Signaling revisited in acute promyelocytic leukemia

P, Lutz; Moog-Lutz, Christel

doi:10.1038/sj.leu.2402728

Cited by 12 publications

(20 citation statements)

References 100 publications

(68 reference statements)

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“…1 is a potent inducer of cell differentiation and growth arrest of malignant cells in vitro and in vivo (1)(2)(3)(4)(5)(6). This agent has potent effects against acute promyelocytic leukemia blast cells, and its introduction in the clinical management of the disease has dramatically changed the outcome of this historically fatal subtype of acute leukemia (5).…”

Section: All-trans-retinoic Acid (Ra)mentioning

confidence: 99%

Activation of Protein Kinase Cδ by All-trans-retinoic Acid

Kambhampati

Verma

et al. 2003

Journal of Biological Chemistry

102

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All-trans-retinoic acid (RA) is a potent inhibitor of leukemia cell proliferation and induces differentiation of acute promyelocytic leukemia cells in vitro and in vivo.For RA to induce its biological effects in target cells, binding to specific retinoic acid nuclear receptors is required. The resulting complexes bind to RA-responsive elements (RAREs) in the promoters of RA-inducible genes to initiate gene transcription and to generate protein products that mediate the biological effects of RA. In this report, we provide evidence that a member of the protein kinase C (PKC) family of proteins, PKC␦, is activated during RA treatment of the NB-4 and HL-60 acute myeloid leukemia cell lines as well as the MCF-7 breast cancer cell line. Such RA-dependent phosphorylation was also observed in primary acute promyelocytic leukemia cells and resulted in activation of the kinase domain of PKC␦. In studies aimed at understanding the functional relevance of PKC␦ in the induction of RA responses, we found that pharmacological inhibition of PKC␦ (but not of other PKC isoforms) diminished RA-dependent gene transcription via RAREs. On the other hand, overexpression of a constitutively active form of the kinase strongly enhanced RA-dependent gene transcription via RAREs. Gel shift assays and chromatin immunoprecipitation studies demonstrated that PKC␦ associated with retinoic acid receptor-␣ and was present in an RA-inducible protein complex that bound to RAREs. Pharmacological inhibition of PKC␦ activity abrogated the induction of cell differentiation and growth inhibition of NB-4 blast cells, demonstrating that its function is required for such effects. Altogether, our data provide strong evidence that PKC␦ is activated in an RA-dependent manner and plays a critical role in the generation of the biological effects of RA in malignant cells.

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Section: All-trans-retinoic Acid (Ra)mentioning

confidence: 99%

Activation of Protein Kinase Cδ by All-trans-retinoic Acid

Kambhampati

Verma

et al. 2003

Journal of Biological Chemistry

102

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“…1) In about 95-98% of the cases, APL is associated with the reciprocal translocation, t(15; 17)(q22; q21) 2,3) and the reciprocal fusion of the retinoic acid receptor (RAR)a gene on chromosome 17 with the promyelocytic leukemia (PML) gene on chromosome 15. The resulting PML-RARa fusion gene encodes a chimeric protein 4,5) that causes the pathogenesis of APL.…”

mentioning

confidence: 99%

Clinical Pharmacokinetic Study of Arsenic Trioxide in an Acute Promyelocytic Leukemia (APL) Patient: Speciation of Arsenic Metabolites in Serum and Urine

Fukai

Hirata

Ueno

et al. 2006

Biological & Pharmaceutical Bulletin

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Acute promyelocytic leukemia (APL) is characterized M3 in the French-American and British (FAB) classification and represents approximately 5-10% of all leukemia in adults. 1) In about 95-98% of the cases, APL is associated with the reciprocal translocation, t(15; 17)(q22; q21) 2,3) and the reciprocal fusion of the retinoic acid receptor (RAR)a gene on chromosome 17 with the promyelocytic leukemia (PML) gene on chromosome 15. The resulting PML-RARa fusion gene encodes a chimeric protein 4,5) that causes the pathogenesis of APL. 2,6) Huang et al. reported that all-trans retinoic acid (ATRA)-a vitamin A derivative-yielded a high rate of complete remission for APL patients.7) Several clinical studies have shown that ATRA treatment in combination with chemotherapy induced survival rate of 67-84% at 2-4-years. [8][9][10][11] Currently, ATRA has become a first-line treatment of newly diagnosed APL. [8][9][10][11] The combination of ATRA with chemotherapy can obtain long-term survival in 70% of newly diagnosed APL. Nevertheless, the remaining 30% of patients relapse and are often resistant to further treatment with ATRA and chemotherapy. 12) In 1996, the Chinese Shanghai II Medical University Group reported that arsenic trioxide induced apoptosis of APL cells, 13) and 14 of 15 patients who relapsed after ATRA therapy achieved complete remission (CR) with no serious adverse events.14) Several studies reported that intravenous infusion of arsenic trioxide was effective in approximately 90% of relapsed APL patients who are resistant to ATRA and chemotherapy.14-16) However these studies have not accurately investigated the metabolism of arsenic trioxide after the intravenous infusion.In this study, arsenic trioxide was administered intravenously to ATRA-resistant APL patient, and we determined the efficacy of arsenic trioxide in APL as well as the serum or urine concentrations of inorganic arsenic and the methylated metabolites. MATERIALS AND METHODS PatientThe patient was a 72-year-old male patient weighing 57.5 kg. In September 1999, he was diagnosed with APL. The marrow smears showed increased promyelocytes (80%). Chromosome analysis revealed 47; ϩ8, t(15; 17)(q22; q11-21). He achieved first CR with ATRA and chemotherapy. Subsequently the consolidation therapy was started on Day 56, which led to PML-RARa negative, followed by one-year maintenance therapy with ATRA. In January 2001, He relapsed and achieved second CR with ATRA. However, in July 2001, the bone marrow smear obtained during the maintenance therapy revealed an increase of promyelocytes, and the patient was diagnosed as relapsed and ATRA resistant APL. Because the cumulative dose of anthracyclines had reached a limiting dose, and the patient was elderly, the induction therapy with further chemotherapy seemed to be highly risky. Before arsenic trioxide treatment, the protocol was reviewed and approved by the institutional ethical committee of our hospital, and written informed consent was obtained from the patient and his family (based on the ethical principle...

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“…The t(15;17)(q22;q21) is the most common form of the chromosomal translocations that target RAR , and seems to be responsible for transformed phenotype of APL [12,15,68,81,83,88,91]. This chromosomal translocation represents over 95% clinically relevant APL cases [1,27,83]. The PML/RAR may disrupt the normal function of RAR and PML [24,98].…”

Section: Rar Associated Fusions In Subtypes Of Acute Myeloid Leukemiamentioning

confidence: 99%

“…Thus, to terminally differentiate and mature, cells have to pass through hierarchy of successive developmental stages [1,2]. In each stage, the regulatory genes for hematopoiesis are either activated or silenced in a cell typespecific or lineage-specific manner to ensure a precise finetuning of the process [3][4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

The Common Leukemic Fusions in Pathogenesis and in Treatment Response in Acute Myeloid Leukemia

Fufan¹,

.²,

Persson

2010

TOLEUKEMIAJ

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Chromosomal abnormalities are the most common alterations in acute myeloid leukemia (AML). Among those abnormalities, chromosomal translocations that produce the oncogenic fusion proteins have been frequently observed in different subtypes of AML. Although molecular mechanisms underlying the consequences of the oncogenic transformation resulted from the fusion proteins have been extensively studied, little is known about the molecular events cooperative with the oncogenic fusion proteins in the pathogenesis of leukemia and the cellular mechanisms with regard to the predictive roles of the fusions in treatment response. In this article, we will present an overview of the important aspects of AML-associated fusion proteins and their regulated transcriptional networks in pathogenesis and prognosis of AML. We will also discuss the recent findings pertaining to the functional link between the oncogenic fusions and response of leukemic cells to the treatment. Understanding the regulation of AML-associated fusions and their association with disease characteristics, patient outcome and treatment response will be of fundamental importance for predicting the effectiveness of the treatment and design the specific therapeutic strategies.

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Signaling revisited in acute promyelocytic leukemia

Cited by 12 publications

References 100 publications

Activation of Protein Kinase Cδ by All-trans-retinoic Acid

Activation of Protein Kinase Cδ by All-trans-retinoic Acid

Clinical Pharmacokinetic Study of Arsenic Trioxide in an Acute Promyelocytic Leukemia (APL) Patient: Speciation of Arsenic Metabolites in Serum and Urine

The Common Leukemic Fusions in Pathogenesis and in Treatment Response in Acute Myeloid Leukemia

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