Ptch2 loss drives myeloproliferation and myeloproliferative neoplasm progression

Claudius Klein, Anabel Zwick, Sandra Kissel, Christine Ulrike Forster, Dietmar Pfeifer, Marie Follo, Anna Lena Illert, Sarah Decker, Thomas Benkler, Heike Pahl, Robert A.J. Oostendorp, Konrad Aumann (+2 others)
2016 Journal of Cell Biology  
MPNs are characterized by a long indolent chronic period of disease with increased erythrocytes (polycythemia vera), increased thrombocytes (essential thrombocytosis) or cytopenias (osteomyelofibrosis), and splenomegaly, which frequently progress into a rapidly lethal leukemia. The mechanisms driving the disease acceleration finally leading to leukemic transformation are currently not understood. The hedgehog (HH) signaling pathway is involved in various aspects of embryonic development and in
more » ... development and in regeneration processes during adulthood. Canonical HH pathway activation occurs via binding of HH ligands to the PAT CHED (PTCH) receptors PTCH1/2, which results in release of the inhibited SMO OTHEN ED (SMO) receptor, followed by activation of the intracellular HH signaling complex (including SUFU) and consecutive activation of the GLI transcription factors GLI1-3. In addition, HH ligand binding to the PTCH1 receptor drives the following two SMOindependent pathways: (1) ERK phosphorylation directly mediated by the C-terminal intracellular PTCH1-signaling domain, which binds to SH3-encoding domains of proteins such as GRB2 or p85β (Chang et al., 2010) and (2) retention of activated CYC LINB1 within the cytoplasm as a result of binding to the sterol sensing domain of the PTCH receptors and therefore control of the cell cycle specifically at mitosis (Barnes et al., 2001) . The exclusive activation of the SMO-dependent canonical HH signaling pathway by point mutations in PTCH1 (inactivating), SMO (activating), or SUFU (inactivating) drives cancer development of some specific tumor entities, such as medulloblastomas (Goodrich and Scott, 1998), rhabdomyosarcomas, and basal cell carcinomas (Gorlin, 1987) . However, the majority of solid cancers (Thayer et al., 2003; Watkins et al., 2003; Datta and Datta, 2006) and especially hematologic malignancies, are driven by excess ligand secretion and therefore activate both the classical SMO-mediated canonical HH signaling and PTCH1-dependent noncanonical HH signaling, thereby stimulating ERK phosphorylation. In this situation, HH ligands not only act on the malignant cells but also stimulate the surrounding tumor-promoting stromal cells or niche cells, propagating part of their effects (Dierks et al., 2007; Chan et al., 2012; Lunardi et al., 2014) . In chronic lym-JAK2V617F + myeloproliferative neoplasms (MPNs) frequently progress into leukemias, but the factors driving this process are not understood. Here, we find excess Hedgehog (HH) ligand secretion and loss of PTCH2 in myeloproliferative disease, which drives canonical and noncanonical HH-signaling. Interestingly, Ptch2 −/− mice mimic dual pathway activation and develop a MPN-phenotype with leukocytosis (neutrophils and monocytes), strong progenitor and LKS mobilization, splenomegaly, anemia, and loss of lymphoid lineages. HSCs exhibit increased cell cycling with improved stress hematopoiesis after 5-FU treatment, and this results in HSC exhaustion over time. Cytopenias, LKS loss, and mobilization are all caused by loss of Ptch2 in the niche, whereas hematopoietic loss of Ptch2 drives leukocytosis and promotes LKS maintenance and replating capacity in vitro. Ptch2 −/− niche cells show hyperactive noncanonical HH signaling, resulting in reduced production of essential HSC regulators (Scf, Cxcl12, and Jag1) and depletion of osteoblasts. Interestingly, Ptch2 loss in either the niche or in hematopoietic cells dramatically accelerated human JAK2V617F-driven pathogenesis, causing transformation of nonlethal chronic MPNs into aggressive lethal leukemias with >30% blasts in the peripheral blood. Our findings suggest HH ligand inhibitors as possible drug candidates that act on hematopoiesis and the niche to prevent transformation of MPNs into leukemias.
doi:10.1083/jcb.2123oia11 fatcat:prh3uf2ry5dd5llkjsiutnmpdq