Novel Retinoic Acid Receptor-  Transcripts in Acute Promyelocytic Leukemia Responsive to All-trans-Retinoic Acid

Abstract The majority of acute promyelocytic leukemia (APL) cases are characterized by the presence of a promyelocytic leukemia–retinoic acid receptor alpha(RARA) fusion gene. In a small subset, RARA is fused to a different partner, usually involved in regulating cell growth and differentiation. Here, we identified a novel RARA fusion transcript, BCOR-RARA, in a t(X;17)(p11;q12) variant of APL with unique morphologic features, including rectangular and round cytoplasmic inclusion bodies. Although the patient was clinically responsive to all-trans retinoic acid, several relapses occurred with standard chemotherapy and all-trans retinoic acid. BCOR is a transcriptional corepressor through the proto-oncoprotein, BCL6, recruiting histone deacetylases and polycomb repressive complex 1 components. BCOR-RARA was found to possess common features with other RARA fusion proteins. These included: (1) the same break point in RARA cDNA; (2) self-association; (3) retinoid X receptor alpha is necessary for BCOR-RARA to associate with the RARA responsive element; (4) action in a dominant-negative manner on RARA transcriptional activation; and (5) aberrant subcellular relocalization. It should be noted that there was no intact BCOR found in the 45,-Y,t(X;17)(p11;q12) APL cells because they featured only a rearranged X chromosome. These results highlight essential features of pathogenesis in APL in more detail. BCOR appears to be involved not only in human congenital diseases, but also in a human cancer.

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PLZF-RARα, NPM1-RARα, and Other Acute Promyelocytic Leukemia Variants: The PETHEMA Registry Experience and Systematic Literature Review

Cancers ◽

10.3390/cancers12051313 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1313 ◽

Cited By ~ 1

Author(s):

Marta Sobas ◽

Maria Carme Talarn-Forcadell ◽

David Martínez-Cuadrón ◽

Lourdes Escoda ◽

María J. García-Pérez ◽

...

Keyword(s):

Retinoic Acid ◽

Complete Remission ◽

Acute Promyelocytic Leukemia ◽

Fusion Gene ◽

Retinoic Acid Receptor ◽

Promyelocytic Leukemia ◽

High Relapse Rate ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Shed Light

It has been suggested that 1–2% of acute promyelocytic leukemia (APL) patients present variant rearrangements of retinoic acid receptor alpha (RARα) fusion gene, with the promyelocytic leukaemia zinc finger (PLZF)/RARα being the most frequent. Resistance to all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has been suggested in PLZF/RARα and other variant APLs. Herein, we analyze the incidence, characteristics, and outcomes of variant APLs reported to the multinational PETHEMA (Programa para el Tratamiento de Hemopatias Malignas) registry, and we perform a systematic review in order to shed light on strategies to improve management of these extremely rare diseases. Of 2895 patients with genetically confirmed APL in the PETHEMA registry, 11 had variant APL (0.4%) (9 PLZF-RARα and 2 NPM1-RARα), 9 were men, with median age of 44.6 years (3 months to 76 years), median leucocytes (WBC) 16.8 × 109/L, and frequent coagulopathy. Eight patients were treated with ATRA plus chemotherapy-based regimens, and 3 with chemotherapy-based. As compared to previous reports, complete remission and survival was slightly better in our cohort, with 73% complete remission (CR) and 73% survival despite a high relapse rate (43%). After analyzing our series and performing a comprehensive and critical review of the literature, strong recommendations on appropriate management of variant APL are not possible due to the low number and heterogeneity of patients reported so far.

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Benzodithiophenes Potentiate Differentiation of Acute Promyelocytic Leukemia Cells by Lowering the Threshold for Ligand-Mediated Corepressor/Coactivator Exchange with Retinoic Acid Receptor α and Enhancing Changes in all-trans-Retinoic Acid–Regulated Gene Expression

Cancer Research ◽

10.1158/0008-5472.can-05-1056 ◽

2005 ◽

Vol 65 (17) ◽

pp. 7856-7865 ◽

Cited By ~ 7

Author(s):

Ke Xu ◽

Fabien Guidez ◽

Annegret Glasow ◽

Danna Chung ◽

Kevin Petrie ◽

...

Keyword(s):

Gene Expression ◽

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Retinoic Acid Receptor ◽

Promyelocytic Leukemia ◽

Leukemia Cells ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Retinoic Acid Receptor Α ◽

Regulated Gene Expression

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Extramedullary Involvement at Relapse in Acute Promyelocytic Leukemia Patients Treated or Not With All-Trans Retinoic Acid: A Report by the Gruppo Italiano Malattie Ematologiche dell’Adulto

Journal of Clinical Oncology ◽

10.1200/jco.2001.19.20.4023 ◽

2001 ◽

Vol 19 (20) ◽

pp. 4023-4028 ◽

Cited By ~ 96

Author(s):

Giorgina Specchia ◽

Francesco Lo Coco ◽

Marco Vignetti ◽

Giuseppe Avvisati ◽

Paola Fazi ◽

...

Keyword(s):

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Retinoic Acid Receptor ◽

Promyelocytic Leukemia ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Increased Risk ◽

Junction Type ◽

Wbc Count

PURPOSE: Recent reports of extramedullary disease (EMD) at recurrence in acute promyelocytic leukemia (APL) have raised increasing concern about a possible role of retinoic acid (RA) therapy. PATIENTS AND METHODS: We analyzed the risk of developing EMD localization at relapse in APL patients enrolled onto two consecutive studies of the Gruppo Italiano Malattie Ematologiche dell’Adulto. The studies investigated chemotherapy alone (LAP0389) versus RA plus chemotherapy (AIDA). RESULTS: When all relapse types were taken into account, 94 (51%) of 184 patients and 131 (18%) of 740 patients who attained hematologic remission underwent relapse in the LAP0389 and AIDA studies, respectively (P < .0001). EMD localization was documented in five (5%) of 94 and 16 (12%) of 131 patients (P = .08). Hematologic and/or molecular relapse was diagnosed concomitantly in all but two patients with EMD in the AIDA study. For patients in the LAP0389 and AIDA series, the probability of EMD localization of any type at relapse was 3% and 4.5%, respectively (P = .79), while the probability of CNS involvement was 0.6% and 2% (P = .28). No significant differences were found with regard to mean WBC count and promyelocytic leukemia/retinoic acid receptor-alpha junction type in comparisons of patients with EMD and hematologic relapse. CONCLUSION: APL patients receiving all-trans retinoic acid in addition to chemotherapy have no increased risk of developing EMD at relapse as compared with those treated with chemotherapy alone.

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Stat1 Is Induced and Activated by All-Trans Retinoic Acid in Acute Promyelocytic Leukemia Cells

Blood ◽

10.1182/blood.v89.3.1001 ◽

1997 ◽

Vol 89 (3) ◽

pp. 1001-1012 ◽

Cited By ~ 89

Author(s):

Maurizio Gianni ◽

Mineko Terao ◽

Ida Fortino ◽

Marco LiCalzi ◽

Vincenzo Viggiano ◽

...

Keyword(s):

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Intracellular Signaling ◽

Retinoic Acid Receptor ◽

Leukemia Cell ◽

Promyelocytic Leukemia ◽

Myelogenous Leukemia ◽

Oligoadenylate Synthetase ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

Abstract Treatment of freshly isolated acute promyelocytic leukemia (APL) cells and the myelogenous leukemia cell lines, NB4, HL-60, and U937, with all-trans retinoic acid (ATRA) results in a remarkable elevation in the amounts of Stat1α and Stat2 proteins. Stat1α protein levels are augmented by ATRA as a consequence of elevated amounts of the corresponding transcripts. The retinoid increases the levels of nuclear complexes that are capable of binding to interferon (IFN)-regulated consensus sequences and contain Stat1 and/or Stat2 proteins, and causes a rapid and long-lasting elevation in Stat1α tyrosine phosphorylation. Transient transfection experiments show that ATRA enhances the transactivating properties of Stat1α observed on an appropriate reporter gene, in the presence of the RARα retinoic acid receptor, but not in the presence of the PML-RAR protein. Treatment of NB4 cells with ATRA is associated with a remarkable upregulation of the two IFN-responsive genes IFN-responsive factor 1 and 2′-5′ oligoadenylate synthetase, as well as with an augmentation in the levels of IFNα secretion. Our data show that ATRA is capable of modulating the amounts and the state of activation of some of the components of the IFN intracellular signaling pathways. They also suggest that the retinoid can bypass IFN/IFN-receptor interactions and induce the expression of IFN-regulated genes.

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Disseminated Exfoliative Dermatitis Associated with All-Transretinoic Acid in the Treatment of Acute Promyelocytic Leukemia

Case Reports in Medicine ◽

10.1155/2012/236174 ◽

2012 ◽

Vol 2012 ◽

pp. 1-3 ◽

Cited By ~ 4

Author(s):

Yonal Ipek ◽

Dogru Hulya ◽

Aktan Melih

Keyword(s):

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Retinoic Acid Receptor ◽

Great Majority ◽

Promyelocytic Leukemia ◽

Chromosome 17 ◽

Whole Body ◽

Exfoliative Dermatitis ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

Acute promyelocytic leukemia (APL) is a biologically and clinically separate type of acute myeloid leukemia characterized by a translocation involving the retinoic acid receptor-alpha (RARa) locus on chromosome 17, the great majority of which is t(15; 17)(q24.1; q21.1) (Collins (1998), Melnick and Licht (1999), and Grimwade (1999)). Retinoic acid is a critical ligand in the differentiation pathway of multiple tissues, mediated through binding to an RAR. All-trans retinoic acid (ATRA) is a subgroup of the retinoid family, which induces complete remission (CR) in APL by causing differentiation and apoptosis in immature malignant promyelocytes rather than inducing cell death by cytotoxicity (Warrell et al. (1993), Liu et al. (2000), and Cassinat et al. (2001)). ATRA-associated toxicity consisting of headache, fever, weakness, fatigue, dry skin, dermatitis, gastrointestinal disorders, and hypertriglyceridemia has been shown to be mild (Kurzrock et al. (1993)). Herein, we describe a patient with APL that developed an erythematous reaction of the whole body followed by desquamation and exfoliation during ATRA therapy.

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Rearrangements in the second intron of the RARA gene are present in a large majority of patients with acute promyelocytic leukemia and are used as molecular marker for retinoic acid-induced leukemic cell differentiation

Blood ◽

10.1182/blood.v78.10.2696.2696 ◽

1991 ◽

Vol 78 (10) ◽

pp. 2696-2701 ◽

Cited By ~ 55

Author(s):

SJ Chen ◽

YJ Zhu ◽

JH Tong ◽

S Dong ◽

W Huang ◽

...

Keyword(s):

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Retinoic Acid Receptor ◽

Leukemic Cell ◽

Promyelocytic Leukemia ◽

Chromosome 17 ◽

Specific Marker ◽

Gene Rearrangements ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

Abstract Chromosome 17 breakpoints in translocation t(15;17), a hallmark for acute promyelocytic leukemia (APL), have been shown to disrupt the retinoic acid receptor-alpha (RARA) gene. In this study, DNA probes around the second exon of the RARA gene showed rearrangements not previously detected. Analysis of 25 Chinese APL cases showed that RARA gene rearrangements were present in 23 cases (92%). The breakpoints were mapped unequivocally in 22 cases within the second intron of the gene. Therefore, the RARA gene rearrangement provides us with a specific marker of the disease. Simultaneous molecular and cytologic studies showed that the RARA gene rearrangements persisted during the first 2 to 3 weeks of all-trans retinoic acid (ATRA) therapy when differentiated granulocytes predominated in bone marrow, while these rearrangements disappeared after achieving complete remission. These data indicate that ATRA induces differentiation of APL cells.

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Rearrangements in the second intron of the RARA gene are present in a large majority of patients with acute promyelocytic leukemia and are used as molecular marker for retinoic acid-induced leukemic cell differentiation

Blood ◽

10.1182/blood.v78.10.2696.bloodjournal78102696 ◽

1991 ◽

Vol 78 (10) ◽

pp. 2696-2701 ◽

Cited By ~ 1

Author(s):

SJ Chen ◽

YJ Zhu ◽

JH Tong ◽

S Dong ◽

W Huang ◽

...

Keyword(s):

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Retinoic Acid Receptor ◽

Leukemic Cell ◽

Promyelocytic Leukemia ◽

Chromosome 17 ◽

Specific Marker ◽

Gene Rearrangements ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

Chromosome 17 breakpoints in translocation t(15;17), a hallmark for acute promyelocytic leukemia (APL), have been shown to disrupt the retinoic acid receptor-alpha (RARA) gene. In this study, DNA probes around the second exon of the RARA gene showed rearrangements not previously detected. Analysis of 25 Chinese APL cases showed that RARA gene rearrangements were present in 23 cases (92%). The breakpoints were mapped unequivocally in 22 cases within the second intron of the gene. Therefore, the RARA gene rearrangement provides us with a specific marker of the disease. Simultaneous molecular and cytologic studies showed that the RARA gene rearrangements persisted during the first 2 to 3 weeks of all-trans retinoic acid (ATRA) therapy when differentiated granulocytes predominated in bone marrow, while these rearrangements disappeared after achieving complete remission. These data indicate that ATRA induces differentiation of APL cells.

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All-trans-retinoic acid induces CD52 expression in acute promyelocytic leukemia

Blood ◽

10.1182/blood-2002-05-1426 ◽

2003 ◽

Vol 101 (5) ◽

pp. 1977-1980 ◽

Cited By ~ 8

Author(s):

Shi-Wu Li ◽

Dongqi Tang ◽

Kim P. Ahrens ◽

Jin-Xiong She ◽

Raul C. Braylan ◽

...

Keyword(s):

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Retinoic Acid Receptor ◽

Leukemia Cell ◽

Myeloid Cell ◽

Promyelocytic Leukemia ◽

Leukemic Cells ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

High Level

It is well known that all-trans-retinoic acid (ATRA) can induce myeloid cell differentiation in acute promyelocytic leukemia (APL) cells. In this study, we found that ATRA treatment of the APL cell line NB4 induced the expression of CD52, both at transcriptional and translational levels. CD52 is a 21- to 28-kDa nonmodulating cell surface glycosylphosphatidylinositol-linked glycoprotein expressed on lymphocytes and monocytes, but not in human myeloid cells. The ATRA-dependent induction of CD52 expression was not observed in non-promyelocytic leukemia cell lines such as K562, U937, and HL-60, suggesting that induction of CD52 by ATRA may be specific to leukemic cells that express promyelocytic leukemia–retinoic acid receptor α (PML-RARα) or are at the promyelocytic stage of myeloid development. Antibodies against CD52 are used therapeutically against lymphocytes in certain leukemias and in patients undergoing transplantation. An ATRA-induced high level of CD52 expression might potentially serve as a novel therapeutic target in treatment of APL.

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