Colour variation and alternative reproductive strategies in females of the Common lizard Lacerta vivipara

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Pim kinases modulate resistance to tyrosine kinase inhibitors in FLT3-ITD acute myeloid leukemia

Fms-related tyrosine kinase-3 internal tandem duplication (FLT3-ITD) mutations are frequently detected in acute myeloid leukemia (AML) patients and are associated with a dismal long-term prognosis. FLT3 tyrosine kinase inhibitors (TKI) may provide efficient short-term disease control, however virtually all responding patients relapse within few months. The oncogenic Pim protein kinases are FLT3 targets expressed in AML cells but their participation in disease pathogenesis is incompletely understood. Here we show that Pim-2 overexpression is frequently found in samples from AML patients experiencing resistance to TKI therapy. Pim-2 activity is critical for tumor propagation in TKI-resistant cells and in a mouse model of FLT3-ITD-induced myeloproliferative neoplasm ectopic Pim-2 expression induces TKI resistance. Inhibition of Pim kinases enhances TKI docking on FLT3 ATPbinding pocket therefore restoring its ability to block downstream receptor signaling. Finally, combined Pim and FLT3 kinases inhibitors efficiently eradicate FLT3-mutated cell lines and primary AML samples. The implication of Pim kinases in TKI resistance open new perspectives for AML targeted therapies

Pim kinases modulate resistance to FLT3 tyrosine kinase inhibitors in FLT3-ITD acute myeloid leukemia

Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is frequently detected in acute myeloid leukemia (AML) patients and is associated with a dismal long-term prognosis. FLT3 tyrosine kinase inhibitors provide short-term disease control, but relapse invariably occurs within months. Pim protein kinases are oncogenic FLT3-ITD targets expressed in AML cells. We show that increased Pim kinase expression is found in relapse samples from AML patients treated with FLT3 inhibitors. Ectopic Pim-2 expression induces resistance to FLT3 inhibition in both FLT3-ITD-induced myeloproliferative neoplasm and AML models in mice. Strikingly, we found that Pim kinases govern FLT3-ITD signaling and that their pharmacological or genetic inhibition restores cell sensitivity to FLT3 inhibitors. Finally, dual inhibition of FLT3 and Pim kinases eradicates FLT3-ITD(+) cells including primary AML cells. Concomitant Pim and FLT3 inhibition represents a promising new avenue for AML therapy