Department of Microbiology, Hematology and Immunology, Faculty of Pharmacy, Damascus University, Ministry of High Education, Damascus, Syria.
Department of Molecular Biology and Biotechnology, Human Genetics Division, Atomic Energy Commission, Damascus, Syria.
J Med Case Rep. 2021 Jan 26;15(1):22. doi: 10.1186/s13256-020-02587-3.
Approximately 30% of adult acute myeloid leukemia (AML) acquire within fms-like tyrosine kinase 3 gene (FLT3) internal tandem duplications (FLT3/ITDs) in their juxtamembrane domain (JMD). FLT3/ITDs range in size from three to hundreds of nucleotides, and confer an adverse prognosis. Studies on a possible relationship between of FLT3/ITDs length and clinical outcomes in those AML patients were inconclusive, yet.
Here we report a 54-year-old Arab male diagnosed with AML who had two FLT3-ITD mutations in addition to NPM1 mutation. Cytogenetic approaches (banding cytogenetics) and fluorescence in situ hybridization (FISH) using specific probes to detect translocations t(8;21), t(15;17), t(16;16), t(12;21), and deletion del(13q)) were applied to exclude chromosomal abnormalities. Molecular genetic approaches (polymerase chain reaction (PCR) and the Sanger sequencing) identified a yet unreported combination of two new mutations in FLT3-ITDs. The first mutation induced a frameshift in JMD, and the second led to a homozygous substitution of c.1836T>A (p.F612L) also in JMD. Additionally a NPM1 type A mutation was detected. The first chemotherapeutic treatment was successful, but 1 month after the initial diagnosis, the patient experienced a relapse and unfortunately died.
To the best of our knowledge, a combination of two FLT3-ITD mutations in JMD together with an NPM1 type A mutation were not previously reported in adult AML. Further studies are necessary to prove or rule out whether the size of these FLT3-ITDs mutations and potential other double mutations in FLT3-ITD are correlated with the observed adverse outcome.
约 30%的成人急性髓系白血病（AML）在其近膜结构域（JMD）中获得 fms 样酪氨酸激酶 3 基因（FLT3）内串联重复（FLT3/ITD）。FLT3/ITD 的大小从三个到数百个核苷酸不等，并赋予不良预后。然而，关于 AML 患者中 FLT3/ITD 长度与临床结局之间可能存在的关系的研究尚无定论。
这里我们报告了一名 54 岁的阿拉伯男性，被诊断为 AML，除了 NPM1 突变外，还存在两种 FLT3-ITD 突变。细胞遗传学方法（带型细胞遗传学）和荧光原位杂交（FISH）使用特定探针检测易位 t(8;21)、t(15;17)、t(16;16)、t(12;21) 和缺失 del(13q)）排除染色体异常。分子遗传学方法（聚合酶链反应（PCR）和 Sanger 测序）鉴定了 FLT3-ITD 中两种新突变的尚未报道的组合。第一个突变在 JMD 中诱导移码，第二个突变导致 JMD 中 c.1836T>A(p.F612L)的纯合取代。此外，还检测到 NPM1 型 A 突变。首次化疗治疗成功，但在初始诊断后 1 个月，患者复发，不幸去世。
据我们所知，JMD 中两种 FLT3-ITD 突变与 NPM1 型 A 突变的组合在成人 AML 中尚未报道。需要进一步研究来证实或排除这些 FLT3-ITD 突变的大小以及潜在的其他 FLT3-ITD 双突变是否与观察到的不良结果相关。
