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.

• Authors: Emiliano Fabiani, Laura Cicconi, Anna Maria Nardozza, Antonio Cristiano, Marianna Rossi, Tiziana Ottone, Giulia Falconi, Mariadomenica Divona, Anna Maria Testi, Ombretta Annibali, Roberto Castelli, Vladimir Lazarevic, Eduardo Rego, Pau Montesinos, Jordi Esteve, Adriano Venditti, Matteo Della Porta, William Arcese, Francesco Lo-Coco, Maria Teresa Voso
• Journal: Cancer medicine (Cancer Med) Vol. 10 Issue 12 Pg. 3839-3847 (06 2021) ISSN: 2045-7634 [Electronic] United States
• PMID: 34042280 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Chemical References

• ARID1A protein, human
• ARID2 protein, human
• Antineoplastic Agents
• DNA-Binding Proteins
• Nuclear Proteins
• Oncogene Proteins, Fusion
• Promyelocytic Leukemia Zinc Finger Protein
• RARA protein, human
• Retinoic Acid Receptor alpha
• Transcription Factors
• ZBTB16 protein, human
• Tretinoin
• SMARCA4 protein, human
• DNA Helicases
• Arsenic Trioxide

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (therapeutic use)
• Arsenic Trioxide (therapeutic use)
• Bone Marrow (pathology)
• Child
• Chromosomes, Human, Pair 11
• Chromosomes, Human, Pair 17
• DNA Helicases (genetics)
• DNA-Binding Proteins (genetics)
• Disseminated Intravascular Coagulation (epidemiology)
• Female
• High-Throughput Nucleotide Sequencing
• Humans
• Leukemia, Myeloid, Acute (drug therapy, genetics, pathology)
• Leukemia, Promyelocytic, Acute (genetics, pathology)
• Male
• Middle Aged
• Nuclear Proteins (genetics)
• Oncogene Proteins, Fusion (genetics)
• Prognosis
• Promyelocytic Leukemia Zinc Finger Protein (genetics)
• Retinoic Acid Receptor alpha (genetics)
• Transcription Factors (genetics)
• Translocation, Genetic
• Tretinoin (therapeutic use)