Myeloproliferative Neoplasms

Myeloproliferative neoplasms (MPN) are the most frequent myeloid neoplasms, with an overall incidence of about 20-30 newly diagnosed patients per 100,000/year. Although major advances in the treatment of MPN have been made in recent years, most MPN are incurable chronic disorders with substantial morbidity and mortality. The only curative treatment approach that can be offered at present is hematopoietic stem cell transplantation (SCT). Unfortunately, this procedure can only be performed in a small group of patients (young and fit). In all other patients, management is largely based on symptom-control and the use of growth-inhibitory drugs. However, most drugs used thus far in MPN, including the recently developed tyrosine kinase inhibitors (TKI), have little if any curative potential. In addition, resistance to growth-inhibitory drugs is often seen in advanced MPN. So far, little is known about molecules, signaling networks, and mechanisms underlying disease evolution, progression, and resistance in various MPN. The situation is complicated by the fact that neoplastic stem cells (SC) exhibit intrinsic resistance, have multiple interactions with the SC-protective microenvironment, the so-called stem cell niche, and acquire resistance in multiple subclones during disease evolution. Finally, the genetic background as well as epigenetic mechanisms are considered to play a role in disease evolution and progression in MPN. The general aim of this research program is to address the cellular, biochemical and functional complexity in various MPN by an integrated multidisciplinary approach, to exploit network analyses and resulting concepts to define critical target profiles in neoplastic (stem) cells, and to develop targeted treatment-strategies. The specific long-term aim of the SFB is to develop novel SC-eradicating treatment approaches in Ph+ and Ph- MPN. Ph+ chronic myeloid leukemia (CML) will serve as a paradigmatic disease model in this SFB. In addition, the SFB will focus on JAK2 V617F- mutated MPN, KIT D816V-mutated systemic mastocytosis (SM) and mast cell leukemia (MCL), and FIP1L1/PDGFRA+ chronic eosinophilic leukemia (CEL). It can be expected that the SFB will substantially contribute to a better understanding of molecular and cellular mechanisms underlying the etiology, progression, and resistance of neoplastic cells in these MPN. Furthermore, data generated in this SFB should provide a solid basis for the development of improved diagnostic and therapeutic concepts in these neoplasms.