Abstract:
:Signaling from the human hematopoietic stem cell (HSC) niche formed by osteoblastic cells regulates hematopoiesis. We previously found that retinoic acid receptor alpha (RARα), a transcription factor activated by retinoic acid (RA), mediates both granulocytic and osteoblastic differentiation. This effect depends on decreased phosphorylation of serine 77 of RARα (RARαS77) by the cyclin-dependent kinase-activating kinase (CAK) complex, a key cell-cycle regulator. In this article, we report that, by suppressing CAK phosphorylation of RARα, RA induces FGF8f to mediate osteosarcoma U2OS cell differentiation in an autocrine manner. By contrast, paracrine FGF8f secreted into osteoblast-conditioned medium by U2OS cells transduced with FGF8f or a phosphorylation-defective RARαS77 mutant, RARαS77A, bypasses RA stimuli to cross-mediate granulocytic differentiation of different types of human leukemic myeloblasts and normal primitive hematopoietic CD34(+) cells, possibly through modulating mitogen-activated protein kinase (MAPK) pathways. Further experiments using recombinant human FGF8f (rFGF8f) stimuli, antibody neutralization, and peptide blocking showed that paracrine FGF8f is required for mediating terminal leukemic myeloblast differentiation. These studies indicate a novel regulatory mechanism of granulocytic differentiation instigated by RA from the HSC niche, which links loss of CAK phosphorylation of RARα with paracrine FGF8f-mediated MAPK signaling to mediate leukemic myeloblast differentiation in the absence of RA. Therefore, these findings provide a compelling molecular rationale for further investigation of paracrine FGF8f regulation, with the intent of devising HSC niche-based FGF8f therapeutics for myeloid leukemia, with or without RA-resistance.
journal_name
Mol Cancer Therjournal_title
Molecular cancer therapeuticsauthors
Chaudhry P,Yang X,Wagner M,Jong A,Wu Ldoi
10.1158/1535-7163.MCT-11-0584subject
Has Abstractpub_date
2012-02-01 00:00:00pages
267-76issue
2eissn
1535-7163issn
1538-8514pii
1535-7163.MCT-11-0584journal_volume
11pub_type
杂志文章abstract::The increasing characterization of childhood acute lymphoblastic leukemia (ALL) has led to the identification of multiple molecular targets but has yet to translate into more effective targeted therapies, particularly for high-risk, relapsed T-cell ALL. Searching for master regulators controlling multiple signaling pa...
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journal_title:Molecular cancer therapeutics
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pub_type: 杂志文章,随机对照试验
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更新日期:2013-04-01 00:00:00
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pub_type: 杂志文章
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pub_type: 杂志文章
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-09-0119
更新日期:2009-08-01 00:00:00
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pub_type: 杂志文章
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pub_type: 杂志文章
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更新日期:2011-09-01 00:00:00
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更新日期:2018-10-01 00:00:00
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pub_type: 杂志文章
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更新日期:2016-11-01 00:00:00
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