Novel strategies for the treatment of myelofibrosis driven by recent advances in understanding the role of the microenvironment in its etiology

Abstract

Myelofibrosis is the advanced stage of the Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), characterized by systemic inflammation, hematopoietic failure in the bone marrow, and development of extramedullary hematopoiesis, mainly in the spleen. The only potentially curative therapy for this disease is hematopoietic stem cell transplantation, an option that may be offered only to those patients with a compatible donor and with an age and functional status that may face its toxicity. By contrast, with the Philadelphia-positive MPNs that can be dramatically modified by inhibitors of the novel BCR-ABL fusion-protein generated by its genetic lesion, the identification of the molecular lesions that lead to the development of myelofibrosis has not yet translated into a treatment that can modify the natural history of the disease. Therefore, the cure of myelofibrosis remains an unmet clinical need. However, the excitement raised by the discovery of the genetic lesions has inspired additional studies aimed at elucidating the mechanisms driving these neoplasms towards their final stage. These studies have generated the feeling that the cure of myelofibrosis will require targeting both the malignant stem cell clone and its supportive microenvironment. We will summarize here some of the biochemical alterations recently identified in MPNs and the novel therapeutic approaches currently under investigation inspired by these discoveries.

Genetics and Pathogenetic Role of Inflammasomes in Philadelphia Negative Chronic Myeloproliferative Neoplasms: A Narrative Review

“…Importantly, the anti-JAK2 miRNA leads only to a partial inhibition of IL-6 and IL-1, supporting that they are mostly released by stromal cells, rather than mutated cells [ 32 , 33 ]. The evidence of immunological dysregulation in PMF derives also from the murine Gata1 low mouse model, which shows a high level of TGF-β1 and collagen in megakaryocytes and abnormal signature in TGF-β1 signaling gene expression in spleen and marrow [ 34 , 35 , 36 ]. The dysregulation of immune system in MPNs stems, in part, from the defective differentiation of monocytes into dendritic cells [ 37 ] and from their inability to produce and release cytokines, such as IL-1β, TNF-α, IL-6 and IL-10, in response to infectious stimulus and to migrate into damaged tissues [ 38 , 39 ].…”

Contribution of Extramedullary Hematopoiesis to Atherosclerosis. The Spleen as a Neglected Hub of Inflammatory Cells

“…Other pathological conditions, like infection or metabolic stress, can also promote EMH. Further research on the cellular and molecular mechanisms involved in EMH are important to prevent its pathological activation (31)(32)(33). Mobilized peripheral HSPCs are considered key players for inducing EMH (18).…”

Novel targets to cure primary myelofibrosis from studies on Gata1low mice

“…Studies in vitro and in mouse models suggest that the erythroid or megakaryocyte phenotype is determined by the levels of activation of STAT5, the signaling element immediately downstream to JAK2 V617F with high and low levels of STAT5 activation driving PV or ET, respectively . In addition, the mechanisms determining the block in maturation of the hyperproliferating megakaryocytes in PMF may be represented by a RSP14 ribosomopathy (reviewed in Reference ).…”

“…Besides the TGF‐β/P‐selectin circuit discussed above, the profile of Gata1 low mice and PMF patients includes several additional abnormalities many of which are also druggable (Table ). The preclinical studies which are in progress to validate their use as therapeutic targets for PMF are reviewed in Reference .…”