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.

Mutational profile of ZBTB16-RARA-positive acute myeloid leukemia / Fabiani, E.; Cicconi, L.; Nardozza, A. M.; Cristiano, A.; Rossi, M.; Ottone, T.; Falconi, G.; Divona, M.; Testi, A. M.; Annibali, O.; Castelli, R.; Lazarevic, V.; Rego, E.; Montesinos, P.; Esteve, J.; Venditti, A.; Della Porta, M.; Arcese, W.; Lo-Coco, F.; Voso, M. T.. - In: CANCER MEDICINE. - ISSN 2045-7634. - 10:12(2021), pp. 3839-3847. [10.1002/cam4.3904]

Mutational profile of ZBTB16-RARA-positive acute myeloid leukemia

Castelli R.;
2021

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.
Mutational profile of ZBTB16-RARA-positive acute myeloid leukemia / Fabiani, E.; Cicconi, L.; Nardozza, A. M.; Cristiano, A.; Rossi, M.; Ottone, T.; Falconi, G.; Divona, M.; Testi, A. M.; Annibali, O.; Castelli, R.; Lazarevic, V.; Rego, E.; Montesinos, P.; Esteve, J.; Venditti, A.; Della Porta, M.; Arcese, W.; Lo-Coco, F.; Voso, M. T.. - In: CANCER MEDICINE. - ISSN 2045-7634. - 10:12(2021), pp. 3839-3847. [10.1002/cam4.3904]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11388/254513
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