KFO 344:  Untangling and Targeting Mechanisms of Myelofibrosis in Myeloproliferative Neoplasms (MPN)

• Subject Area: Medicine
• Term: since 2019
• Website: Homepage
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 417911533

The overall aim of the Clinical Research Unit 344 is to better understand the biology of Myeloproliferative Neoplasms (MPN), with a special focus on myelofibrosis (MF), and to identify new treatment options for patients with MPN-associated MF. In the first funding period, we succeeded to 1) dissect the stromal cell compartment in MPN at the single cell level, 2) reveal inflammatory cytokine secretion specific to disease progression, 3) understand the role of aging in the disease course, and 4) develop novel disease models. These findings now allow an intensified translational focus of our aims for the second funding period. The phase Ib/II TasquForce MPN clinical trial, which will assess the efficacy and tolerability of the small molecule inhibitor tasquinimod, targeting the alarmin heterodimer S100A8/A9, in patients with MF, will start recruiting in late summer of 2022. Our goal is to use this success model from our first funding period as a template for the second funding period – to directly move our findings to application in patients. We will leverage here the data warehouse installed by the service project (SP) as a central resource to validate our findings from pre-clinical models in primary human material accompanied by clinical data annotation. Through the work outlined in the present proposal, we will better understand key drivers of and roadblocks to early expansion of the MPN clone (P5, P6, SP) and which of these are amenable to preventive strategies of progression towards overt myelofibrosis, such as early administration of interferon or demethylating agents, and nanomedicines and receptor fusion proteins against pro-inflammatory cytokines (P2, P4, P5, P6, SP). Moreover, we will generate and evaluate spatio-temporal and epigenetic information of BM fibrosis to identify novel therapeutic targets and optimize and prognosticate the success of allogeneic stem cell transplantation (P1, P2, P3, P4, SP). Together, these projects will allow us to design better means of early diagnosis and prevention of MPN progression in patients with early-stage MPN and better treatment options for patients with later-stage MPN, particularly overt MF.

• DFG Programme: Clinical Research Units
• International Connection: Netherlands

Projects

• Coordination Funds (Applicant Koschmieder, Steffen )
• Dissecting the spatio-temporal dynamics of bone marrow fibrosis in MPN in response to therapy (Applicants Crysandt, Martina ;  Schneider-Kramann, Rebekka )
• Impact of Disease Burden and Timing of Disease Initiation on the Response to Interferonalpha (IFNa) in MPN-associated myelofibrosis (Applicants Hornef, Mathias Walter ;  Koschmieder, Steffen )
• Integrative platform for clinical and genomic data in Myeloproliferative Neoplasms (MPN) (Applicants Brümmendorf, Tim Henrik ;  Gesteira Costa Filho, Ivan )
• Molecular targeting of STAT3-activating cytokines in the MPN pre-fibrotic niche (Applicants Müller-Newen, Gerhard ;  Schemionek-Reinders, Mirle )
• Spatial transcriptome mapping to identify druggable targets in the early-intermediate progression of bone marrow fibrosis (Applicants Hayat, Sikander ;  Kramann, Rafael )
• Targeting aberrant DNA methylation in myeloproliferative neoplasms (Applicants Gleitz, Ph.D., Helene ;  Wagner, Wolfgang )
• Targeting the bone marrow inflammatory niche in myelofibrosis with nanomedicine therapeutics (Applicants Chatain, Ph.D., Nicolas ;  Sofias, Alexandros Marios )

• Spokesperson: Professor Dr. Tim Henrik Brümmendorf
• Project Heads: Nicolas Chatain, Ph.D.; Dr. Martina Crysandt; Professor Dr. Ivan Gesteira Costa Filho; Helene Gleitz, Ph.D.; Dr. Sikander Hayat; Professor Dr. Rafael Kramann; Professor Dr. Gerhard Müller-Newen; Privatdozentin Dr. Mirle Schemionek-Reinders; Professorin Dr. Rebekka Schneider-Kramann; Dr. Alexandros Marios Sofias; Natalia Torow, Ph.D.; Professor Dr. Wolfgang Wagner
• Leader: Professor Dr. Steffen Koschmieder