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PML is located in chromosome band 15q24, and contains nine exons producing several alternative spliced transcripts. This derives from a cytogenetic translocation leading to the rearrangement of PML and RARA genes. The PML-RARA fusion gene is the most critical event involved in the pathogenesis of APL. The present review discusses some of the most recent findings concerning the molecular genetics of APL, beyond the PML-RARA fusion gene and its variants, both at diagnosis and relapse and includes the main strategies for minimal residual disease (MRD) monitoring in patients.
#SINGLES HAPPY END RAR FILES PLUS#
This fusion gene has been demonstrated to be responsible for cellular transformation, and confers a particular sensitivity to treatment with differentiating agents such as all-trans-retinoic acid (ATRA) plus chemotherapy or ATRA plus arsenic-trioxide (ATO), converting this once fatal leukemia into a highly curable disease both for pediatric and adult patients (cure rates of approximately 90%).
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This translocation involves the retinoic acid receptor alpha ( RARA) gene on chromosome 17 and the promyelocytic leukemia ( PML) gene on chromosome 15 that results in a PML-RARA fusion gene. Finally, we will discuss how novel molecular findings can improve the management of this disease.Īcute promyelocytic leukemia (APL) is a biologically and clinically distinct subtype of acute myeloid leukemia (AML) with unique molecular pathogenesis, clinical manifestations and treatment that is cytogenetically characterized by a balanced translocation t(15 17) (q24 q21). We will also describe different standardized molecular approaches to study MRD, including those recently developed. In this review, we will focus on the molecular characterization of APL patients at diagnosis, relapse and resistance, in both children and adults. However, the gene expression profile of genes, such as ID1, BAALC, ERG, and KMT2E, 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. 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. How this mutational spectrum, including point mutations in the PML-RARA fusion gene, could contribute to the 10%–15% of relapsed or resistant APL patients is still unknown. Additional somatic mutations are known to occur recurrently in several genes, such as FLT3, WT1, NRAS and KRAS, whereas mutations in other common AML genes are rarely detected, resulting in a different molecular profile compared to other AML subtypes. However, this abnormality alone is not able to trigger the whole leukemic phenotype and secondary cooperating events might contribute to APL pathogenesis. APL is defined by the PML-RARA rearrangement as a consequence of the translocation t(15 17)(q24 q21). 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.