC in Germinal Center‐derived lymphomas: Mechanisms and therapeutic opportunities

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