Inhibition of the TGF-β receptor I kinase promotes hematopoiesis in MDS

Abstract

MDS is characterized by ineffective hema- IntroductionThe myelodysplastic syndromes (MDSs) are clonal stem cell disorders characterized by cytologic dysplasia and ineffective hematopoiesis. [1][2][3] Although approximately one third of patients may progress to acute leukemia, refractory cytopenias are the principal cause of morbidity and mortality in patients with MDS. 4 In fact, approximately two-thirds of patients present with lower risk disease characterized by hypercellular marrows with increased rates of apoptosis in the progenitor and differentiated cell compartments in the marrow. [5][6][7][8] Ineffective hematopoiesis arising from abortive maturation leads to peripheral cytopenias. Higher grade or more advanced disease categories are associated with a significant risk of leukemia transformation, with a corresponding lower apoptotic index and higher percentage of marrow blasts.Cytokines play important roles in the regulation of normal hematopoiesis, and a balance between the actions of hematopoietic growth factors and myelosuppressive factors is required for optimal production of different hematopoietic cell lineages. Excess production of inhibitory cytokines amplifies ineffective hematopoiesis inherent to the MDS clone. Transforming growth factor-␤ (TGF-␤) is a myelosuppressive cytokine that has been implicated in the hematopoietic suppression in MDS. The plasma levels of TGF-␤ have been reported to be elevated in some [9][10][11][12][13] but not all studies [14][15][16][17] and are supported by greater TGF-␤ immunohistochemical staining in selected studies. In addition to direct myelosuppressive effects, TGF-␤ has also been implicated in the autocrine production of other myelosuppressive cytokines (TNF, IL-6, and IFN␥) in MDS. 18 Conflicting data may arise from technical limitations of bone marrow immunohistochemical analyses of a secreted protein as well as the biologic heterogeneity of the disease itself. In addition, plasma levels of TGF-␤ may not be an accurate reflection of the biologic effects of this cytokine in the MDS bone marrow microenvironment. Thus we investigated the role of TGF-␤ in MDS by direct examination of receptor signal activation to conclusively determine its role in the pathogenesis of ineffective hematopoiesis in MDS.Our previous studies have shown that signaling pathways activated by myelosuppressive cytokines can serve as therapeutic targets in low-risk MDS. We showed that interferons (IFN␣, IFN␤, and IFN␥), TGF-␤, and tumor necrosis factor ␣ (TNF␣) can all activate the p38 mitogen-activated protein kinase (MAPK) in primary human hematopoietic progenitors and that activation of p38 is required for myelosuppressive actions of these cytokines on hematopoiesis. 19,20 We subsequently confirmed overactivation of p38 MAPK in the bone marrow progenitors of low-risk MDS patients. Our data showed that inhibition of this cytokinestimulated p38 MAPK pathway partially rescues hematopoiesis in MDS progenitors. This led to a clinical trial of a p38 inhibitor, SCIO-469, in low-risk MDS; the ...

MicroRNA-23a mediates post-transcriptional regulation of CXCL12 in bone marrow stromal cells

“…34 Moreover, it has been reported that hBMSC from patients with high-risk MDS show a significant increase of TGFB1. 35 However, Bhagat et al recently reported that increased activity of the TGFB pathway is common in MDS patients and that loss of inhibitory function of SMAD-7 is responsible for the dysplastic phenotype.…”

SETBP1 mutations drive leukemic transformation of ASXL1-mutated MDS

“…[56][57][58] Intriguingly, Zhou et al reported that SMAD2, a downstream mediator of TGF-β receptors, is constitutively activated and overexpressed in MDS BM precursors and that shRNA-mediated down-regulation or pharmacologic inhibition of TGF-β receptor 1 leads to enhanced hematopoiesis in a variety of MDS subtypes in vitro. 59 Thus, it is tempting to consider that the TGF-β signaling pathway inhibits leukemic transformation of MDS and that SETBP1 mutations contribute to the down-regulation of this important pathway.…”

Aberrant Epigenetic and Genetic Marks Are Seen in Myelodysplastic Leukocytes and Reveal Dock4 as a Candidate Pathogenic Gene on Chromosome 7q

“…Individual datasets were obtained from seven independent studies (2, 26 -31) from NCBI Gene Expression Omnibus database, an on-line repository of all gene expression profiles reported in the literature (26). Methods to find and extract data have been described previously (32,33). The datasets were integrated based on UniGene identifications and were quantile-normalized to ensure cross-study comparability, based on our previous approach (32,33).…”

“…Methods to find and extract data have been described previously (32,33). The datasets were integrated based on UniGene identifications and were quantile-normalized to ensure cross-study comparability, based on our previous approach (32,33). Analyses were performed using SAS (SAS Institute, Cary, NC) and the R language.…”

“…5A). To further test DOCK4 expression in a larger set of MDS-derived bone marrow CD34 ϩ cells, we utilized a recently constructed meta-analytical data base of MDS bone marrow gene expression profiles (32,33). DOCK4 was significantly underexpressed in 89 MDS CD34 ϩ cell samples when compared with 61 normal bone marrow CD34 ϩ cells (p value ϭ 4.3 ϫ 10…”