Department of Biomedicine and Prevention, University Tor Vergata Rome, Rome, Italy.
UniCamillus-Saint Camillus International University of Health Sciences, Rome, Italy.
Cancer Med. 2021 Jun;10(12):3839-3847. doi: 10.1002/cam4.3904. Epub 2021 May 27.
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.
The mutational profile of ZBTB16-RARA rearranged AML has not been described so far.
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).
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%).
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.
ZBTB16-RARA 融合基因是由 11 号染色体上的 ZBTB16 与 17 号染色体上的 RARA 基因之间的相互易位形成的[ t(11;17)(q23;q21)]，在急性髓系白血病（AML）中很少见，约占 RARA 重排的 1%。具有这种罕见易位的 AML 具有不寻常的骨髓（BM）形态，介于急性早幼粒细胞白血病（APL）和成熟 AML 之间。患者在诊断时可能有弥漫性血管内凝血的高发生率，对全反式维甲酸（ATRA）和三氧化二砷反应不佳，且总体预后较差。
ZBTB16-RARA 重排 AML 的突变谱尚未描述。
我们对 7 例 ZBTB16-RARA+AML、103 例非 RARA 重排 AML 和 46 例 APL 的 BM 诊断样本进行了 24 种髓系基因的靶向下一代测序。然后对这 7 例 ZBTB16-RARA 阳性患者进行了额外突变的筛选，使用全外显子组测序（n=3）或包括 409 个基因的扩展癌症面板（n=4）。
与 APL 和其他 AML 相比，ZBTB16-RARA+AML 患者的每个患者的突变数量和涉及的基因数量均处于中间水平。特别是，我们发现 ZBTB16-RARA+AML 中 ARID1A 突变的发生率很高（7 例中的 5 例，71%）。在一个病例中还发现了 ARID2 和 SMARCA4 突变，这两种突变也是 SWI/SNF 染色质重塑复合物的肿瘤抑制基因。
我们的数据表明 ARID1A 基因突变和其他 SWI/SNF 染色质重塑复合物成员与 ZBTB16-RARA+AML 的关联，它们可能支持该疾病的特殊表型。
