scholarly journals Intrinsic Retinoic Acid Receptor α-Cyclin-Dependent Kinase-Activating Kinase Signaling Involves Coordination of the Restricted Proliferation and Granulocytic Differentiation of Human Hematopoietic Stem Cells

Stem Cells ◽  
2007 ◽  
Vol 25 (10) ◽  
pp. 2628-2637 ◽  
Author(s):  
Peihua Luo ◽  
Anxun Wang ◽  
Kimberly J. Payne ◽  
Hui Peng ◽  
Jian-guang Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Retinoic Acid ◽  
Hematopoietic Stem Cells ◽  
Retinoic Acid Receptor ◽  
Cyclin Dependent Kinase ◽  
Kinase Signaling ◽  
Granulocytic Differentiation ◽  
Hematopoietic Stem ◽  
Acid Receptor ◽  
Retinoic Acid Receptor Α

Modulation of Aldehyde Dehydrogenase and Retinoid Signaling Induces the Expansion of Human Hematopoietic Stem Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1713-1713
Author(s):  
John P. Chute ◽  
Garrett G. Muramoto ◽  
John Whitesides ◽  
Michael Colvin ◽  
Rachid Saffi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Retinoic Acid ◽  
Hematopoietic Stem Cells ◽  
Aldehyde Dehydrogenase ◽  
Retinoic Acid Receptor ◽  
Critical Role ◽  
Hematopoietic Stem ◽  
Regulatory Pathways ◽  
Retinoid Signaling ◽  
Retinoic Acids

Abstract Aldehyde dehydrogenases are cytosolic enzymes that convert aldehydes into carboxylic acids. Human aldehyde dehydrogenase 1 (ALDH1) is highly expressed in the liver and in hematopoietic stem cells (HSCs). Although ALDH1 is a selectable marker of HSCs, its HSC-specific function is unknown. We hypothesized that ALDH might play a critical role in HSC fate determinations since it is required for the production of retinoic acids, which are broadly implicated in tissue differentiation, tissue patterning and embryonic development in vertebrates. In this study, highly purified human CD34+CD38−lin− HSCs were cultivated with early acting cytokines, thrombopoietin, stem cell factor and Flt-3 ligand (TSF) in the presence or absence of the competitive ALDH inhibitor, diethylaminobenzaldehyde (DEAB). Treatment of human BM and CB HSCs with TSF x 7 days caused a loss of CD34+CD38− cells in culture, morphologic differentiation, amplification of committed colony forming cells (CFCs) and a loss of primitive cells capable of repopulating non-obese diabetic/severe combined immunedeficient mice (SCID-Repopulating Cells, SRCs). Conversely, 7 day culture of BM and CB HSCs with TSF plus 100 μM DEAB blocked the morphologic differentiation and lineage commitment of HSCs in culture, expanded the CD34+CD38− population, and amplified SRCs 2-fold compared to input, indicating a fundamental role for ALDH in HSC differentiation. The effects of DEAB could be reversed by the co-administration of the retinoic acid receptor (RAR) agonist, all-trans retinoic acid (ATRA), suggesting that the ability of ALDH to produce retinoic acids is important in determining HSC fate. Via screening studies of direct ligands of RAR and RXR, we also identified a selective RXR modulator which functioned similarly to DEAB by impeding HSC differentiation and causing the 4-fold expansion of SRCs. Interestingly, treatment with either DEAB or the RXR modulator reversed the down-modulation of HOXB4 transcription that was otherwise observed in CD34+CD38−lin- cells during culture with cytokines, suggesting that inhibition of ALDH or RXR modulation may promote HSC self-renewal via discrete interactions with other regulatory pathways. Modulation of ALDH activity and retinoid signaling is a novel and effective strategy to amplify human HSCs.

scholarly journals PML-Retinoic Acid Receptor α Inhibits PML IV Enhancement of PU.1-Induced C/EBPε Expression in Myeloid Differentiation

2007 ◽  
Vol 27 (16) ◽  
pp. 5819-5834 ◽  
Author(s):  
Hitoshi Yoshida ◽  
Hitoshi Ichikawa ◽  
Yusuke Tagata ◽  
Takuo Katsumoto ◽  
Kazunori Ohnishi ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Fusion Protein ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Myeloid Differentiation ◽  
Granulocytic Differentiation ◽  
Acid Receptor ◽  
Type Iv ◽  
Retinoic Acid Receptor Α ◽  
Deficient Mice

ABSTRACT PML and PU.1 play important roles in myeloid differentiation. PML-deficient mice have an impaired capacity for terminal maturation of their myeloid precursor cells. This finding has been explained, at least in part, by the lack of PML action to modulate retinoic acid-differentiating activities. In this study, we found that C/EBPε expression is reduced in PML-deficient mice. We showed that PU.1 directly activates the transcription of the C/EBPε gene that is essential for granulocytic differentiation. The type IV isoform of PML interacted with PU.1, promoted its association with p300, and then enhanced PU.1-induced transcription and granulocytic differentiation. In contrast to PML IV, the leukemia-associated PML-retinoic acid receptor α fusion protein dissociated the PU.1/PML IV/p300 complex and inhibited PU.1-induced transcription. These results suggest a novel pathogenic mechanism of the PML-retinoic acid receptor α fusion protein in acute promyelocytic leukemia.

Retinoic Acid Inhibits Nitric Oxide Synthase-2 Expression through the Retinoic Acid Receptor-α

2000 ◽  
Vol 270 (3) ◽  
pp. 846-851 ◽  
Author(s):  
Allan Sirsjö ◽  
Andreas C Gidlöf ◽  
Anneli Olsson ◽  
Hans Törmä ◽  
Mikko Ares ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Retinoic Acid ◽  
Nitric Oxide Synthase ◽  
Retinoic Acid Receptor ◽  
Acid Receptor ◽  
Retinoic Acid Receptor Α ◽  
Nitric Oxide Synthase 2 ◽  
Oxide Synthase

Identification of Highly Potent Retinoic Acid Receptor α-Selective Antagonists

1997 ◽  
Vol 40 (16) ◽  
pp. 2445-2451 ◽  
Author(s):  
Min Teng ◽  
Tien T. Duong ◽  
Alan T. Johnson ◽  
Elliott S. Klein ◽  
Liming Wang ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Acid Receptor ◽  
Selective Antagonists ◽  
Retinoic Acid Receptor Α

scholarly journals Inhibition of Abcg2 transporter on primitive hematopoietic stem cells by All-trans retinoic acid increases sensitivity to anthracycline

2010 ◽  
Vol 30 (1) ◽  
pp. 55-62 ◽  
Author(s):  
Lawrence Lein ◽  
Yasuo Nagai ◽  
Yo Mabuchi ◽  
Sadafumi Suzuki ◽  
Satoru Morikawa ◽  
...  
Keyword(s):  
Stem Cells ◽  
Retinoic Acid ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid
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