Bruno Samantha, Bandini Lorenza, Patuelli Agnese, Robustelli Valentina, Venturi Claudia, Mancini Manuela, Forte Dorian, De Santis Sara, Monaldi Cecilia, Grassi Alessandra, Chiurumbolo Gabriella, Paolini Stefania, Cristiano Gianluca, Papayannidis Cristina, Sartor Chiara, Nanni Jacopo, Ottaviani Emanuela, Curti Antonio, Cavo Michele, Soverini Simona
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy.
Front Oncol. 2021 Sep 30;11:728613. doi: 10.3389/fonc.2021.728613. eCollection 2021.
FMS-like tyrosine kinase 3 (FLT3) is among the most common driver genes recurrently mutated in acute myeloid leukemia (AML), accounting for approximately 30% of cases. Activating mutations of the FLT3 receptor include internal tandem duplications (ITD) that map to the auto-inhibitory juxtamembrane (JM) domain or point mutations within the tyrosine kinase domain (TKD). Several FLT3 tyrosine kinase inhibitors have been developed in the last few years, but midostaurin is currently the only one approved for the treatment of newly diagnosed patients harboring mutations. Here we describe for the first time a novel in-frame deletion in exon 14 (JM domain) of the gene, that we identified in a young woman with CBFb-MYH11-positive AML. We demonstrated that this novel variant is pathogenic, since it is responsible for constitutive activation of FLT3 receptor. Finally, studies demonstrated that this novel mutation is sensitive to midostaurin.
FMS样酪氨酸激酶3（FLT3）是急性髓系白血病（AML）中最常见的反复突变的驱动基因之一，约占病例的30%。FLT3受体的激活突变包括定位于自身抑制性近膜（JM）结构域的内部串联重复（ITD）或酪氨酸激酶结构域（TKD）内的点突变。在过去几年中已经开发了几种FLT3酪氨酸激酶抑制剂，但米哚妥林是目前唯一被批准用于治疗携带该突变的新诊断患者的药物。在此，我们首次描述了在一名CBFb-MYH11阳性AML年轻女性中鉴定出的FLT3基因外显子14（JM结构域）中的一种新型框内缺失。我们证明这种新型变体具有致病性，因为它导致FLT3受体的组成性激活。最后，研究表明这种新型突变对米哚妥林敏感。
