The FMS like Tyrosine Kinase 3 (FLT3) Is Overexpressed in a Subgroup of Multiple Myeloma Patients with Inferior Prognosis

• Main Authors: Normann Steiner, Karin Jöhrer, Selina Plewan, Andrea Brunner-Véber, Georg Göbel, David Nachbaur, Dominik Wolf, Eberhard Gunsilius, Gerold Untergasser
• Format: Article
• Language: English
• Published: MDPI AG 2020-08-01
• Series: Cancers
• Subjects: multiple myeloma; <i>FLT3</i>; midostaurin; gilteritinib; overexpression
• Online Access: https://www.mdpi.com/2072-6694/12/9/2341

Therapy resistance remains a major challenge in the management of multiple myeloma (MM). We evaluated the expression of FLT3 tyrosine kinase receptor (FLT3, CD135) in myeloma cells as a possible clonal driver. FLT3 expression was analyzed in bone marrow biopsies of patients with monoclonal gammopathy of undetermined significance or smoldering myeloma (MGUS, SMM), newly diagnosed MM (NDMM), and relapsed/refractory MM (RRMM) by immunohistochemistry (IHC). <i>FLT3</i> gene expression was analyzed by RNA sequencing (RNAseq) and real-time PCR (rt-PCR). Anti-myeloma activity of FLT3 inhibitors (midostaurin, gilteritinib) was tested in vitro on MM cell lines and primary MM cells by ³H-tymidine incorporation assays or flow cytometry. Semi-quantitative expression analysis applying a staining score (FLT3 expression IHC-score, FES, range 1–6) revealed that a high FES (>3) was associated with a significantly shorter progression-free survival (PFS) in NDMM and RRMM patients (<i>p</i> = 0.04). RNAseq and real-time PCR confirmed the expression of <i>FLT3</i> in CD138-purified MM samples. The functional relevance of FLT3 expression was corroborated by demonstrating the in vitro anti-myeloma activity of FLT3 inhibitors on FLT3-positive MM cell lines and primary MM cells. FLT3 inhibitors might offer a new targeted therapy approach in a subgroup of MM patients displaying aberrant FLT3 signaling.