Preclinical rationale for TGF-β inhibition as a therapeutic target for the treatment of myelofibrosis

Ceglia, Ilaria; Dueck, Amylou C.; Masiello, Francesca; Martelli, Fabrizio; He, Wei; Federici, Giulia; Petricoin, Emanuel F.; Zeuner, Ann; Iancu‐Rubin, Camelia; Weinberg, Rona Singer; Hoffman, Ronald; Mascarenhas, John; Migliaccio, Anna Rita

doi:10.1016/j.exphem.2016.08.007

Cited by 38 publications

(31 citation statements)

References 47 publications

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“…This model was tested by experiments indicating that chemical inhibition of TGF‐β signaling or genetic ablation of P‐selectin completely restores megakaryocyte maturation (Figure ) and rescues the myelofibrotic phenotype of Gata1 low mice. These observations support the therapeutic hypothesis that cure of myelofibrosis requires targeting the abnormalities of both the malignant stem cells and of their supporting microenvironment . This hypothesis is testable since both TGF‐β and P‐selectin are druggable by products developed for clinical use in other diseases.…”

Section: Pmf Megakaryocytes Are Hypomorphic For Gata1supporting

confidence: 65%

“…These observations support the therapeutic hypothesis that cure of myelofibrosis requires targeting the abnormalities of both the malignant stem cells and of their supporting microenvironment. 67 This hypothesis is testable since both TGF-β and P-selectin are druggable by products developed for Megakaryocytes were identified on the basis of CD41/CD61 markers, as indicated. Expression of high levels of P-selectin in Gata1 low megakaryocytes was also detected by electron microscopy 31 clinical use in other diseases.…”

Section: Myelofibrosis Is a Disease Of The Microenvironment Sustainmentioning

confidence: 99%

“…69 P-selectin may instead be inhibited by crizanlizumab, an antibody developed by Novartis, which has been shown effective to prevent pain crisis in Sickle Cell Diseases. 67 Phases 1-2 clinical trials with AVID200 (NCT03094169, open for accrual) and Crizanlizumab (NCT not available as yet) in combination with ruxolitinib are in progress. The identification of biomarkers to evaluate disease progression or response to therapy is another important facet in the process to address the clinical need of a disease.…”

Section: Myelofibrosis Is a Disease Of The Microenvironment Sustainmentioning

confidence: 99%

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Novel targets to cure primary myelofibrosis from studies on Gata1^low mice

et al. 2019

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In 2002, we discovered that mice carrying the hypomorphic Gata1 low mutation that reduces expression of the transcription factor GATA1 in megakaryocytes (Gata1 low mice) develop myelofibrosis, a phenotype that recapitulates the features of primary myelofibrosis (PMF), the most severe of the Philadelphianegative myeloproliferative neoplasms (MPNs). At that time, this discovery had a great impact on the field because mutations driving the development of PMF had yet to be discovered. Later studies identified that PMF, as the others MPNs, is associated with mutations activating the thrombopoietin/JAK2 axis raising great hope that JAK inhibitors may be effective to treat the disease.Unfortunately, ruxolitinib, the JAK1/2 inhibitor approved by FDA and EMEA for PMF, ameliorates symptoms but does not improve the natural course of the disease, and the cure of PMF is still an unmet clinical need. Although GATA1is not mutated in PMF, reduced GATA1 content in megakaryocytes as a consequence of ribosomal deficiency is a hallmark of myelofibrosis (both in humans and mouse models) and, in fact, a driving event in the disease. Conversely, mice carrying the hypomorphic Gata1 low mutation express an activated TPO/JAK2 pathway and partially respond to JAK inhibitors in a fashion similar to PMF patients (reduction of spleen size but limited improvement of the natural history of the disease). These observations cross-validated Gata1 low mice as a bona fide animal model for PMF and prompted the use of this model to identify abnormalities that might be targeted to cure the disease. We will summarize here data generated in Gata1 low mice indicating that the TGF-β/P-

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Section: Pmf Megakaryocytes Are Hypomorphic For Gata1supporting

confidence: 65%

Section: Myelofibrosis Is a Disease Of The Microenvironment Sustainmentioning

confidence: 99%

Section: Myelofibrosis Is a Disease Of The Microenvironment Sustainmentioning

confidence: 99%

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Novel targets to cure primary myelofibrosis from studies on Gata1^low mice

et al. 2019

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“…Unfortunately, the trial was interrupted prematurely due to pharmaceutical company decision to discontinue antibody production and distribution for clinical investigation. However, new generation TGF-β inhibitors are currently under development and represent interesting therapeutic options, alone or in combination with JAK inhibitors, for PMF [112]. …”

Section: Role Played By Hypomorphic Gata1low Mice Models To Identify mentioning

confidence: 99%

GATA1 insufficiencies in primary myelofibrosis and other hematopoietic disorders: consequences for therapy

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Crispino

Zingariello

et al. 2018

Expert Review of Hematology

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Introduction: GATA1, the founding member of a family of transcription factors, plays important roles in the development of hematopoietic cells of several lineages. Although loss of GATA1 has been known to impair hematopoiesis in animal models for nearly 25 years, the link between GATA1 defects and human blood diseases has only recently been realized. Areas covered: Here the current understanding of the functions of GATA1 in normal hematopoiesis and how it is altered in disease is reviewed. GATA1 is indispensable mainly for erythroid and megakaryocyte differentiation. In erythroid cells, GATA1 regulates early stages of differentiation, and its deficiency results in apoptosis. In megakaryocytes, GATA1 controls terminal maturation and its deficiency induces proliferation. GATA1 alterations are often found in diseases involving these two lineages, such as congenital erythroid and/or megakaryocyte deficiencies, including Diamond Blackfan Anemia (DBA), and acquired neoplasms, such as acute megakaryocytic leukemia (AMKL) and the myeloproliferative neoplasms (MPNs). Expert Commentary: Since the first discovery of GATA1 mutations in AMKL, the number of diseases that are associated with impaired GATA1 function has increased to include DBA and MPNs. With respect to the latter, we are only just now appreciating the link between enhanced JAK/STAT signaling, GATA1 deficiency and disease pathogenesis.

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“…Among the abnormally expressed cytokines in MF, TGF-β1 has received attention due to its critical role in inducing fibrosis not only in bone marrow (15)(16)(17)(18), but other organs (19)(20)(21). TGF-β1 may be produced by abnormal megakaryocytes or monocytes, and this in turn may remodel the MSCs that promote the changes illustrated by MF (22)(23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%