scholarly journals Acute promyelocytic leukemia lacking t(15;17): Molecular evidence of atypical PML/RAR-α transcriptional variant by gene sequencing

2020 ◽  
Vol 77 (1) ◽  
pp. 97-102
Author(s):  
Vesna Djordjevic ◽  
Natasa Tosic ◽  
Marija Dencic-Fekete ◽  
Marijana Virijevic ◽  
Jelica Jovanovic ◽  
...  
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Retinoic Acid Receptor ◽  
Fusion Transcript ◽  
Promyelocytic Leukemia ◽  
Molecular Evidence ◽  
Fish Analysis ◽  
Conventional Cytogenetic Analysis ◽  
The Impact

Introduction. The accurate diagnosis of acute promyelocytic leukemia (APL), not only on the morphological and clinical, but also on the molecular level, is very important for application of targeted therapies. Case report. A 62- year-old woman presented with APL. By using conventional cytogenetic analysis as well as applying the fluorescence in situ hybridization (FISH) analysis it has not been possible to confirm the presence of t(15;17) in the presented patient. Using reverse transcriptase polymerase chain reaction (RT-PCR) two atypical promyelotic leukemia/ retinoic acid receptor alpha (PML/RAR-?) fusion transcripts were identified. Both detected transcripts were isoforms. The larger transcript was in-frame, coding for functional aberrant PML/RAR-? protein, while the shorter transcript was an out-of-frame. Conclusion. Our study highlights the need for the application of molecular methodology in daily clinical practice. Precise characterization of PML/RAR-? fusion transcript creates a basis for identifying rare individual cases that require special caution when treating such patients. To our knowledge this is only the fifth case of atypical PML/RAR-? transcript containing full PML exon 7a, and among them the only one that was cytogenetically cryptic and FISH negative. All of the herein presented cases had lethal outcome. Therefore, our findings with the additional review of the literature, emphasizes the importance of detailed identification of atypical PML/RAR-? fusions, not only for the purpose of knowing their role in leukemogenesis, but also for the assessment of the impact that they can have on the outcome of the treatment.

scholarly journals Autophagy: New Insights into Mechanisms of Action and Resistance of Treatment in Acute Promyelocytic leukemia

2019 ◽  
Vol 20 (14) ◽  
pp. 3559 ◽  
Author(s):  
Mohammad Amin Moosavi ◽  
Mojgan Djavaheri-Mergny
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Retinoic Acid Receptor ◽  
Mechanisms Of Action ◽  
Promyelocytic Leukemia ◽  
Development Of Resistance ◽  
Therapeutic Benefits ◽  
Differentiating Agent ◽  
Cancer Agent ◽  
The Impact

Autophagy is one of the main cellular catabolic pathways controlling a variety of physiological processes, including those involved in self-renewal, differentiation and death. While acute promyelocytic leukemia (APL) cells manifest low levels of expression of autophagy genes associated with reduced autophagy activity, the introduction of all-trans retinoid acid (ATRA)—a differentiating agent currently used in clinical settings—restores autophagy in these cells. ATRA-induced autophagy is involved in granulocytes differentiation through a mechanism that involves among others the degradation of the PML-RARα oncoprotein. Arsenic trioxide (ATO) is another anti-cancer agent that promotes autophagy-dependent clearance of promyelocytic leukemia retinoic acid receptor alpha gene (PML-RARα) in APL cells. Hence, enhancing autophagy may have therapeutic benefits in maturation-resistant APL cells. However, the role of autophagy in response to APL therapy is not so simple, because some autophagy proteins have been shown to play a pro-survival role upon ATRA and ATO treatment, and both agents can activate ETosis, a type of cell death mediated by the release of neutrophil extracellular traps (ETs). This review highlights recent findings on the impact of autophagy on the mechanisms of action of ATRA and ATO in APL cells. We also discuss the potential role of autophagy in the development of resistance to treatment, and of differentiation syndrome in APL.

scholarly journals Identification of IRF8 as a potent tumor suppressor in murine acute promyelocytic leukemia

2018 ◽  
Vol 2 (19) ◽  
pp. 2462-2466 ◽  
Author(s):  
Coline Gaillard ◽  
Sangeetha Surianarayanan ◽  
Trevor Bentley ◽  
Matthew R. Warr ◽  
Briana Fitch ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Acute Promyelocytic Leukemia ◽  
Retinoic Acid Receptor ◽  
Myeloproliferative Neoplasm ◽  
Promyelocytic Leukemia ◽  
Protein Levels ◽  
Retinoic Acid Receptor Α ◽  
Myeloid Neoplasia ◽  
The Impact

Abstract Although the role of promyelocytic leukemia/retinoic acid receptor α (PML/RARA) fusion protein is well recognized in acute promyelocytic leukemia (APL), its contribution to initiation and maintenance of leukemogenesis is not completely understood. Transcriptome analysis in the murine MRP8-PML/RARA APL model has demonstrated modest alterations in gene expression accompanied by expansion of the promyelocyte compartment. Of particular interest, mice expressing PML/RARA showed downregulation of the transcription factor Irf8 mRNA. Interferon regulatory factor 8 (IRF8) is a known regulator of hematopoiesis. Previous research had implicated IRF8 as a tumor suppressor for myeloid neoplasia, and mice lacking IRF8 develop a well-differentiated myeloproliferative neoplasm characterized by expansion of neutrophilic lineage cells. We hypothesized that PML/RARA-mediated downregulation of Irf8 transcript levels contributes to the initiation of APL. We observed significant downregulation of IRF8 protein levels in highly purified promyelocyte populations of PML/RARA transgenic mice. We also found that loss of IRF8 results in expansion of promyelocytes in vivo, partially phenocopying the impact of PML/RARA expression. Moreover, survival experiments showed that complete loss of IRF8 leads to acceleration of APL onset in our PML/RARA mice. Collectively, these data identify IRF8 downregulation as an important factor in APL initiation and highlight a tumor-suppressor role for IRF8 in this acute leukemia.

scholarly journals Characterizing PML/RAR? Isoforms of Acute Promyelocytic Leukemia (APL) in Malay Patients

2014 ◽  
Vol 13 (3) ◽  
pp. 311-315 ◽  
Author(s):  
Rosline Hassan ◽  
Abu Dzarr Abdullah ◽  
Azlan Husin ◽  
Wan Zaidah Abdullah ◽  
Rapiaah Mustaffa ◽  
...  
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Retinoic Acid Receptor ◽  
Medical Science ◽  
Fusion Transcript ◽  
Promyelocytic Leukemia ◽  
Pcr Analysis ◽  
Chromosome 15 ◽  
Rt Pcr ◽  
Number Of Patients ◽  
Different Types

Aim: Reciprocal translocation between retinoic acid receptor alpha (RAR?) gene on chromo- some 17 and promyelocytic leukemia (PML) gene on chromosome 15 is the hallmark for acute promyelocytic leukemia (APL). Three different PML/RAR? isoforms have been described; S-form, L-form and V-form. Our aims were to characterize the different types of PML/RAR? iso- forms in Malay patients with APL and to determine the outcome of these different types of iso-forms. Materials and methods: RT-PCR analysis was performed on 20 patients recruited from hematology-oncology ward. RT-PCR detected fusion transcript of PML/RAR? in all patients. Results and Discussion: Of these patients, 65% (13 patients) exhibited L/V-form, and 35% (7 patients) S-form. Total white blood cell count (TWBC) was higher in L/V-form (25 x 109/l) compared to S-form (2.1 x 109/l) (p < 0.05). Five years survival rate was 100% and 33.3% for L/V-forms and S-forms respectively (p<0.005). Conclusion: We conclude that L/V- forms is the commonest isoform among Malays. They presented at younger age with higher TWBC counts. Although the sample size is small, our preliminary data showed an interestingly longer survival outcome among L/V-forms compared to S-form. PML/RAR? isoforms could be used in future as risk stratification feature in patients diagnosed as APL. Further study with more number of patients is required. DOI: http://dx.doi.org/10.3329/bjms.v13i3.15553 Bangladesh Journal of Medical Science Vol.13(3) 2014 p.311-315

scholarly journals Acute myeloid leukemia with CPSF6–RARG fusion resembling acute promyelocytic leukemia with extramedullary infiltration

2021 ◽  
Vol 12 ◽  
pp. 204062072097698
Author(s):  
Xiaoyan Han ◽  
Chunxiang Jin ◽  
Gaofeng Zheng ◽  
Yi Li ◽  
Yungui Wang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Myeloid Leukemia ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Specific Factor ◽  
Acid Receptor ◽  
Response To Chemotherapy ◽  
Acute Myeloid

Some subtypes of acute myeloid leukemia (AML) share morphologic, immunophenotypic, and clinical features of acute promyelocytic leukemia (APL), but lack a PML–RARA (promyelocytic leukemia–retinoic acid receptor alpha) fusion gene. Instead, they have the retinoic acid receptor beta (RARB) or retinoic acid receptor gamma (RARG) rearranged. Almost all of these AML subtypes exhibit resistance to all-trans retinoic acid (ATRA); undoubtedly, the prognosis is poor. Here, we present an AML patient resembling APL with a novel cleavage and polyadenylation specific factor 6 ( CPSF6) –RARG fusion, showing resistance to ATRA and poor response to chemotherapy with homoharringtonine and cytarabine. Simultaneously, the patient also had extramedullary infiltration.

scholarly journals ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression

Blood ◽  
2006 ◽  
Vol 107 (8) ◽  
pp. 3330-3338 ◽  
Author(s):  
Beatrice U. Mueller ◽  
Thomas Pabst ◽  
José Fos ◽  
Vibor Petkovic ◽  
Martin F. Fey ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Myeloid Leukemia ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
All Trans Retinoic Acid ◽  
Conditional Expression ◽  
Neutrophil Differentiation ◽  
Acute Myeloid

Abstract Tightly regulated expression of the transcription factor PU.1 is crucial for normal hematopoiesis. PU.1 knockdown mice develop acute myeloid leukemia (AML), and PU.1 mutations have been observed in some populations of patients with AML. Here we found that conditional expression of promyelocytic leukemia-retinoic acid receptor α (PML-RARA), the protein encoded by the t(15;17) translocation found in acute promyelocytic leukemia (APL), suppressed PU.1 expression, while treatment of APL cell lines and primary cells with all-trans retinoic acid (ATRA) restored PU.1 expression and induced neutrophil differentiation. ATRA-induced activation was mediated by a region in the PU.1 promoter to which CEBPB and OCT-1 binding were induced. Finally, conditional expression of PU.1 in human APL cells was sufficient to trigger neutrophil differentiation, whereas reduction of PU.1 by small interfering RNA (siRNA) blocked ATRA-induced neutrophil differentiation. This is the first report to show that PU.1 is suppressed in acute promyelocytic leukemia, and that ATRA restores PU.1 expression in cells harboring t(15;17).

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