Targeting Kindlin-3-mediated integrin activation and signaling to eradicate persistent MPN clones

Full proposal of the previous application:

Myeloproliferative neoplasms (MPNs) originate from transformed hematopoietic stem cells that harbor welldefined driver mutations (e.g. BCR-ABL (BA), JAK2V617F, CALR, or MPL). These induce oncogenic signaling pathways resulting in increased leukemic stem cell (LSC) proliferation, hyperplasia of the bone marrow and peripheral blood, and splenomegaly. Disease progression and persistence is driven by clonal evolution of the leukemic cells and the establishment of a tumor promoting and protecting niche. Whereas site and composition of the malignant niche is likely dictated by the type of MPN, homing of leukemic cells from the circulation to and retention within the niche requires integrin-mediated adhesion to extracellular matrix proteins and cell surface-presented ligands. Utilizing BA expressing transgenic mice and cell lines, we have demonstrated that the integrin activating protein Kindlin-3 (K3) is regulated by BA and contributes to increased leukemic cell adhesion required for retention, proliferation, and survival of LSCs in the malignant niche.
We hypothesize that K3 expression is regulated by common MPN signaling pathways and enables the LSC-niche interaction independently of the MPN driver mutation. We aim to 1) analyze K3 expression and its regulation, 2) assess K3-mediated integrin adhesion and chemoresistance, and 3) analyze K3 requirement for disease maintenance, progression and clonal persistence in model systems of BA negative MPNs.
The here proposed project aims to establish K3 depletion as a driver mutation independent and generally applicable treatment approach to target chemotherapy resistant LSCs, the origin of persistent clones and relapses.

The suggested project is part of the DFG Forschungsgruppe Rahmenantrag Initiative "TARgetinG clonal pErsisTence and evolution of MyeloProliferative Neoplasms ". Spokesperson Florian H. Heidel; Projectpartner Steffen Koschmieder.