BCR/ABL Inhibits Mismatch Repair to Protect from Apoptosis and Induce Point Mutations

Stokłosa, Tomasz; Popławski, Tomasz; Koptyra, Mateusz; Nieborowska‐Skorska, Margaret; Basak, Grzegorz; Słupianek, Artur; Rayevskaya, Marina; Seferyńska, Ilona; Herrera, Larry; Błasiak, Janusz; Skórski, Tomasz

doi:10.1158/0008-5472.can-07-6858

Cited by 94 publications

(61 citation statements)

References 23 publications

(24 reference statements)

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“…[38][39][40] There is also solid evidence for a direct link among BCR-ABL expression, genetic instability, and IM resistance. [41][42][43][44] Using an immortalized BCR-ABL-dependent cell line model resembling blast crisis cells, we also provided such evidence by showing that BCR-ABL overexpression catalyzes mutagenesis and IM resistance development to an even greater extent than chemical mutagenesis by ENU ( Figure 5B).…”

Section: Discussionmentioning

confidence: 74%

Low BCR-ABL expression levels in hematopoietic precursor cells enable persistence of chronic myeloid leukemia under imatinib

Kumari

Brendel

Hochhaus

et al. 2012

Blood

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Section: Discussionmentioning

confidence: 74%

Low BCR-ABL expression levels in hematopoietic precursor cells enable persistence of chronic myeloid leukemia under imatinib

Kumari

Brendel

Hochhaus

et al. 2012

Blood

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“…[47][48][49][50][51] It has been recently shown that expression of the fusion tyrosine kinase BCR/ABL reduced the MMR response to single base mismatches and DNA damage-induced signaling. 52 Nevertheless, how these oncogenic tyrosine kinases impair MMR function is largely unknown.…”

Section: Discussionmentioning

confidence: 99%

“…56 In this regard, it is known that MSI results are dependent on the markers chosen for analysis, the threshold chosen for instability, and the sensitivity of the assay used. 34 Although other oncogenic tyrosine kinases, such as BCR/ABL, have been reported to suppress MMR, 52 the mechanisms have not been previously studied. We believe that our study has shed light on the possible mechanisms by which oncogenic tyrosine kinases deregulate MMR.…”

Section: Discussionmentioning

confidence: 99%

Fusion Tyrosine Kinase NPM-ALK Deregulates MSH2 and Suppresses DNA Mismatch Repair Function

Young

Bone

Wang

et al. 2011

The American Journal of Pathology

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The fusion tyrosine kinase NPM-ALK is central to the pathogenesis of ALK-positive anaplastic large cell lymphoma (ALK ؉ ALCL). We recently identified that MSH2, a key DNA mismatch repair (MMR) protein integral to the suppression of tumorigenesis, is an NPM-ALK-interacting protein. In this study, we found in vitro evidence that enforced expression of NPM-ALK in HEK293 cells suppressed MMR function. Correlating with these findings, six of nine ALK ؉ ALCL tumors displayed evidence of microsatellite instability, as opposed to none of the eight normal DNA control samples (P ‫؍‬ 0.007, Student's t-test). Using co-immunoprecipitation, we found that increasing levels of NPM-ALK expression in HEK293 cells resulted in decreased levels of MSH6 bound to MSH2, whereas MSH2·NPM-ALK binding was increased. The NPM-ALK·MSH2 interaction was dependent on the activation/autophosphorylation of NPM-ALK, and the Y191 residue of NPM-ALK was a crucial site for this interaction and NPM-ALK-mediated MMR suppression. MSH2 was found to be tyrosine phosphorylated in the presence of NPM-ALK. Finally, NPM-ALK impeded the expected DNA damage-induced translocation of MSH2 out of the cytoplasm. To conclude, our data support a model in which the suppression of MMR by NPM-ALK is attributed to its ability to interfere with normal MSH2 biochemistry and function.

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“…In vitro studies have suggested that the amino acid changes in the BCR-ABL protein might be promoted by the self-mutagenic activity of BCR-ABL itself. 9,10 Leukemic clones containing mutations are subsequently selected by continuous BCR-ABL inhibitor treatment and multiply to high levels within a patient. In addition to the kinase domain, resistance-associated mutations may be seen very occasionally in the regulatory SH2-SH3 domain of BCR-ABL.…”

Section: Significance Of Bcr-abl Mutations In Imatinib Resistancementioning

confidence: 99%

Impact ofBCR-ABLmutations on patients with chronic myeloid leukemia

Hochhaus¹,

Rosée²,

Müller³

et al. 2011

Cell Cycle

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BCR/ABL Inhibits Mismatch Repair to Protect from Apoptosis and Induce Point Mutations

Abstract: BCR/ABL kinase-positive chronic myelogenous leukemia

Cited by 94 publications

References 23 publications

Low BCR-ABL expression levels in hematopoietic precursor cells enable persistence of chronic myeloid leukemia under imatinib

Low BCR-ABL expression levels in hematopoietic precursor cells enable persistence of chronic myeloid leukemia under imatinib

Fusion Tyrosine Kinase NPM-ALK Deregulates MSH2 and Suppresses DNA Mismatch Repair Function

Impact ofBCR-ABLmutations on patients with chronic myeloid leukemia

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