Dataset Information

Mutational profile of ZBTB16-RARA-positive acute myeloid leukemia.

ABSTRACT:

Background

The ZBTB16-RARA fusion gene, resulting from the reciprocal translocation between ZBTB16 on chromosome 11 and RARA genes on chromosome 17 [t(11;17)(q23;q21)], is rarely observed in acute myeloid leukemia (AML), and accounts for about 1% of retinoic acid receptor-α (RARA) rearrangements. AML with this rare translocation shows unusual bone marrow (BM) morphology, with intermediate aspects between acute promyelocytic leukemia (APL) and AML with maturation. Patients may have a high incidence of disseminated intravascular coagulation at diagnosis, are poorly responsive to all-trans retinoic acid (ATRA) and arsenic tryoxyde, and are reported to have an overall poor prognosis.

Aims

The mutational profile of ZBTB16-RARA rearranged AML has not been described so far.

Materials and methods

We performed targeted next-generation sequencing of 24 myeloid genes in BM diagnostic samples from seven ZBTB16-RARA+AML, 103 non-RARA rearranged AML, and 46 APL. The seven ZBTB16-RARA-positive patients were then screened for additional mutations using whole exome sequencing (n = 3) or an extended cancer panel including 409 genes (n = 4).

Results

ZBTB16-RARA+AML showed an intermediate number of mutations per patient and involvement of different genes, as compared to APL and other AMLs. In particular, we found a high incidence of ARID1A mutations in ZBTB16-RARA+AML (five of seven cases, 71%). Mutations in ARID2 and SMARCA4, other tumor suppressor genes also belonging to SWI/SNF chromatin remodeling complexes, were also identified in one case (14%).

Discussion and conclusion

Our data suggest the association of mutations of the ARID1A gene and of the other members of the SWI/SNF chromatin remodeling complexes with ZBTB16-RARA+AMLs, where they may support the peculiar disease phenotype.

SUBMITTER: Fabiani E

PROVIDER: S-EPMC8209618 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCytogenetic analysis continues to have an important role in the management of acute myeloid leukemia (AML) because it is essential for prognostication. It is also necessary to diagnose specific categories of AML and to determine the most effective form of treatment. Reports from South Asia are few because the availability of cytogenetic services is relatively limited.MethodsWe performed a retrospective analysis of the cytogenetic findings in adults with AML seen consecutively in a single centre in India. The results were categorised according to the 2022 World Health Organisation (WHO), International Consensus Classification (ICC) and European LeukemiaNet (ELN) classifications.ResultsThere were 1791 patients aged 18-85 years (median age 42, 1086 males). Normal karyotypes were seen in 646 (36%) patients. The 1145 (64%) abnormal karyotypes comprised 585 (32.7%) with recurrent genetic abnormalities (RGA), 403 (22.5%) with myelodysplasia-related cytogenetic abnormalities (MRC), and 157 (8.8%) with other abnormalities. There were 567 (31.7%) patients with solitary abnormalities and 299 (16.7%) with two abnormalities. Among the 279 (15.6%) patients with ≥ 3 abnormalities, 200 (11.2%) had complex karyotypes (CK) as per the WHO/ICC and 184 (10.3%), as per the ELN definition. There were 158 (8.8%) monosomal karyotypes (MK). Patients with normal karyotypes had a higher median age (45 years) than those with abnormal karyotypes (40 years, p < 0.001), and those with ≥ 3 abnormalities (43 years), than those with fewer abnormalities (39 years, p = 0.005). Patients with CK (WHO/ICC) and monosomal karyotypes had a median age of 48 years. Those with RGA had a lower median age (35 years, p < 0.001) than MRC (46 years) or other abnormalities (44 years). The t(15;17) was the most common abnormality (16.7%),followed by trisomy 8 (11.6%), monosomy 7/del 7q (9.3%), t(8;21) (7.2%), monosomy 5/del 5q (6.7%) and monosomy 17/del 17p (5.2%).ConclusionOur findings confirm the lower age profile of AML in India and show similarities and differences with respect to the frequencies of individual abnormalities compared to the literature. The frequencies of the t(15;17), trisomy 8 and the high-risk abnormalities monosomy 7 and monosomy 5/del 5q were higher, and that of the inv(16), lower than in most reports.