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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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Springuel, Lorraine [UCL] Losdyck, Elisabeth [UCL] Saussoy, Pascale [UCL] Turcq, Béatrice Mahon, François-Xavier Knoops, Laurent [UCL] Renauld, Jean-Christophe [UCL]

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.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès libre
Publication date 2016
Language Anglais
Journal information "Cellular and Molecular Life Sciences" - Vol. 73, no. 24, p. 4739-4748 (2016)
Peer reviewed yes
Publisher Birkhaeuser Verlag AG ((Switzerland) Basel)
issn 1420-682X
e-issn 1420-9071
Publication status Publié
Affiliations UCL - SSS/DDUV/GECE - Génétique cellulaire
UCL - SSS/DDUV/MEXP - Médecine expérimentale
UCL - SSS/IREC/SLUC - Pôle St.-Luc
UCL - (SLuc) Service de biologie hématologique
UCL - (SLuc) Service d'hématologie
Links
  1. Stratton Michael R., Campbell Peter J., Futreal P. Andrew, The cancer genome, 10.1038/nature07943
  2. Loeb LA (2001) A mutator phenotype in cancer. Cancer Res 61(8):3230–3239
  3. Fox Edward J., Prindle Marc J., Loeb Lawrence A., Do mutator mutations fuel tumorigenesis?, 10.1007/s10555-013-9426-8
  4. Roche-Lestienne C., Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment, 10.1182/blood.v100.3.1014
  5. Bodmer W., Loeb L. A., Genetic Instability Is Not a Requirement for Tumor Development, 10.1158/0008-5472.can-07-6544
  6. Jiricny Josef, The multifaceted mismatch-repair system, 10.1038/nrm1907
  7. Glaab W., Mutation rate at the hprt locus in human cancer cell lines with specific mismatch repair-gene defects, 10.1093/carcin/18.1.1
  8. Spampinato Claudia P., Gomez Rodrigo L., Galles Celina, Lario Luciana D., From bacteria to plants: A compendium of mismatch repair assays, 10.1016/j.mrrev.2009.07.001
  9. Lynch Henry T., Snyder Carrie L., Shaw Trudy G., Heinen Christopher D., Hitchins Megan P., Milestones of Lynch syndrome: 1895–2015, 10.1038/nrc3878
  10. O'Brien Vincent, Brown Robert, Signalling cell cycle arrest and cell death through the MMR System, 10.1093/carcin/bgi298
  11. Glaab W., Resistance to 6-thioguanine in mismatch repair-deficient human cancer cell lines correlates with an increase in induced mutations at the HPRT locus, 10.1093/carcin/19.11.1931
  12. Ionov Yurij, Peinado Miguel A., Malkhosyan Sergei, Shibata Darryl, Perucho Manuel, Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis, 10.1038/363558a0
  13. Herman J. G., Umar A., Polyak K., Graff J. R., Ahuja N., Issa J.-P. J., Markowitz S., Willson J. K. V., Hamilton S. R., Kinzler K. W., Kane M. F., Kolodner R. D., Vogelstein B., Kunkel T. A., Baylin S. B., Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma, 10.1073/pnas.95.12.6870
  14. Simpkins S. B., Bocker T., Swisher E. M., Mutch D. G., Gersell D. J., Kovatich A. J., Palazzo J. P., Fishel R., Goodfellow P. J., MLH1 Promoter Methylation and Gene Silencing is the Primary Cause of Microsatellite Instability in Sporadic Endometrial Cancers, 10.1093/hmg/8.4.661
  15. Hartmann A, Zanardo L, Bocker-Edmonston T et al (2002) Frequent microsatellite instability in sporadic tumors of the upper urinary tract. Cancer Res 62(23):6796–6802
  16. Gu Liya, Cline-Brown Brandee, Zhang Fujian, Qiu Lu, Li Guo-Min, Mismatch repair deficiency in hematological malignancies with microsatellite instability, 10.1038/sj.onc.1205695
  17. Ping Siu Lisa Lai, Cheung Chan John Kwok, Wong Kit-Fai, Kwong Yok-Lam, Specific Patterns of Gene Methylation in Natural Killer Cell Lymphomas, 10.1016/s0002-9440(10)64349-0
  18. Matheson E. C., Assessment of mismatch repair function in leukaemic cell lines and blasts from children with acute lymphoblastic leukaemia, 10.1093/carcin/24.1.31
  19. Mao Guogen, Yuan Fenghua, Absher Kimberly, Jennings C Darrell, Howard Dianna S, Jordan Craig T, Gu Liya, Preferential loss of mismatch repair function in refractory and relapsed acute myeloid leukemia: potential contribution to AML progression, 10.1038/cr.2008.14
  20. Griffiths Elizabeth A., Gore Steven D., Hooker Craig M., Mohammad Helai P., McDevitt Michael A., Smith B. Douglas, Karp Judith E., Herman James G., Carraway Hetty E., Epigenetic differences in cytogenetically normal versus abnormal acute myeloid leukemia, 10.4161/epi.5.7.12558
  21. Hangaishi A, Ogawa S, Mitani K et al (1997) Mutations and loss of expression of a mismatch repair gene, hMLH1, in leukemia and lymphoma cell lines. Blood 89(5):1740–1747
  22. Morimoto Hiroaki, Tsukada Junichi, Kominato Yoshihiko, Tanaka Yoshiya, Reduced expression of human mismatch repair genes in adult T-cell leukemia, 10.1002/ajh.20259
  23. Springuel L., Hornakova T., Losdyck E., Lambert F., Leroy E., Constantinescu S. N., Flex E., Tartaglia M., Knoops L., Renauld J.-C., Cooperating JAK1 and JAK3 mutants increase resistance to JAK inhibitors, 10.1182/blood-2014-05-576652
  24. De Smet Charles, Lurquin Christophe, Lethé Bernard, Martelange Valérie, Boon Thierry, DNA Methylation Is the Primary Silencing Mechanism for a Set of Germ Line- and Tumor-Specific Genes with a CpG-Rich Promoter, 10.1128/mcb.19.11.7327
  25. Uyttenhove C., Simpson R. J., Van Snick J., Functional and structural characterization of P40, a mouse glycoprotein with T-cell growth factor activity., 10.1073/pnas.85.18.6934
  26. Louahed J, Kermouni A, Van Snick J et al (1995) IL-9 induces expression of granzymes and high-affinity IgE receptor in murine T helper clones. J Immunol 154(10):5061–5070
  27. Bergmann Anke K., Schneppenheim Sina, Seifert Marc, Betts Matthew J., Haake Andrea, Lopez Cristina, Maria Murga Penas Eva, Vater Inga, Jayne Sandrine, Dyer Martin J.S., Schrappe Martin, Dührsen Ulrich, Ammerpohl Ole, Russell Robert B., Küppers Ralf, Dürig Jan, Siebert Reiner, Recurrent mutation ofJAK3in T-cell prolymphocytic leukemia : RECURRENT JAK3 MUTATION IN T-PLL, 10.1002/gcc.22141
  28. Kiel M. J., Velusamy T., Rolland D., Sahasrabuddhe A. A., Chung F., Bailey N. G., Schrader A., Li B., Li J. Z., Ozel A. B., Betz B. L., Miranda R. N., Medeiros L. J., Zhao L., Herling M., Lim M. S., Elenitoba-Johnson K. S. J., Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia, 10.1182/blood-2014-03-559542
  29. Lynch M., Rate, molecular spectrum, and consequences of human mutation, 10.1073/pnas.0912629107
  30. Lee H., Popodi E., Tang H., Foster P. L., Rate and molecular spectrum of spontaneous mutations in the bacterium Escherichia coli as determined by whole-genome sequencing, 10.1073/pnas.1210309109
  31. Long Hongan, Sung Way, Miller Samuel F., Ackerman Matthew S., Doak Thomas G., Lynch Michael, Mutation Rate, Spectrum, Topology, and Context-Dependency in the DNA Mismatch Repair-Deficient Pseudomonas fluorescens ATCC948, 10.1093/gbe/evu284
  32. Jiang X., Saw K. M., Eaves A., Eaves C., Instability of BCR-ABL Gene in Primary and Cultured Chronic Myeloid Leukemia Stem Cells, 10.1093/jnci/djk150
  33. Grant H, Jiang X, Stebbing J, Foroni L, Craddock C, Griffiths M, Clark R E, O'Brien S, Khorashad J S, Gerrard G, Wang L, Irving J A E, Wang M, Karran L, Dyer M J S, Forrest D, Page K, Eaves C J, Woolfson A, Analysis of BCR–ABL1 tyrosine kinase domain mutational spectra in primitive chronic myeloid leukemia cells suggests a unique mutator phenotype, 10.1038/leu.2010.179
  34. Iqbal Zafar, Aleem Aamer, Iqbal Mudassar, Naqvi Mubashar Iqbal, Gill Ammara, Taj Abid Sohail, Qayyum Abdul, ur-Rehman Najeeb, Khalid Ahmad Mukhtar, Shah Ijaz Hussain, Khalid Muhammad, Haq Riazul, Khan Mahwish, Baig Shahid Mahmood, Jamil Abid, Abbas Muhammad Naeem, Absar Muhammad, Mahmood Amer, Rasool Mahmood, Akhtar Tanveer, Sensitive Detection of Pre-Existing BCR-ABL Kinase Domain Mutations in CD34+ Cells of Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia Patients Is Associated with Imatinib Resistance: Implications in the Post-Imatinib Era, 10.1371/journal.pone.0055717
  35. Bolton-Gillespie E., Schemionek M., Klein H.-U., Flis S., Hoser G., Lange T., Nieborowska-Skorska M., Maier J., Kerstiens L., Koptyra M., Muller M. C., Modi H., Stoklosa T., Seferynska I., Bhatia R., Holyoake T. L., Koschmieder S., Skorski T., Genomic instability may originate from imatinib-refractory chronic myeloid leukemia stem cells, 10.1182/blood-2012-11-466938
  36. Perrotti Danilo, Jamieson Catriona, Goldman John, Skorski Tomasz, Chronic myeloid leukemia: mechanisms of blastic transformation, 10.1172/jci41246
  37. Burke B A, Carroll M, BCR–ABL: a multi-faceted promoter of DNA mutation in chronic myelogeneous leukemia, 10.1038/leu.2010.67
  38. Kim J. H., Activation of the PI3K/mTOR pathway by BCR-ABL contributes to increased production of reactive oxygen species, 10.1182/blood-2004-03-0849
  39. Koptyra M., BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance, 10.1182/blood-2005-07-2815
  40. Sattler Martin, Verma Shalini, Shrikhande Gautam, Byrne Christopher H., Pride Yuri B., Winkler Thomas, Greenfield Edward A., Salgia Ravi, Griffin James D., The BCR/ABL Tyrosine Kinase Induces Production of Reactive Oxygen Species in Hematopoietic Cells, 10.1074/jbc.m002094200
  41. Stoklosa T., Poplawski T., Koptyra M., Nieborowska-Skorska M., Basak G., Slupianek A., Rayevskaya M., Seferynska I., Herrera L., Blasiak J., Skorski T., BCR/ABL Inhibits Mismatch Repair to Protect from Apoptosis and Induce Point Mutations, 10.1158/0008-5472.can-07-6858
  42. Cortes J., Jabbour E., Kantarjian H., Yin C. C., Shan J., O'Brien S., Garcia-Manero G., Giles F., Breeden M., Reeves N., Wierda W. G., Jones D., Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors, 10.1182/blood-2007-03-080838
  43. Shah Neil P., Skaggs Brian J., Branford Susan, Hughes Timothy P., Nicoll John M., Paquette Ronald L., Sawyers Charles L., Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency, 10.1172/jci30890
  44. Soverini S., Gnani A., Colarossi S., Castagnetti F., Abruzzese E., Paolini S., Merante S., Orlandi E., de Matteis S., Gozzini A., Iacobucci I., Palandri F., Gugliotta G., Papayannidis C., Poerio A., Amabile M., Cilloni D., Rosti G., Baccarani M., Martinelli G., Philadelphia-positive patients who already harbor imatinib-resistant Bcr-Abl kinase domain mutations have a higher likelihood of developing additional mutations associated with resistance to second- or third-line tyrosine kinase inhibitors, 10.1182/blood-2009-01-197186
Bibliographic reference Springuel, Lorraine ; Losdyck, Elisabeth ; Saussoy, Pascale ; Turcq, Béatrice ; Mahon, François-Xavier ; et. al. Loss of mutL homolog-1 (MLH1) expression promotes acquisition of oncogenic and inhibitor-resistant point mutations in tyrosine kinases.. In: Cellular and Molecular Life Sciences, Vol. 73, no. 24, p. 4739-4748 (2016)
Permanent URL http://hdl.handle.net/2078.1/184342