Activation of non-canonical TGF-β1 signaling indicates an autoimmune mechanism for bone marrow fibrosis in primary myelofibrosis

Ciaffoni, Fiorella; Cassella, Elena; Varricchio, Lilian; Massa, Margherita; Barosi, Giovanni; Migliaccio, Anna Rita

doi:10.1016/j.bcmd.2014.12.005

Cited by 30 publications

(31 citation statements)

References 42 publications

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“…The knowledge that TGF-β signaling induces normal HSC into quiescence through the SMAD pathway [21, 29], which is not activated in PMF [4, 28], suggested to us that TGF-β may promote proliferation of the malignant clone by directly and competitively suppressing the growth of normal HSC (Fig. 1).…”

Section: Discussionmentioning

confidence: 99%

“…By contrast, microarray analyses of bone marrow (and spleen) from PMF patients and Gata1 low mice provided clear evidence of activation of non-canonical TGF-β signaling [4, 28]. In fact, PMF patients expressed altered levels of 27 TGF-β related genes in bone marrow, 12 of which were also altered in bone marrow from Gata1 low mice, and 32 genes in spleen, 19 of which were also altered in spleens of Gata1 low mice.…”

Section: Introductionmentioning

confidence: 99%

“…In fact, PMF patients expressed altered levels of 27 TGF-β related genes in bone marrow, 12 of which were also altered in bone marrow from Gata1 low mice, and 32 genes in spleen, 19 of which were also altered in spleens of Gata1 low mice. These abnormalities included reduced levels of expression of TGF-β R1 and R2 (a clear indication of receptor activation), reduced expression of SMAD 1, 2 and 4 (a proof that the canonical SMAD-dependent TGF-β signaling is inactive), and increased expression of JUNB3, EVI1 and STAT1, three genes downstream of the non-canonical MAPK signaling [28, 29]. These data, with the caveat that they were obtained from total cell populations, support the hypothesis that TGF-β may promote the development of myelofibrosis by altering the supporting role of the microenvironment, which is sensitive to non-canonical TGF-β signaling [30, 31].…”

Section: Introductionmentioning

confidence: 99%

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

Ceglia

Dueck

Masiello

et al. 2016

Experimental Hematology

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To assess the role of abnormal TGF-β signaling in the pathogenesis of primary myelofibrosis (PMF) the effects of the TGF-β receptor-1 kinase inhibitor SB431542 on ex-vivo expansion of hematopoietic cells in cultures from patients with JAK2V617+-polycythemia vera (PV), PMF (JAK2V617F+, CALRpQ365f+ or unknown) and from normal sources (adult blood, AB, or cord blood, CB) were compared. In cultures of normal sources, SB431542 significantly increased by 2.5-fold the number of progenitor cells generated by Day 1–2 (CD34+) and 6 (colony-forming cells) (CB) and that of precursor cells, mostly immature erythroblasts, by Days 14–17 (AB and CB). In cultures of JAK2V617F+-PV, SB431542 increased by 2-fold the numbers of progenitor cells by Day 10 and had no effect on that of precursors cells by Days 12–17 [fold-increase ~4 fold in all cases]. By contrast, SB431542 had no effect on the number of both progenitor and precursor cells in cultures of JAK2V617F+- and CALR pQ365fs+-PMF. These ontogenetic- and disease-specific effects were associated with variegation in the ability of SB431542 to induce CD34+ cells from AB (increased), CB (decreased) or PV and PMF (unaffected) into cycle and erythroblasts in proliferation (increased for AB and PV and unaffected for CB and PMF). Differences in expansion of erythroblasts from AB, CB and PV were associated with differences in activation of TGF-β signaling (SHCY317, SMAD2S245/250/255 and SMAD1S/S/SMAD5S/S/SMAD8S/S) detectable in these cells by phosphoproteomic profiling. In conclusion, treatment with TGF-β receptor-1 kinase inhibitors may reactivate normal hematopoiesis in PMF patients, providing a proliferative advantage over the unresponsive malignant clone.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Ceglia

Dueck

Masiello

et al. 2016

Experimental Hematology

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“…The bone marrow and spleen from Gata1 low and PMF patients express a similarly abnormal activation of the non-canonical TGF-ß signaling which include high levels of expression of c- JUN [113]. TGF-β activation and altered c-JUN signaling were also recently confirmed in PMF patients and in animal models by the Weissman Laboratory [114].…”

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

confidence: 99%

“…Conversely patients with autoimmune diseases have increased risk to develop PMF [121], and the plasma from PMF patients contains levels of mitochondrial DNA and antimitochondrial antibodies greater than normal [113]. These results suggest that an autoimmune process may contribute to the development of marrow fibrosis in PMF.…”

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

Ling

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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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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Activation of non-canonical TGF-β1 signaling indicates an autoimmune mechanism for bone marrow fibrosis in primary myelofibrosis

Cited by 30 publications

References 42 publications

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

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

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

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

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Activation of non-canonical TGF-β1 signaling indicates an autoimmune mechanism for bone marrow fibrosis in primary myelofibrosis

Cited by 30 publications

References 42 publications

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

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

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

Novel targets to cure primary myelofibrosis from studies on Gata1low mice

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Product

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