A network including TGFβ/Smad4, Gata2, and p57 regulates proliferation of mouse hematopoietic progenitor cells

Billing, Matilda; Rörby, Emma; May, Gillian; Soneji, Shamit; Brown, John; Salminen, Marjo; Karlsson, Göran; Enver, Tariq; Karlsson, Stefán

doi:10.1016/j.exphem.2016.02.001

Cited by 10 publications

(6 citation statements)

References 48 publications

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“…The inhibitory effects of rTGF-β1 on normal hematopoiesis were accompanied by increased p53 and p21 protein levels, which were also downregulated by AVID200 ( Figure 3D ). GATA2 ( 48 ) is involved in mediating TGF-β responses in primitive hematopoietic cells by binding the regulatory region of p57 Kip2 ( 49 ). Treatment of ND MNCs with rTGF-β1 resulted in the upregulation of GATA2, which was eliminated by AVID200 ( Figure 3D ).…”

Section: Resultsmentioning

confidence: 99%

TGF-β1 protein trap AVID200 beneficially affects hematopoiesis and bone marrow fibrosis in myelofibrosis

Varricchio¹,

Iancu‐Rubin²,

Upadhyaya³

et al. 2021

JCI Insight

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Myelofibrosis (MF) is a progressive chronic myeloproliferative neoplasm characterized by hyperactivation of JAK/STAT signaling and dysregulation of the transcription factor GATA1 in megakaryocytes (MKs). TGF- β plays a pivotal role in the pathobiology of MF by promoting BM fibrosis and collagen deposition and by enhancing the dormancy of normal hematopoietic stem cells (HSCs). In this study, we show that MF-MKs elaborated significantly greater levels of TGF- β 1 than TGF- β 2 and TGF- β 3 to a varying degree, and we evaluated the ability of AVID200, a potent TGF- β 1/TGF- β 3 protein trap, to block the excessive TGF- β signaling. Treatment of human mesenchymal stromal cells with AVID200 significantly reduced their proliferation, decreased phosphorylation of SMAD2, and interfered with the ability of TGF- β 1 to induce collagen expression. Moreover, treatment of MF mononuclear cells with AVID200 led to increased numbers of progenitor cells (PCs) with WT JAK2 rather than mutated JAK2V617F . This effect of AVID200 on MF PCs was attributed to its ability to block TGF- β 1–induced p57 Kip2 expression and SMAD2 activation, thereby allowing normal rather than MF PCs to preferentially proliferate and form hematopoietic colonies. To assess the in vivo effects of AVID200, Gata1 lo mice, a murine model of MF, were treated with AVID200, resulting in the reduction in BM fibrosis and an increase in BM cellularity. AVID200 treatment also increased the frequency and numbers of murine progenitor cells as well as short-term and long-term HSCs. Collectively, these data provide the rationale for TGF- β 1 blockade, with AVID200 as a therapeutic strategy for patients with MF.

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Section: Resultsmentioning

confidence: 99%

TGF-β1 protein trap AVID200 beneficially affects hematopoiesis and bone marrow fibrosis in myelofibrosis

Varricchio¹,

Iancu‐Rubin²,

Upadhyaya³

et al. 2021

JCI Insight

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“…In contrast, a rearranged BAC transgene lacking the À77-kb enhancer region failed to drive leukemia development in mice [22]. Transforming growth factor (TGF) b signaling activates Gata2 gene expression via binding of Smad4 to the À77-kb enhancer of the Gata2 gene [23], suggesting that the TGFb signaling pathway may influence the pathogenesis of 3q21q26 syndrome.…”

Section: Diseases Caused By Haplo-insufficiency Of Gata2mentioning

confidence: 99%

GATA-related hematologic disorders

Shimizu

Yamamoto

2016

Experimental Hematology

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“…Intriguingly, both transcription factors are ubiquitously expressed and have been reported to regulate other members of the CIP/Kip family of CDK inhibitors [ 77 , 78 ]. Furthermore, a binding site for GATA2, a transcription factor playing a pivotal role in hematopoiesis, particularly in early and late stages of erythropoiesis, and in the TGF-β-response has also been described [ 79 ]. Finally, this promoter region also contains recognition sequences for the transcriptional repressors CTIP2/Bcl11b, implicated in the developmental process and carcinogenesis, and the T-box transcription factor TBX3, which is involved in the tissue patterning and differentiation during embryonic development and is up-regulated in a plethora of cancers [ 80 ].…”

Section: Introductionmentioning

confidence: 99%

Genetic and Epigenetic Control of CDKN1C Expression: Importance in Cell Commitment and Differentiation, Tissue Homeostasis and Human Diseases

Stampone

Caldarelli

Zullo

et al. 2018

IJMS

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The CDKN1C gene encodes the p57Kip2 protein which has been identified as the third member of the CIP/Kip family, also including p27Kip1 and p21Cip1. In analogy with these proteins, p57Kip2 is able to bind tightly and inhibit cyclin/cyclin-dependent kinase complexes and, in turn, modulate cell division cycle progression. For a long time, the main function of p57Kip2 has been associated only to correct embryogenesis, since CDKN1C-ablated mice are not vital. Accordingly, it has been demonstrated that CDKN1C alterations cause three human hereditary syndromes, characterized by altered growth rate. Subsequently, the p57Kip2 role in several cell phenotypes has been clearly assessed as well as its down-regulation in human cancers. CDKN1C lies in a genetic locus, 11p15.5, characterized by a remarkable regional imprinting that results in the transcription of only the maternal allele. The control of CDKN1C transcription is also linked to additional mechanisms, including DNA methylation and specific histone methylation/acetylation. Finally, long non-coding RNAs and miRNAs appear to play important roles in controlling p57Kip2 levels. This review mostly represents an appraisal of the available data regarding the control of CDKN1C gene expression. In addition, the structure and function of p57Kip2 protein are briefly described and correlated to human physiology and diseases.

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A network including TGFβ/Smad4, Gata2, and p57 regulates proliferation of mouse hematopoietic progenitor cells

Cited by 10 publications

References 48 publications

TGF-β1 protein trap AVID200 beneficially affects hematopoiesis and bone marrow fibrosis in myelofibrosis

TGF-β1 protein trap AVID200 beneficially affects hematopoiesis and bone marrow fibrosis in myelofibrosis

GATA-related hematologic disorders

Genetic and Epigenetic Control of CDKN1C Expression: Importance in Cell Commitment and Differentiation, Tissue Homeostasis and Human Diseases

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