A NUP98-HOXD13 leukemic fusion gene leads to impaired class switch recombination and antibody production

Puthiyaveetil, Abdul Gafoor; Heid, Bettina; Reilly, Christopher M.; HogenEsch, Harm; Caudell, David L.

doi:10.1016/j.exphem.2012.05.002

Cited by 5 publications

(6 citation statements)

References 40 publications

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“…Interestingly, compound NRAS+BCL2 transgenic mice, which develop leukemia in early adulthood, showed an even higher proportion of cells with DNA damage (62%), suggesting that with increasing severity of disease state (from wild-type, via an MDS-like disease, to overt leukemia) the percentage of cells carrying DSBs dramatically increases [51]. Aberrant NHEJ may also be a contributing factor to MDS development in NUP98/HOXD13 transgenic mice; expression levels of important NHEJ genes (including DNA-PKcs , Lig4 and Xrcc4 ) were reduced in B cells of these mice [52] and this was accompanied by impaired class switch recombination [53], a process that depends on proper NHEJ.…”

Section: Dna Repairmentioning

confidence: 99%

Myelodysplastic syndrome: An inability to appropriately respond to damaged DNA?

Zhou

Hasty

Walter

et al. 2013

Experimental Hematology

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Myelodysplastic syndrome (MDS) is considered a hematopoietic stem cell (HSC) disease, characterized by abnormal hematopoietic differentiation and a high propensity to develop acute myeloid leukemia (AML). It is mostly associated with advanced age, but also with prior anti-cancer therapy and inherited syndromes related to abnormalities in DNA repair. Recent technological advances have led to the identification of a myriad of frequently occurring genomic perturbations associated with MDS. These observations suggest that MDS and its progression to AML is a genomic instability disorder, resulting from a step-wise accumulation of genetic abnormalities. The notion is now emerging that the underlying mechanism of this disease may be a defect in one or more pathways that are involved in responding to or repairing damaged DNA. In this review, we will discuss these pathways in relationship to a large number of studies performed with MDS patient samples and MDS mouse models. Moreover, in view of our current understanding of how DNA damage response/repair pathways are affected by age in HSCs, we will also explore how this might relate to MDS development.

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Section: Dna Repairmentioning

confidence: 99%

Myelodysplastic syndrome: An inability to appropriately respond to damaged DNA?

Zhou

Hasty

Walter

et al. 2013

Experimental Hematology

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“…Furthermore our previous studies have shown that B lymphocyte differentiation and CSR are altered in NHD13 mice, with partial blocks occurring during gene recombination events [15]. Based on these findings, we used CSR as a tool to determine the role of NHD13 to induce DNA breaks and thereby analyze the NHEJ-mediated break repair pattern.…”

Section: Discussionmentioning

confidence: 99%

“…A total of 2 × 10 5 cells were treated with 5 μM CFSE and cultured with media containing E. coli Lipopolysaccharide (LPS, Sigma–Aldrich, St. Louis, MO) (25 μg/ml) and IL-4 (PeproTech, Rocky Hill, NJ) (25 ng/ml). To verify that CSR had occurred, cells were harvested at 72 h, labeled with anti-mouse IgG1 and IgE antibodies and analyzed by flow cytometry as previously published [15]. …”

Section: Methodsmentioning

confidence: 99%

“…We have recently shown that expression of NHD13 in stimulated B-lymphocytes results in: (1) impaired B-cell differentiation at stages in the bone marrow that are dependent on VDJ recombination and (2) impaired class switch recombination (CSR) and antibody production [15]. During CSR naïve B lymphocytes undergo DNA breaks on immunoglobulin heavy chain gene and NHEJ-mediated break repair when stimulated with appropriate antigens and cofactors to produce different immunoglobulin isotypes [16].…”

Section: Introductionmentioning

confidence: 99%

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Non-homologous end joining mediated DNA repair is impaired in the NUP98-HOXD13 mouse model for myelodysplastic syndrome

et al. 2013

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Chromosomal translocations typically impair cell differentiation and often require secondary mutations for malignant transformation. However, the role of a primary translocation in the development of collaborating mutations is debatable. To delineate the role of leukemic translocation NUP98-HOXD13 (NHD13) in secondary mutagenesis, DNA break and repair mechanisms in stimulated mouse B lymphocytes expressing NHD13 were analyzed. Our results showed significantly reduced expression of non-homologous end joining (NHEJ)-mediated DNA repair genes, DNA Pkcs, DNA ligase4, and Xrcc4 leading to cell cycle arrest at G2/M phase. Our results showed that expression of NHD13 fusion gene resulted in impaired NHEJ-mediated DNA break repair.

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“…Cells (2 × 10 5 ) were treated with 5 M CFSE and cultured in triplicate in 96 well culture plates (BD Biosciences, San Diego, CA) with media containing E. coli lipopolysaccharide (25 g/ml) (Sigma Aldrich, St. Louis, MO) and IL-4 (25 ng/ml) (Sigma Aldrich) and incubated at 37 • C for 96 h. At the end of the incubation, the LPS + IL-4-treated cells were washed three times and labeled with fluorescently tagged anti-mouse IgG1 and IgE antibodies (e-Biosciences, San Diego, CA) (Puthiyaveetil et al, 2012). The percentage of cells undergoing class switch recombination events was assessed by flow cytometry.…”

Section: Class Switch Recombination Assaymentioning

confidence: 99%