Interactions of STAT5b-RARα, a novel acute promyelocytic leukemia fusion protein, with retinoic acid receptor and STAT3 signaling pathways

Dong, Shuang; Tweardy, David J.

doi:10.1182/blood.v99.8.2637

Cited by 91 publications

(97 citation statements)

References 64 publications

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“…38 Fusion proteins of PML-RAR␣, STAT5b-RAR␣, and NuMa-RAR␣ were shown to enhance STAT3 transcriptional activity in acute promyelocytic leukemia tumor cells. [39][40][41] These observations suggested that RAR␣2 might be related to the activation of STAT3 signaling in other cells. Although ATRA was shown to inhibit MEK/ERK pathways, 42,43 the ligand-independent effects of RAR␣1 and/or RAR␣2 on MEK/ERK signaling pathways were not reported previously.…”

Section: Discussionmentioning

confidence: 91%

RARα2 expression is associated with disease progression and plays a crucial role in efficacy of ATRA treatment in myeloma

Wang

Tricot

Shi

et al. 2009

Blood

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IntroductionMultiple myeloma (MM) is a plasma cell malignancy. 1,2 Although high-dose therapy and tandem bone marrow autotransplantation can produce higher response rates and longer survival than standard chemotherapy, MM remains largely incurable by current therapeutic strategies. 3,4 Furthermore, clinical outcomes of patients with MM are extremely heterogeneous, with survival ranging from only a few months to more than 15 years. [4][5][6] Increasing evidence suggests that genetic heterogeneity in MM cells largely accounts for the divergent clinical outcomes. 6 We have been pursuing the genetic characteristics of MM for nearly 10 years, which has contributed to the classification of MM diseases. [7][8][9][10][11] However, it remains unknown how to transform MM into a curable disease. Therefore, identification of new targets and genetic alterations, especially those for which there are available drugs, is important.All-trans retinoic acid (ATRA)-based regimens have been used in the therapy of acute promyelocytic leukemia (APL) for more than 20 years and have dramatically raised the 5-year disease-free survival to more than 70%. Furthermore, the toxicity of ATRA has been limited compared with conventional cytotoxic chemotherapy. 12 The high efficacy of retinoic acid (RA)-based therapy in APL and its well-documented safety profile have stimulated considerable interests in the treatment of other malignancies, [13][14][15] including myeloma. 16,17 Despite many efforts, however, clinical benefits of ATRA treatment in other tumors have been minor. RAR␣ has 2 major isoforms, RAR␣1 and RAR␣2, which differ in their expression patterns and N-terminal AF-1 functional domains. 18 Both RAR␣1 and RAR␣2 are considered specific receptors for RA-based reagents. However, the specific cellular roles of RAR␣1 and RAR␣2 are still unclear. In this study, we found that RAR␣2 plays a crucial role in myeloma progression, and more importantly, in mediating RA-based therapy of RAR␣2 ϩ MM diseases. Methods Study subjectsCD138 ϩ myeloma cell samples were obtained from patients who were enrolled on the National Institutes of Health (NIH)-sponsored clinical trials UARK 98-026 (Total Therapy 2 [TT2]) and UARK 03-033 (TT3). The Institutional Review Board of the University of Arkansas for Medical Sciences approved the research studies, and all subjects provided written informed consent in accordance with the Declaration of Helsinki.We have an inventory of more than 30 myeloma cell lines in our laboratory. Cells from these cell lines were cultured in RPMI 1640 containing 10% heat-inactivated fetal calf serum (FCS), 2 mM L-glutamine (Gibco), penicillin (100 U/mL), and streptomycin (100 g/mL) in a humidified incubator at 37°C in 5% CO 2 . Gene expression profilingPlasma cell purifications and gene expression profiling, using the Affymetrix U133Plus2.0 microarray, were performed as previously described. 9,11 Signal intensities were preprocessed and normalized by GCOS1.1 software (Affymetrix). 9,11 Myeloma cell samples from 80 newly diagnosed patien...

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Section: Discussionmentioning

confidence: 91%

RARα2 expression is associated with disease progression and plays a crucial role in efficacy of ATRA treatment in myeloma

Wang

Tricot

Shi

et al. 2009

Blood

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“…36,37 However, blasts from the index case were not sensitive to the differentiating effects of ATRA. 19 Addressing this dilemma, Dong et al 36 have speculated that the STAT5b domains might bind an as yet unidentified corepressor.…”

Section: The Role Of Co-repressorsmentioning

confidence: 99%

Variations on a theme: the alternate translocations in APL

2002

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The t(15;17)(q22;q21) translocation is tightly linked to the APL phenotype, and the resultant PML-RAR fusion can be demonstrated in 98% of APL cases. Rare variant translocations have been reported, the majority of which on detailed analysis represent cryptic PML-RAR fusions. However, a handful of APL cases have been described with different genotypes. These include the t(11;17)(q23;q21) that produces the PLZF-RAR fusion, t(5;17)(q35;q21) that forms NPM-RAR, t(11;17)(q13;q21) that generates NUMA-RAR, and der(17) that creates STAT5b-RAR. In this review we will discuss these variant translocations, and discuss the insights that we have gained from their study.

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“…The plasmids for CFP-LacR-tagged RARα, RARα and the RARβ2 promoter-driven luciferase reporter have been described previously [26,39]. All PHF8 mutants were generated by PCRbased site-directed mutagenesis or cloning.…”

Section: Cell Culture Reagents and Plasmidsmentioning

confidence: 99%

“…Transient transfection-based luciferase assay in HeLa cells was performed essentially as described previously [39]. Western blot analysis was performed essentially as described [39].…”

Section: Luciferase and Western Blot Assaysmentioning

confidence: 99%

The X-linked mental retardation gene PHF8 is a histone demethylase involved in neuronal differentiation

et al. 2010

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Recent studies have identified mutations in PHF8, an X-linked gene encoding a JmjC domain-containing protein, as a causal factor for X-linked mental retardation (XLMR) and cleft lip/cleft palate. However, the underlying mechanism is unknown. Here we show that PHF8 is a histone demethylase and coactivator for retinoic acid receptor (RAR). Although activities for both H3K4me3/2/1 and H3K9me2/1 demethylation were detected in cellularbased assays, recombinant PHF8 exhibited only H3K9me2/1 demethylase activity in vitro, suggesting that PHF8 is an H3K9me2/1 demethylase whose specificity may be modulated in vivo. Importantly, a mutant PHF8 (phenylalanine at position 279 to serine) identified in the XLMR patients is defective in enzymatic activity, indicating that the loss of histone demethylase activity is causally linked with the onset of disease. In addition, we show that PHF8 binds specifically to H3K4me3/2 peptides via an N-terminal PHD finger domain. Consistent with a role for PHF8 in neuronal differentiation, knockdown of PHF8 in mouse embryonic carcinoma P19 cells impairs RA-induced neuronal differentiation, whereas overexpression of the wild-type but not the F279S mutant PHF8 drives P19 cells toward neuronal differentiation. Furthermore, we show that PHF8 interacts with RARα and functions as a coactivator for RARα. Taken together, our results suggest that histone methylation modulated by PHF8 plays a critical role in neuronal differentiation.

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Interactions of STAT5b-RARα, a novel acute promyelocytic leukemia fusion protein, with retinoic acid receptor and STAT3 signaling pathways

Cited by 91 publications

References 64 publications

RARα2 expression is associated with disease progression and plays a crucial role in efficacy of ATRA treatment in myeloma

RARα2 expression is associated with disease progression and plays a crucial role in efficacy of ATRA treatment in myeloma

Variations on a theme: the alternate translocations in APL

The X-linked mental retardation gene PHF8 is a histone demethylase involved in neuronal differentiation

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