A large exon 6 break in V-form acute promyelocytic leukemia: relevance to clinical management

Bussaglia, Elena; Nomdedéu, Josep F.

doi:10.1038/sj.leu.2404799

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“…These are characterized by cDNA deletions of either the distal region of PML exon 6 (from 8 to 146 nucleotides), or the entire exon 6, as a result of a mis-splicing event or a genomic break within PML exon 6 (rarely in PML exon 5). Likewise, atypical bcr2 are frequently associated with insertions of three to 127 extra nucleotides (1 to 42 extra amino acids) of genomic DNA from RARA intron 2 [63,[68][69][70][71][72][73][74]. In most of the cases, V-forms are "private", being observed in single APL patients.…”

Section: Pml-rara Atypical Isoformsmentioning

confidence: 99%

Acute Promyelocytic Leukemia: A Constellation of Molecular Events around a Single PML-RARA Fusion Gene

Liquori

Ibáñez

Sargas

et al. 2020

Cancers

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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 PML-RARA 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 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. 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. 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 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. 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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