Loss of MLH1 expression promotes the acquisition of oncogenic JAK1 and JAK3 mutations that cooperatively increase resistance to JAK inhibitors
(2015)
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- Authors
- Supervisors
- Renauld, Jean-Christophe
- Abstract
- Malignant transformation evolves as the outcome of 2 connected processes operating within a population of competing cells: on the one hand, the continuous accumulation of random mutations by individual cells at a rate dictated by the degree of genetic instability and, on the other hand, the simultaneous natural selection acting on the resultant phenotypes. Successive rounds of environmental pressures lead to the emergence of cells that acquired diverse advantageous hallmarks such as growth factor-independent proliferation, mostly driven by constitutively activated signaling cascades to which neoplastic cells develop an addiction that can be therapeutically exploited. For instance, the JAK-STAT pathway is frequently hyperactivated in T-ALL and the use of JAK inhibitors in lymphoid malignancies is currently under pre-clinical investigations. In the present thesis, we took advantage of the TS1 cell line recapitulating in vitro JAK-STAT pathway-driven T-cell transformation in order to unravel the underlying genetic events and evaluate the efficacy of JAK inhibitors. In our first study, we found that growth factor-independent TS1 clones acquired an activating point mutation in JAK1 and/or JAK3, which function as partners in the signal transduction downstream of γc-sharing cytokine receptors. Furthermore, TS1 cells transformed by an activated mutant of JAK1 became resistant to JAK inhibitors by acquiring a secondary mutation in JAK3 and vice versa. We demonstrated that the presence of two inhibitor-sensitive JAK1 and JAK3 mutants cooperatively activate STAT3 and STAT5 factors thereby increasing the resistance to JAK inhibitors. In our second study, we focused on the molecular mechanism underlying the high rate of spontaneous mutagenesis in TS1 cells. We demonstrated that loss of MLH1 expression, a key component of the mismatch repair system, promotes the occurrence of oncogenic point mutations in JAK kinases driving transformation and acquired resistance to inhibitors. We confirmed the clinical relevance of our findings by showing that chronic myeloid leukemia cells from patients that relapsed upon ABL-targeted therapy have a lower expression of MLH1 messenger RNA than leukemic cells from patients at diagnosis. Moreover we identified a particular mutational signature present in our TS1 cell model and corresponding to the one described in primitive CD32+ cells from chronic myeloid leukaemia patients that might attest MLH1-deficiency. Taken together, our findings suggest that MLH1 status should be considered in order to predict response to targeted therapies.
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Citations
Springuel, L. (2015). Loss of MLH1 expression promotes the acquisition of oncogenic JAK1 and JAK3 mutations that cooperatively increase resistance to JAK inhibitors. https://hdl.handle.net/2078.5/189235