miR-21 mediates hematopoietic suppression in MDS by activating TGF-β signaling

Bhagat, Tushar D.; Zhou, Li; Sokol, Lubomir; Kessel, Rachel; Cáceres, Gisela; Gundabolu, Krishna; Tamari, Roni; Gordon, Shanisha; Mantzaris, Ioannis; Jodlowski, Tomasz; Yu, Yiting; Jing, Xin; Polineni, Rahul; Bhatia, Kavi; Pellagatti, Andrea; Boultwood, Jacqueline; Kambhampati, Suman; Steidl, Ulrich; Stein, C. A.; Ju, Wenjun; Liu, Gang; Kenny, Paraic A.; List, Alan F.; Bitzer, Markus; Verma, Amit

doi:10.1182/blood-2011-12-397067

Cited by 127 publications

(90 citation statements)

References 33 publications

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“…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. 22,23 In addition to these pathophysiological mechanisms exerted by TGFB we describe MDS patients with increased TGFB and miR-23a levels and decreased CXCL12 levels, which is in accordance with the regulatory effect of TGFB on CXCL-12 via miR-23 described here. Although there is currently no clear experimental evidence of how reduced CXCL12 levels could contribute to MDS, there are some data suggesting that loss of CXCL12/CXCR4 signaling could lead to increased HSPC proliferation, 4,24 which may be a precaution for MDS development.…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nsupporting

confidence: 88%

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

et al. 2014

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The chemokine CXCL12 regulates the interaction between hematopoietic stem and progenitor cells and bone marrow stromal cells. Although its relevance in the bone marrow niche is well recognized, the regulation of CXCL12 by microRNA is not completely understood. We transfected a library of 486 microRNA in the bone marrow stromal cell line SCP-1 and studied the expression of CXCL12. Twenty-seven microRNA were shown to downregulate expression of CXCL12. Eight microRNA (miR-23a, 130b, 135, 200b, 200c, 216, 222, and 602) interacted directly with the 3´UTR of CXCL12. Next, we determined that only miR-23a is predicted to bind to the 3´UTR and is strongly expressed in primary bone marrow stromal cells. Modulation of miR-23a changes the migratory potential of hematopoietic progenitor cells in co-culture experiments. We discovered that TGFB1 mediates its inhibitory effect on CXCL12 levels by upregulation of miR-23a. This process was partly reversed by miR-23a molecules. Finally, we determined an inverse expression of CXCL12 and miR-23a in stromal cells from patients with myelodysplastic syndrome indicating that the interaction has a pathophysiological role. Here, we show for the first time that CXCL12-targeting miR23a regulates the functional properties of the hematopoietic niche. MicroRNA-23a mediates post-transcriptional regulation of CXCL12 in bone marrow stromal cells ABSTRACT © F e r r a t a S t o r t i F o u n d a t i o nproteases. 11,12 Furthermore, CXCL12 expression can be transcriptionally modulated by a variety of cytokines and growth factors, namely transforming growth factor-beta 1 (TGFB1). TGFB1 has a negative growth effect on HSPC which is mediated, in part, by the regulation of CXCL12 arising from stromal cells. 13 Thus, engraftment and response to cytotoxic drugs may vary according to CXCL12 levels provided by niche cells. 14,15 Recently, Pillai et al. suggested that CXCL12 can also be regulated by microRNA (miRNA) in human marrow stromal cells. 16 There are more than 1000 miRNA which form 1-2% of the human genome. Approximately half of human structural genes are predicted to be under miRNA control. In animals, miRNA act by targeting the 3ú ntranslated region (UTR) of genes with the consequence of repressing output of the respective protein. A classical switch interaction is used to avoid protein expression in a particular cell type, whereas tuning interactions are needed to supply the cell with the optimal level of protein. 17 In the hematopoietic system, CXCL12 must be fine-tuned in response to differing physiological requirements.We, therefore, decided to study the interaction of CXCL12 and miRNA by applying a strategy of overexpression of a library to reveal the various miRNA responsible for CXCL12 regulation in primary human bone marrow stromal cells (hBMSC). Moreover, we mapped expression of candidate miRNA in primary hBMSC to understand their physiological function in fine tuning CXCL12 expression in the hematopoietic niche. Methods Cell linesHS5, HS27, HL60, K562, KG1a, and HeLa cell lines were ob...

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Section: © F E R R a T A S T O R T I F O U N D A T I O Nsupporting

confidence: 88%

“…patients 22,23 we additionally determined TGFB1 values in a subgroup of samples. We observed a substantial increase in the expression of TGFB1 in MDS samples ( Figure 6C).…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

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

et al. 2014

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“…Our results are consistent with and expand the impact of prior reports that showed systemic treatment with monoclonal antibodies that target TGFβ ligands or the type II TGFβ receptor inhibit metastatic invasion of breast cancer cells in the 4T1 model [38][39], and previous reports on the impact of systemic treatment with small molecule inhibitors of TGFβ on in vivo xenograft and murine models of metastatic pancreatic cancer and glioblastoma [16][17][18]40]. In addition, our data further support prior reports showing the activity of the TGFβ pathway in promoting MDS [41]. Based on this information, a predefined PK/PD model guided the first-in-human dose escalation study and was critical for defining a predictive and safe therapeutic window [34].…”

Section: Discussionsupporting

confidence: 90%

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2018

Oncotarget

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“…FcgRIIA transgenic mice were treated with 25 mg/kg anti-miR-148a or scrambled anti-miR control for 5 times total on alternative days. We based our treatment on the protocol of Bhagat et al, 31 who used this approach in modulating mouse hematopoietic cell miRNA. The sequence of the chosen 14-nucleotide anti-miR is complementary to mmu/hsa-miR-148a-3p sequence ( Figure 4A).…”

Section: Downregulation Of Mir-148a Led To De-repression Of Tula-2 Inmentioning

confidence: 99%

“…25 In cardiovascular diseases, miRNA inhibition has been used to regulate atherosclerosis, cardiac function, and vascular biology in animal models. [26][27][28][29][30] Bhagat et al 31 showed that anti-miR-21 treatment in mice elevated SMAD7 expression and stimulated hematopoiesis. Garchow et al 32 identified anti-miR-21 effects in a mouse model of systemic lupus erythematosus.…”

Section: Introductionmentioning

confidence: 99%

Anti–miR-148a regulates platelet FcγRIIA signaling and decreases thrombosis in vivo in mice

Zhou

Abraham

André

et al. 2015

Blood

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miR-21 mediates hematopoietic suppression in MDS by activating TGF-β signaling

Abstract: Key Points We observed that SMAD7, a negative regulator of TGF-β receptor-I kinase, is markedly reduced in MDS, and leads to ineffective hematopoiesis. Increased levels of microRNA-21 are seen in MDS and reduce SMAD7 levels, thus overactivating TGF-β signaling.

Cited by 127 publications

References 33 publications

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

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

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Anti–miR-148a regulates platelet FcγRIIA signaling and decreases thrombosis in vivo in mice

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