Adaptive responses to mTOR targeting sustain hematopoietic and leukemia stem cell proliferation II

mTOR is an important anti-cancer target that integrates diverse signals to control protein synthesis and cell growth. Numerous studies by using mTOR inhibitors and/or gene deletion of mTOR negative regulators have implicated mTOR targeting in suppressing gene expression and cell proliferation. However, we found that gene targeting of mTOR in mouse hematopoietic stem cells (HSCs) results in a loss of quiescence and increased proliferation. Adaptive to mTOR loss, mTOR-/- HSCs increase chromatin access and activate global gene expression, in contrast to short-term inhibition by mTOR inhibitors. Such genomic changes are due to a compensatory activation of a MAPK/Mnk/eIF4E signaling pathway that enhances the translation of RNA pol-II and consequent c-myc expression. This adaptive mechanism can also be adopted by leukemia stem cells undergone long-term mTOR inhibitor treatment to confer resistant to mTOR targeting. Our studies provide new insights and a foregone strategy for overcoming drug resistance in mTOR targeted therapy.