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Loss of mutL homolog-1 (MLH1) expression promotes acquisition of oncogenic and inhibitor-resistant point mutations in tyrosine kinases

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Abstract

Genomic instability drives cancer progression by promoting genetic abnormalities that allow for the multi-step clonal selection of cells with growth advantages. We previously reported that the IL-9-dependent TS1 cell line sequentially acquired activating substitutions in JAK1 and JAK3 upon successive selections for growth factor independent and JAK inhibitor-resistant cells, suggestive of a defect in mutation avoidance mechanisms. In the first part of this paper, we discovered that the gene encoding mutL homolog-1 (MLH1), a key component of the DNA mismatch repair system, is silenced by promoter methylation in TS1 cells. By means of stable ectopic expression and RNA interference methods, we showed that the high frequencies of growth factor-independent and inhibitor-resistant cells with activating JAK mutations can be attributed to the absence of MLH1 expression. In the second part of this paper, we confirm the clinical relevance of our findings by showing that chronic myeloid leukemia relapses upon ABL-targeted therapy correlated with a lower expression of MLH1 messenger RNA. Interestingly, the mutational profile observed in our TS1 model, characterized by a strong predominance of T:A>C:G transitions, was identical to the one described in the literature for primitive cells derived from chronic myeloid leukemia patients. Taken together, our observations demonstrate for the first time a causal relationship between MLH1-deficiency and incidence of oncogenic point mutations in tyrosine kinases driving cell transformation and acquired resistance to kinase-targeted cancer therapies.

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Acknowledgments

This work was supported in part by the Belgian Program on Interuniversity Poles of Attraction initiated by the Belgian State, Prime Minister’s Office, Science Policy Programming (Grant IAP-P7/39 to J.C.R.), by the Actions de Recherche Concertées of the Communauté Française de Belgique (Grant ARC09/14-021 to J.C.R.), by the Fondation contre le Cancer, by the Foundation Salus Sanguinis, Belgium, and by the Fonds pour la formation à la Recherche dans l’Industrie et dans l’Agriculture (F.R.I.A). E.L. is the recipient of a fellowship from FRS-FNRS Télévie. L.K. is a MD fellow of the Fonds National de la Recherche Scientifique (F.N.R.S.), Belgium.

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Authors and Affiliations

  1. Ludwig Institute for Cancer Research, Brussels Branch, Avenue Hippocrate 74, 1200, Brussels, Belgium

    Lorraine Springuel, Elisabeth Losdyck, Laurent Knoops & Jean-Christophe Renauld

  2. de Duve Institute, Université Catholique de Louvain, Brussels, Belgium

    Lorraine Springuel, Elisabeth Losdyck, Laurent Knoops & Jean-Christophe Renauld

  3. Hematology Unit, Cliniques Universitaires Saint-Luc, Brussels, Belgium

    Pascale Saussoy & Laurent Knoops

  4. Leukemic Hematopoiesis and Therapeutic Targets Laboratory, University of Bordeaux, Bordeaux, France

    Béatrice Turcq & François-Xavier Mahon

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  1. Lorraine Springuel
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Correspondence to Laurent Knoops or Jean-Christophe Renauld.

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L. Knoops and J.-C. Renauld shared senior co-authorship.

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Springuel, L., Losdyck, E., Saussoy, P. et al. Loss of mutL homolog-1 (MLH1) expression promotes acquisition of oncogenic and inhibitor-resistant point mutations in tyrosine kinases. Cell. Mol. Life Sci. 73, 4739–4748 (2016). https://doi.org/10.1007/s00018-016-2310-2

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