Janus Kinase 2 and Transforming Growth Factor Beta Signal Transduction Targeted Therapies in BCR/ABL-Negative Myeloproliferative Neoplasms

The classic BCR/ABL-negative myeloproliferative neoplasms (MPNs), including polycythaemia vera (PV), essential thrombocythaemia (ЕТ) and primary myelofibrosis (PMF), originate from a stem cell-derived clonal myeloproliferation represented with variable hematopoietic cell lineages and the possibility to convert to PMF and progress into acute myeloid leukemia. Their molecular pathogenesis has been associated with persistent and acquired gain-of-function mutations in the Janus kinase 2 (JAK2) and thrombopoietin receptor (MPL) genes. Furthermore, familial MPNs have an autosomal dominant inheritance with decreased penetrance. Additionally, mutations in TET2, IDH1/2, EZH2, and ASXL1 genes which appear to affect the epigenome of MPN patients have been described. The transforming growth factor-beta (TGF-β) signaling pathway has a defined role in regulating normal hematopoiesis and is frequently dysregulated in hematologic malignancies. During hematopoiesis, the TGF-τ potently inhibits proliferation and stimulates cell differentiation and apoptosis. MPNs are resistant to normal homeostatic regulation by TGF-τ mainly due to mutations or deletion of members of TGF-τ signaling pathways or deregulation by oncoproteins. Despite the heterogeneity and genetic complexity of MPNs, the improvement in understanding of their pathogenetic mechanism of myeloid transformation, coupled with the increasing availability of agents acting as tyrosine kinase inhibitors, facilitated the development of therapeutics capable of suppressing the constitutive activation of the JAK/STAT pathway. In addition, advances in the TGF-τ signaling area enable targeting it for the treatment of hematologic malignancies. In this chapter we will discuss new insights in the molecular pathomechanism of MPN, the new innovative JAK inhibitor drugs and potential therapeutic strategies by targeting TGF-τ signaling as well as the potential combinatory use of JAK inhibitors and TGF-τ signal transduction modulators for the treatment of BCR/ABL-negative MPNs.

Keywords: Angiogenesis, essential thrombocythemia, JAK2, JAK2 inhibitors, JAK-STAT pathway, myeloproliferative neoplasms, polycythemia vera, primary myelofibrosis, therapies, transforming growth factor-beta.