Acute Promyelocytic Leukemia: A Constellation of Molecular Events around a Single <i>PML-RARA</i> Fusion Gene
Although acute promyelocytic leukemia (APL) is one of the most characterized forms of acute myeloid leukemia (AML), the molecular mechanisms involved in the development and progression of this disease are still a matter of study. APL is defined by the <i>PML-RARA</i> rearrangement as a c...
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MDPI AG
2020-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/3/624 |
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| author | Alessandro Liquori Mariam Ibañez Claudia Sargas Miguel Ángel Sanz Eva Barragán José Cervera |
| author_facet | Alessandro Liquori Mariam Ibañez Claudia Sargas Miguel Ángel Sanz Eva Barragán José Cervera |
| author_sort | Alessandro Liquori |
| collection | DOAJ |
| description | Although acute promyelocytic leukemia (APL) is one of the most characterized forms of acute myeloid leukemia (AML), the molecular mechanisms involved in the development and progression of this disease are still a matter of study. APL is defined by the <i>PML-RARA</i> rearrangement as a consequence of the translocation t(15;17)(q24;q21). However, this abnormality alone is not able to trigger the whole leukemic phenotype and secondary cooperating events might contribute to APL pathogenesis. Additional somatic mutations are known to occur recurrently in several genes, such as <i>FLT3</i>, <i>WT1</i>, <i>NRAS</i> and <i>KRAS</i>, whereas mutations in other common AML genes are rarely detected, resulting in a different molecular profile compared to other AML subtypes. How this mutational spectrum, including point mutations in the <i>PML-RARA</i> fusion gene, could contribute to the 10%−15% of relapsed or resistant APL patients is still unknown. Moreover, due to the uncertain impact of additional mutations on prognosis, the identification of the APL-specific genetic lesion is still the only method recommended in the routine evaluation/screening at diagnosis and for minimal residual disease (MRD) assessment. However, the gene expression profile of genes, such as <i>ID1, BAALC, ERG</i>, and <i>KMT2E,</i> once combined with the molecular events, might improve future prognostic models, allowing us to predict clinical outcomes and to categorize APL patients in different risk subsets, as recently reported. In this review, we will focus on the molecular characterization of APL patients at diagnosis, relapse and resistance, in both children and adults. We will also describe different standardized molecular approaches to study MRD, including those recently developed. Finally, we will discuss how novel molecular findings can improve the management of this disease. |
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| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T18:23:25Z |
| publishDate | 2020-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-bc70e85bb50d4645b7b1df08a7c3ffa42023-08-02T08:40:25ZengMDPI AGCancers2072-66942020-03-0112362410.3390/cancers12030624cancers12030624Acute Promyelocytic Leukemia: A Constellation of Molecular Events around a Single <i>PML-RARA</i> Fusion GeneAlessandro Liquori0Mariam Ibañez1Claudia Sargas2Miguel Ángel Sanz3Eva Barragán4José Cervera5Accredited Research Group in Hematology and Hemotherapy, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, SpainDepartment of Hematology, Hospital Universitario y Politécnico La Fe, 46026 Valencia, SpainAccredited Research Group in Hematology and Hemotherapy, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, SpainDepartment of Hematology, Hospital Universitario y Politécnico La Fe, 46026 Valencia, SpainDepartment of Hematology, Hospital Universitario y Politécnico La Fe, 46026 Valencia, SpainDepartment of Hematology, Hospital Universitario y Politécnico La Fe, 46026 Valencia, SpainAlthough acute promyelocytic leukemia (APL) is one of the most characterized forms of acute myeloid leukemia (AML), the molecular mechanisms involved in the development and progression of this disease are still a matter of study. APL is defined by the <i>PML-RARA</i> rearrangement as a consequence of the translocation t(15;17)(q24;q21). However, this abnormality alone is not able to trigger the whole leukemic phenotype and secondary cooperating events might contribute to APL pathogenesis. Additional somatic mutations are known to occur recurrently in several genes, such as <i>FLT3</i>, <i>WT1</i>, <i>NRAS</i> and <i>KRAS</i>, whereas mutations in other common AML genes are rarely detected, resulting in a different molecular profile compared to other AML subtypes. How this mutational spectrum, including point mutations in the <i>PML-RARA</i> fusion gene, could contribute to the 10%−15% of relapsed or resistant APL patients is still unknown. Moreover, due to the uncertain impact of additional mutations on prognosis, the identification of the APL-specific genetic lesion is still the only method recommended in the routine evaluation/screening at diagnosis and for minimal residual disease (MRD) assessment. However, the gene expression profile of genes, such as <i>ID1, BAALC, ERG</i>, and <i>KMT2E,</i> once combined with the molecular events, might improve future prognostic models, allowing us to predict clinical outcomes and to categorize APL patients in different risk subsets, as recently reported. In this review, we will focus on the molecular characterization of APL patients at diagnosis, relapse and resistance, in both children and adults. We will also describe different standardized molecular approaches to study MRD, including those recently developed. Finally, we will discuss how novel molecular findings can improve the management of this disease.https://www.mdpi.com/2072-6694/12/3/624acute promyelocytic leukemiaaplngsminimal residual diseasemrdpml-raraisoformrelapsesplicing |
| spellingShingle | Alessandro Liquori Mariam Ibañez Claudia Sargas Miguel Ángel Sanz Eva Barragán José Cervera Acute Promyelocytic Leukemia: A Constellation of Molecular Events around a Single <i>PML-RARA</i> Fusion Gene Cancers acute promyelocytic leukemia apl ngs minimal residual disease mrd pml-rara isoform relapse splicing |
| title | Acute Promyelocytic Leukemia: A Constellation of Molecular Events around a Single <i>PML-RARA</i> Fusion Gene |
| title_full | Acute Promyelocytic Leukemia: A Constellation of Molecular Events around a Single <i>PML-RARA</i> Fusion Gene |
| title_fullStr | Acute Promyelocytic Leukemia: A Constellation of Molecular Events around a Single <i>PML-RARA</i> Fusion Gene |
| title_full_unstemmed | Acute Promyelocytic Leukemia: A Constellation of Molecular Events around a Single <i>PML-RARA</i> Fusion Gene |
| title_short | Acute Promyelocytic Leukemia: A Constellation of Molecular Events around a Single <i>PML-RARA</i> Fusion Gene |
| title_sort | acute promyelocytic leukemia a constellation of molecular events around a single i pml rara i fusion gene |
| topic | acute promyelocytic leukemia apl ngs minimal residual disease mrd pml-rara isoform relapse splicing |
| url | https://www.mdpi.com/2072-6694/12/3/624 |
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