Challenges and Perspectives for Therapeutic Targeting of Myeloproliferative Neoplasms

Abstract

Myeloproliferative neoplasms (MPNs) are hematopoietic stem cell disorders with dysregulated myeloid blood cell production and propensity for transformation to acute myeloid leukemia, thrombosis, and bleeding. Acquired mutations in JAK2, MPL, and CALR converge on hyperactivation of Janus kinase 2 (JAK2) signaling as a central feature of MPN. Accordingly, JAK2 inhibitors have held promise for therapeutic targeting. After the JAK1/2 inhibitor ruxolitinib, similar JAK2 inhibitors as fedratinib are entering clinical use. While patients benefit with reduced splenomegaly and symptoms, disease-modifying effects on MPN clone size and clonal evolution are modest. Importantly, response to ruxolitinib may be lost upon treatment suggesting the MPN clone acquires resistance. Resistance mutations, as seen with other tyrosine kinase inhibitors, have not been described in MPN patients suggesting that functional processes reactivate JAK2 signaling. Compensatory signaling, which bypasses JAK2 inhibition, and other processes contribute to intrinsic resistance of MPN cells restricting efficacy of JAK2 inhibition overall. Combinations of JAK2 inhibition with pegylated interferon-α, a well-established therapy of MPN, B-cell lymphoma 2 inhibition, and others are in clinical development with the potential to enhance therapeutic efficacy. Novel single-agent approaches targeting other molecules than JAK2 are being investigated clinically. Special focus should be placed on myelofibrosis patients with anemia and thrombocytopenia, a delicate patient population at high need for options. The extending range of new treatment approaches will increase the therapeutic options for MPN patients. This calls for concomitant improvement of our insight into MPN biology to inform tailored therapeutic strategies for individual MPN patients.

Aberrant expression of SPAG6 may affect the disease phenotype and serve as a tumor biomarker in BCR/ABL1‑negative myeloproliferative neoplasms

“…Although patients share similar driver gene mutations in Janus kinase (JAK)2 ( 4 ), MPL proto-oncogene thrombopoietin receptor (MPL) ( 5 ) and calreticulin (CALR) ( 6 ), which are responsible for the constitutive activation of the JAK/STAT signaling pathway, there are a number of unknown cooperating molecular and genetic aberrations that contribute to the disease phenotypes, transformation and progression ( 7 ). Current treatment regimens involve cytoreductive therapy, aspirin and novel drugs targeting specific gene mutations, such as JAK inhibitors, which successfully control symptoms and reduce spleen volume, but do not necessarily halt disease progression ( 2 , 8 ). Allogeneic stem cell transplantation remains the only curative therapy option available for patients with MPNs; however, it is only offered to a limited number of patients with MF with advanced-risk disease and without prohibitive comorbidities ( 9 ).…”

Molecular pathogenesis of the myeloproliferative neoplasms

“…It is interesting to note that further acquired mutations in JAK2 do not appear to be a significant contributor to resistance in patients. There is evidence to support alternative heterodimer formation between JAK2 and JAK1 or TYK1 in MPN cell line models persistently exposed to ruxolitinib and evidence to support recruitment of alternative MAPK signalling bypassing the JAK/STAT pathway as mechanistic explanations of this resistance [ 150 ]. The complexity of the genetic changes within the MPN clone may also determine the responsiveness of the cell to ruxolitinib, whilst new somatic mutations driving clonal evolution on therapy and subsequent expansion of new clones has been clearly documented [ 151 , 152 ].…”

Recent Advances in Molecular Diagnostics and Targeted Therapy of Myeloproliferative Neoplasms

“…Several additional innovative treatment approaches are under clinical investigation, such as telomerase inhibition interfering with telomere function, MDM2 inhibition impacting on TP53 tumor suppressor function, and others [110]. These efforts will hopefully soon add valid options to the molecularly targeted treatment approaches for MPN patients.…”