Dissecting the interaction of the PIM1/CXCR4 axis and Hedgehog signaling within the nichedeterming HSC mobilization and leukemic transformation

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The CXCR4/CXCL12 axis and the Hedgehog (HH) signaling pathway are components determining the interaction of the hematopoietic stem cells with the stem cell niche, and are essentially controlling HSC retention and stem cell maintenance. In the first part of our previous work, we could show that PIM1 inhibition strongly increases and prolongs CXCR4-inhibitor induced HSC mobilization from the BM, due to effects on the niche (reduced CXCL12 levels) and on HSCs (downregulation of the CXCR4 receptor). Interestingly, HH ligands also directly affect the CXCR4 axis by controlling CXCR4 protein stability and CXCL12 secretion. In the second project part, we found that in myeloproliferative diseases, excess production of HH ligands and/or frequent loss of Ptch2 drive hyperactivation of canonical- and non-canonical HH signaling, resulting in Gli1 transcription and Erk activation. Accordingly, deletion of Ptch2 in mice induces a myeloproliferative phenotype, partially driven by the overactivation of HH signaling within hematopoiesis, but also due to alterations within the niche, including reduced CXCL12 secretion by CAR cells, which causes HSC mobilization. Hyperactivation of HH signaling in a JAK2V617F+MPN mouse model resulted in transformation of a non-lethal myeloproliferative disease into a lethal leukemia, implicating Hedgehog signaling as a potential driver of leukemic transformation in human MPNs. In future experiments, we aim to validate canonical- (Smo) or non-canonical (Erk) HH inhibitors targeting hematopoiesis and the niche to block the leukemic transformation of myeloproliferative diseases. Furthermore, we aim to understand, if the effect of SMO inhibitors in AML is caused by effects on the niche (MSPCs) or on LSCs. In addition, we aim to characterize the physiological role of DHH (endothelial cells) and PIM1 (CAR cells) on the composition of the niche, on the localization of HSCs, the entry of HSCs into the blood stream, as well as the influence of secreted HH ligands on the CXCR4/CXCL12 axis in niche cells as well as hematopoietic cells. The experiments will allow us to understand the influence of the Hedgehog/CXCR4 signaling pathways on the composition of the niche, and their influence on leukemic transformation.