title: Loss of mutL homolog-1 (MLH1) expression promotes acquisition of oncogenic and inhibitor-resistant point mutations in tyrosine kinases.
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.
authors.affiliation: Ludwig Institute for Cancer Research, Brussels Branch, Avenue Hippocrate 74, 1200, Brussels, Belgium.|de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Springuel
authors.affiliation: Ludwig Institute for Cancer Research, Brussels Branch, Avenue Hippocrate 74, 1200, Brussels, Belgium.|de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Losdyck
authors.affiliation: Hematology Unit, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
authors.forename: Pascale
authors.initials: P
authors.lastname: Saussoy
authors.affiliation: Leukemic Hematopoiesis and Therapeutic Targets Laboratory, University of Bordeaux, Bordeaux, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Turcq
authors.affiliation: Leukemic Hematopoiesis and Therapeutic Targets Laboratory, University of Bordeaux, Bordeaux, France.
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Mahon
authors.affiliation: Ludwig Institute for Cancer Research, Brussels Branch, Avenue Hippocrate 74, 1200, Brussels, Belgium. laurent.knoops@uclouvain.be.|de Duve Institute, Université Catholique de Louvain, Brussels, Belgium. laurent.knoops@uclouvain.be.|Hematology Unit, Cliniques Universitaires Saint-Luc, Brussels, Belgium. laurent.knoops@uclouvain.be.
authors.forename: Laurent
authors.initials: L
authors.lastname: Knoops
authors.affiliation: Ludwig Institute for Cancer Research, Brussels Branch, Avenue Hippocrate 74, 1200, Brussels, Belgium. jean-christophe.renauld@bru.licr.org.|de Duve Institute, Université Catholique de Louvain, Brussels, Belgium. jean-christophe.renauld@bru.licr.org.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Renauld
mesh_terms: D000818:Animals; D002460:Cell Line; D002999:Clone Cells; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D053612:Janus Kinases / Q000235:genetics*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis / Q000235:genetics; D051379:Mice; D000070957:MutL Protein Homolog 1 / Q000235:genetics / Q000378:metabolism*; D009857:Oncogenes; D017354:Point Mutation / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D053612:Janus Kinases; D000070957:MutL Protein Homolog 1
keywords: DNA mismatch repair; Drug resistance; Janus kinase (JAK); MLH1; Oncogenic mutations; Tyrosine kinase inhibitor