Expression of NPM-RARα fusion gene in hematopoietic cells confers sensitivity to troglitazone-induced apoptosis

Kamel‐Reid, Suzanne; Zhang, Tong; Wells, Richard A.

doi:10.1038/sj.onc.1206696

Cited by 14 publications

(12 citation statements)

References 41 publications

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“…Our work is complementary to other lines of evidence that support the involvement of X-RARa/RXRa in leukemogenesis (Kamel-Reid et al, 2003;Kamashev et al, 2004;Zeisig et al, 2007;Zhu et al, 2007). Indeed, our work provides in vivo evidence for the necessary role for RXRa in the transcriptional function of X-RARa.…”

Section: Discussionsupporting

confidence: 57%

“…Characterization of mutant RXRa (RXRa DDB ) We characterized the subcellular localization (by western blot) and transcriptional properties of RXRa DDB (by luciferase assay; Kamel-Reid et al, 2003;Supplementary Information).…”

Section: Methodsmentioning

confidence: 99%

“…PLZF-RARa/ RXRa heterodimers also bind to nonconsensus RAREs, suggesting that these heterodimers contribute to APL pathogenesis through regulation of novel gene expression (So et al, 2000). NPM-RARa and NuMA-RARa form heterodimers with RXRa; these complexes can bind and repress transcription from the RARE (Kamel-Reid et al, 2003). Dimerization with RXRa is required for STAT5b-RARa-mediated transformation and DNA binding (Zeisig et al, 2007), and for PML-RARa-mediated leukemogenesis in vivo (Zhu et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Evidence of functional interaction between NuMA-RARα and RXRα in an in vivo model of acute promyelocytic leukemia

et al. 2008

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Acute promyelocytic leukemia (APL) is characterized by reciprocal balanced chromosomal translocations involving retinoic acid receptor-a (RARa). RARa heterodimerizes with the retinoid X receptor-a (RXRa) and transcriptionally regulates myeloid differentiation in response to ATRA (all-trans retinoic acid). Several lines of evidence suggest that APL fusion proteins interact with RXRa. To elucidate the role of RXRa in APL, we conditionally knocked out RXRa in the hCG-NuMA-RARa APL mouse model. Phenotype analysis of NuMA-RARa þ mice demonstrated that these mice developed a myeloproliferative disease-like myeloid leukemia within 4 months of birth. While hemizygous and homozygous RXRa conditional knockout mice were phenotypically normal as late as 12 months of age, we observed that the leukemic phenotype in NuMA-RARa þ mice was dependent on the presence of functional RXRa. Bone marrow promyelocyte counts were significantly reduced in NuMA-RARa þ mice with RXRa knocked down. Significant differences in the accumulations of Gr-1 þ and Mac-1 þ cells were also seen. We further observed that genes previously identified to be cooperating events in APL were also regulated in an RXRa-dependent manner. We therefore propose that the APL fusion protein NuMA-RARa cooperates with RXRa in the development of leukemia in hCG-NuMA-RARa transgenic mice and suggest a novel role for RXRa in the pathogenesis of APL.

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Section: Discussionsupporting

confidence: 57%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evidence of functional interaction between NuMA-RARα and RXRα in an in vivo model of acute promyelocytic leukemia

et al. 2008

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“…This is supported by the finding that NPM-RARα -expressing cells are sensitive to conventional ATRA doses in vitro [50]. Troglitazone also induces apoptosis in U937 cells transfected with NPM-RARα via the caspase pathway [51]. …”

Section: Introductionsupporting

confidence: 62%

Molecular Characteristics and Clinical Significance of 12 Fusion Genes in Acute Promyelocytic Leukemia: A Systematic Review

Yan

Zhang²

2016

Acta Haematol

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Acute promyelocytic leukemia (APL) is characterized by the generation of the promyelocytic leukemia-retinoic acid (RA) receptor α (PML-RARα) fusion gene. PML-RARα is the central leukemia-initiating event in APL and is directly targeted by all-trans-RA (ATRA) as well as arsenic. In classic APL harboring PML-RARα transcripts, more than 90% of patients can achieve complete remission when treated with ATRA combined with arsenic trioxide chemotherapy. In the last 20 years, more than 10 variant fusion genes have been found and identified in APL patients. These variant APL cases present different clinical phenotypes and treatment outcomes. All variant APL cases show a similar breakpoint within the RARα gene, whereas its partner genes are variable. These fusion proteins have the ability to repress rather than activate retinoic targets. These chimeric proteins also possess different molecular characteristics, thereby resulting in variable sensitivities to ATRA and clinical outcomes. In this review, we comprehensively analyze various rearrangements in variant APL cases that have been reported in the literature as well as the molecular characteristics and functions of the fusion proteins derived from different RARα partner genes and their clinical implications.

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“…The latter may therefore be acting via a PPARγ-independent mechanism. A PPARγ-independent mechanism has also been demonstrated in other cell types, such as colon cancer cells and monoblastic cell lines [32, 33]. …”

Section: Discussionmentioning

confidence: 99%

Troglitazone Inhibits Cell Growth and Induces Apoptosis of B-Cell Acute Lymphoblastic Leukemia Cells with t(14;18)

et al. 2006

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Peroxisome proliferator-activated receptor-γ (PPARγ), a member of the nuclear receptor superfamily, has been detected in several human leukemia cells. Recent studies reported that PPARγ ligands inhibit cell proliferation and induce apoptosis in both normal and malignant B-lineage cells. We investigated the expression of PPARγ and the effects of PPARγ ligands on UTree-O2, Bay91 and 380, three B-cell acute lymphoblastic leukemia (B-ALL) cell lines with t(14;18), which show a poor prognosis, accompanying c-myc abnormality. Western blot analysis identified expression of PPARγ protein and real-time PCR that of PPARγ mRNA on the three cell lines. Troglitazone (TGZ), a synthetic PPARγ ligand, inhibited cell growth in these cell lines in a dose-dependent manner, which was associated with G₁ cell cycle arrest and apoptosis. We also found this effect PPARγ independent since PPARγ antagonists failed to reverse this effect. We assessed the expression of c-myc, an apoptosis-regulatory gene, since c-myc abnormality was detected in most B-ALL cells with t(14;18). TGZ was found to dose-dependently downregulate the expression of c-myc mRNA and c-myc protein in the three cell lines. These results suggest that TGZ inhibits cell growth via induction of G₁ cell cycle arrest and apoptosis in these cell lines and that TGZ-induced apoptosis, at least in part, may be related to the downregulation of c-myc expression. Moreover, the downregulation of c-myc expression by TGZ may depend on a PPARγ-independent mechanism. Further studies indicate that PPARγ ligands may serve as a therapeutic agent in B-ALL with t(14;18).

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Expression of NPM-RARα fusion gene in hematopoietic cells confers sensitivity to troglitazone-induced apoptosis

Cited by 14 publications

References 41 publications

Evidence of functional interaction between NuMA-RARα and RXRα in an in vivo model of acute promyelocytic leukemia

Evidence of functional interaction between NuMA-RARα and RXRα in an in vivo model of acute promyelocytic leukemia

Molecular Characteristics and Clinical Significance of 12 Fusion Genes in Acute Promyelocytic Leukemia: A Systematic Review

Troglitazone Inhibits Cell Growth and Induces Apoptosis of B-Cell Acute Lymphoblastic Leukemia Cells with t(14;18)

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