RARγ is critical for maintaining a balance between hematopoietic stem cell self-renewal and differentiation

Purton, Louise E.; Dworkin, Sebastian; Olsen, Gemma Haines; Walkley, Carl R.; Fabb, Stewart A.; Collins, Steven J.; Chambon, Pierre

doi:10.1083/jcb1734oia9

Cited by 40 publications

(53 citation statements)

References 22 publications

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“…Our data demonstrating differences in the expression of various critical adhesion molecules known to be associated with the engraftment and homing potential of WT stem/progenitor cells clearly illustrates this point. Others have also reported a lack of correlation between phenotypic markers and function of stem cells in both mutant mice as well as upon perturbing normal steady-state hematopoiesis [39][40][41][42][43].…”

Section: Discussionmentioning

confidence: 99%

Deficiency of Src family kinases compromises the repopulating ability of hematopoietic stem cells

Orschell

Borneo

Munugalavadla

et al. 2008

Experimental Hematology

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Objective-Src family kinases (SFK) have been implicated in regulating growth factor and integrin-induced proliferation, migration, and gene expression in multiple cell types. However, little is known about the role of these kinases in the growth, homing, and engraftment potential of hematopoietic stem and progenitor cells.Results-Here we show that loss of hematopoietic-specific SFKs Hck, Fgr, and Lyn results in increased number of Sca-1 + Lin − cells in the bone marrow, which respond differentially to cytokine-induced growth in vitro and manifest a significant defect in the long-term repopulating potential in vivo. Interestingly, a significant increase in expression of adhesion molecules, known to coincide with the homing potential of wild-type bone marrow cells is also observed on the surface of SFK −/− cells, although, this increase did not affect the homing potential of more primitive Lin − Sca-1 + SFK −/− cells. The stem cell-repopulating defect observed in mice transplanted with SFK −/− bone marrow cells is due to the loss of Lyn Src kinase, because deficiency of Lyn, but not Hck or Fgr, recapitulated the long-term stem cell defect observed in mice transplanted with SFK −/− bone marrow cells.Conclusions-Taken together, our results demonstrate an essential role for Lyn kinase in positively regulating the long-term and multilineage engraftment of stem cells, which is distinct from its role in mature B cells and myeloid cells. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptEngraftment and reconstitution of normal hematopoiesis following transplantation of hematopoietic stem/progenitor (HSC/P) cells is the product of several important parameters, including the ability of hematopoietic stem cells (HSC) to home to, anchor within, and survive in specialized bone marrow (BM) niches, followed by timely proliferation and selfrenewal of stem cells for life-long hematopoiesis. While investigators have sought to understand the mechanisms behind each individual step, engraftment remains largely undefined.Besides homing and anchoring of HSC/P cells following transplantation, signals emanating from cytokine receptors also play a prominent role in regulating HSC/P cell growth and survival. In general, both positive and negative signals induced in response to cytokine stimulation contribute to this process. Deregulated signaling downstream from cytokine receptors can alter the growth and differentiation of these cells and, in some cases, contribute to leukemogenesis. Examples of molecules that are activated in response to hematopoietic growth factors include, but are not limited to, nonreceptor tyrosine kinases, such as Src family kinases (SFKs). SFKs function in signal transduction from growth factor receptors for granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3, IL-5, stem cell factor (SCF), erythropoietin, M-CSF, G-CSF, thrombopoietin, and Flt3 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Although diverse cytokine receptors activat...

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Section: Discussionmentioning

confidence: 99%

Deficiency of Src family kinases compromises the repopulating ability of hematopoietic stem cells

Orschell

Borneo

Munugalavadla

et al. 2008

Experimental Hematology

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“…These data lead to the hypothesis that RAI2 depletion is not only involved in the onset of dissemination but might also affect survival of DTCs in the bone marrow. Importantly, bone marrow represents a retinoic acid-rich microenvironment ( 40 ); also, retinoic acid signaling regulates differentiation and self-renewal of hematopoietic stem cells in the bone marrow ( 40,41 ). Because DTCs may lodge in the hematopoietic stem cell niches in bone marrow ( 42 ), DTCs might be exposed to the same regulatory mechanisms and therefore the RAI2 protein might also be involved in the control of overt bone metastasis formation.…”

Section: Research Articlementioning

confidence: 99%

Suppression of Early Hematogenous Dissemination of Human Breast Cancer Cells to Bone Marrow by Retinoic Acid–Induced 2

et al. 2015

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Regulatory pathways that drive early hematogenous dissemination of tumor cells are insuffi ciently defi ned. Here, we used the presence of disseminated tumor cells (DTC) in the bone marrow to defi ne patients with early disseminated breast cancer and identifi ed low retinoic acid-induced 2 (RAI2) expression to be signifi cantly associated with DTC status. Low RAI2 expression was also shown to be an independent poor prognostic factor in 10 different cancer datasets. Depletion of RAI2 protein in luminal breast cancer cell lines resulted in dedifferentiation marked by downregulation of ERα, FOXA1, and GATA3, together with increased invasiveness and activation of AKT signaling. Functional analysis of the previously uncharacterized RAI2 protein revealed molecular interaction with CtBP transcriptional regulators and an overlapping function in controlling the expression of a number of key target genes involved in breast cancer. These results suggest that RAI2 is a new metastasis-associated protein that sustains differentiation of luminal breast epithelial cells. SIGNIFICANCE:We identifi ed downregulation of RAI2 as a novel metastasis-associated genetic alteration especially associated with early occurring bone metastasis in ERα-positive breast tumors. We specifi ed the role of the RAI2 protein to function as a transcriptional regulator that controls the expression of several key regulators of breast epithelial integrity and cancer. Cancer Discov;5(5);

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“…This suggested that the anaemic phenotype is non-erythroid cell autonomous and occurs due to a deregulated environment in the absence of RARc. The diverse roles of RARc in the intrinsic and extrinsic regulation of haematopoiesis make interpretation of the RARc À/À phenotype difficult in the absence of data from lineage restricted deletion models (Purton et al, 2006;Walkley et al, 2007). Work in cell line models that retain multi-lineage potential had suggested that retinoids (Pronk & Bryder, 2010) are shown for control and mutant mice with (E) megakaryocyte-erythroid progenitor (MEP), (F) megakaryocyte-committed progenitors (MkP), (G) erythroid colony-forming unit (CFU-E), pre CFU, megakaryocyte-erythroid (pre MegE) and pre-granulocyte-macrophage (pre GM) fractions.…”

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confidence: 99%

Erythroid‐extrinsic regulation of normal erythropoiesis by retinoic acid receptors

et al. 2013

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Vitamin A and its derivatives (retinoids) are important regulators of haematopoiesis, acting via retinoic acid receptors (RARs). Epidemiological studies indicated an association of vitamin A deficiency with anaemia in humans. To define the requirements of RARs in erythropoiesis, we evaluated erythroid parameters in RAR germline deficient and conditional knock out mice with erythroid specific deletion of RARs. Adult RARc À/À mice were anaemic, however, Epor-Cre Rara fl/fl , Epor-Cre Rarg fl/fl and Epor-Cre Rara fl/fl g fl/fl mice were normal, indicating a lack of an erythroid intrinsic RAR function. Therefore, erythroid-specific RAR function is dispensable for erythropoiesis and RARc plays an erythroid extrinsic role in erythropoiesis.

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RARγ is critical for maintaining a balance between hematopoietic stem cell self-renewal and differentiation

Cited by 40 publications

References 22 publications

Deficiency of Src family kinases compromises the repopulating ability of hematopoietic stem cells

Deficiency of Src family kinases compromises the repopulating ability of hematopoietic stem cells

Suppression of Early Hematogenous Dissemination of Human Breast Cancer Cells to Bone Marrow by Retinoic Acid–Induced 2

Erythroid‐extrinsic regulation of normal erythropoiesis by retinoic acid receptors

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