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Case Reports
. 2021 Sep 30:11:728613.
doi: 10.3389/fonc.2021.728613. eCollection 2021.

Case Report: A Novel Activating FLT3 Mutation in Acute Myeloid Leukemia

Samantha Bruno  1 , Lorenza Bandini  2 , Agnese Patuelli  2 , Valentina Robustelli  1   2 , Claudia Venturi  1 , Manuela Mancini  2 , Dorian Forte  1 , Sara De Santis  1 , Cecilia Monaldi  1 , Alessandra Grassi  2 , Gabriella Chiurumbolo  2 , Stefania Paolini  2 , Gianluca Cristiano  1 , Cristina Papayannidis  2 , Chiara Sartor  1 , Jacopo Nanni  1 , Emanuela Ottaviani  2 , Antonio Curti  2 , Michele Cavo  1   2 , Simona Soverini  1
Affiliations
Case Reports

Case Report: A Novel Activating FLT3 Mutation in Acute Myeloid Leukemia

Samantha Bruno et al. Front Oncol. .

Abstract

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 FLT3 mutations. Here we describe for the first time a novel in-frame deletion in exon 14 (JM domain) of the FLT3 gene, that we identified in a young woman with CBFb-MYH11-positive AML. We demonstrated that this novel FLT3 variant is pathogenic, since it is responsible for constitutive activation of FLT3 receptor. Finally, ex-vivo studies demonstrated that this novel mutation is sensitive to midostaurin.

Keywords: FLT3 mutation; NGS - next generation sequencing; acute myeloid leukemia; midostaurin; targeted therapy.

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Conflict of interest statement

AC was employed by Novartis, Pfizer, Abbvie and acted as speaker in Advisory Board for Novartis and Abbvie. CP was employed by Astellas, Amgen and acted as speaker in Advisory Board for Abbvie, Janssen, Novartis, Pfizer and Astellas. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation showing timeline of treatment course and clinical information. FLAI-5, fludarabine-cytarabine-idarubicin; Allo-SCT, allogeneic stem cell transplantation; WBC, white blood cells; Hb, hemoglobin; PLTs, platelets.
Figure 2
Figure 2
Sanger sequencing chromatogram showing the FLT3 deletion identified in the BM at diagnosis. TMD, transmernbrane domain; JMD, juxtamembrane domain; TKD, tyrosine kinase domain.
Figure 3
Figure 3
Western blot analysis of FLT-3 expression and of its down-stream signalling pathway. (A) Analysis of patient cells at two different time points (Dx: diagnosis with FLT3 carrying the c.1770_1784del15; CR: complete remission with wt FLT3). (B) Analysis of 5 AML patients with wt FLT3 along with 5 patients carrying FLT3-ITD, used as control of FLT3 downstream signalling. BM, bone marrow; PBL, peripheral blood.
Figure 4
Figure 4
Effects of increasing doses of midostaurin on the clonogenic capacity of primary BM and PBL cells carrying the reported FLT3 deletion (c.1770_1784del15; p.Phe590_Arg595delinsLeu).
See this image and copyright information in PMC

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