Project Details
Projekt
Identification of niche factors and inflammatory cytokines driving clonal progression in MPN
Applicant
Professorin Dr. Christine Dierks
Subject Area
Hematology, Oncology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 517204983
Progression from MPN to AML is associated with a very poor prognosis and short survival. Analysis from MPN patients indicate that increased inflammation (CRP) and leukocytosis, which mainly consists of mature granulocytes are strongly associated with a higher risk for leukemic transformation. JAK2-V617F+ MPN granulocytes have a longer life span, are hyperactive compared to normal granulocytes and induce chronic inflammatory processes which includes secretion of excess amounts of inflammatory cytokines like IL-6, TNF-α or Hedgehog ligands (HH). In our previous work, we identified HH ligand driven constitutive Hedgehog signaling within HSCs and the stem cell niche as one major disease driver inducing leukemic progression in MPN (Dierks, 2008; Klein, 2016). While HH activation alone induced an MPN phenotype in mice (leukocytosis, blast mobilization and splenomegalie), the combination of HH activation in the niche with JAK2 V617F expression in haematopoiesis caused a transformation towards a lethal acute leukemia in all cases. In the bone marrow of MPN patients JAK2 V617F+ granulocytes produce excess amounts of HH ligands, which stimulate HH receptors on niche cells causing reorganization/destabilization of the stem cell niche, with loss of osteoblasts, alterations in niche factors like Cxcl12, Angiopoetin and SCF, and lost HSC/LSC adherence to the bone marrow (Cxcr4) (Müller, 2019; Grundler, 2009; Dierks, 2007). Remaining HSCs in this altered leukemic niche have a higher proliferation rate, accumulate secondary mutations/chromosomal aberrations and have a higher incidence of leukemic transformation. In concordance, the inhibition of HH signaling by SMO inhibitors in AML mouse models/xenografts effectively reduced disease progression, inhibited blast mobilization and blocked re-transplantability of the disease (Dierks, 2008; Klein et al., in revision). Results were confirmed in clinical trials, and the SMO-inhibitor Glasdegib is approved for the treatment of AML in elderly patients. Major questions arise from our previous findings in MPN and shall be answered within Target-MPN: a) Can SMO or HH ligand inhibitors block the transformation process from MPN to AML and should be used as a preventive therapy in MPN patients. b) Can SMO/HH ligand inhibitors reverse niche changes caused by JAK2- or CALR- mutations. c) Can blocking/ reducing the inflammatory granulocytic pool inhibit MPN transformation, and reverse niche changes? d) Which ligand/receptor pairs mediate the interaction of granulocytes with HSCs/LSCs and different niche cells in the MPN bone marrow and might be alternative targets to block the transformation process. Taken together, we aim to understand and block granulocyte driven inflammatory processes in MPN patients to prevent the transformation of chronic myeloproliferative neoplasms into aggressive leukemias.
DFG Programme
Research Units
