Persistence of myelofibrosis treated with ruxolitinib: biology and clinical implications
Journal Title
Haematologica
Publication Type
epub ahead of print
Abstract
Activation of JAK-STAT signaling is one of the hallmarks of myelofibrosis, a myeloproliferative neoplasm that leads to inflammation, progressive bone marrow failure, and a risk of leukemic transformation. Around 90% of patients with myelofibrosis have a mutation in JAK2, MPL, or CALR: so-called 'driver' mutations that lead to activation of JAK2. Ruxolitinib, and other JAK2 inhibitors in clinical use, provide clinical benefit but do not have a major impact on the abnormal hematopoietic clone. This phenomenon is termed 'persistence', in contrast to usual patterns of resistance. Multiple groups have shown that type 1 inhibitors of JAK2, which bind the active conformation of the enzyme, lead to JAK2 becoming resistant to degradation with consequent accumulation of phospho-JAK2. In turn, this can lead to exacerbation of inflammatory manifestations when the JAK inhibitor is discontinued, and it may also contribute to disease persistence. The ways in which JAK2 V617F and CALR mutations lead to activation of JAK-STAT signaling are incompletely understood. We summarize what is known about pathological JAK-STAT activation in myelofibrosis and how this might lead to future novel therapies for myelofibrosis with greater disease-modifying potential.
Publisher
Ferrata-Storti Foundation
Research Division(s)
Structural Biology
PubMed ID
33472356
Open Access at Publisher's Site
https://doi.org/10.3324/haematol.2020.262691
Terms of Use/Rights Notice
Refer to copyright notice on published article.


Creation Date: 2021-03-09 08:05:51
Last Modified: 2021-03-09 08:45:45
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