Novel Combination Therapies for Acute Leukemia

Dear Colleagues,

Acute leukemia is a heterogeneous group of diseases characterized by clonal expansion of immature blast cells in the peripheral blood, bone marrow and other tissues resulting in bone marrow failure. Over the last ten years, a great number of molecular aberrations have been identified in either acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), making these disease optimal candidates for the development of investigational drugs targeting driver genetic mutations. It is now evident that most of these abnormalities could trigger the development of acute leukemia or have an important role in the pathogenesis and/or clonal expansion of leukemia. The routine application of novel molecular biology technologies such as next generation sequencing (NGS) and whole genome sequencing (WHS) has facilitated the development of such genetic lesions, with relevant clinical and therapeutical application. Recent publications have shown that these somatically acquired genetic lesions are particularly important for diagnostic classification and risk assessment in patients with AML and ALL. Systematic studies of the genomic landscape of AML, such as analyses of data from the Cancer Genome Atlas, have generated a catalogue of leukemia-associated genes that is increasingly comprehensive and exhaustive, marking AML as a complex, dynamic disease. Furthermore, an increasing number of clinical trials have been testing “druggable” mutations in the context of novel targeted therapies, making this area more and more interesting in several areas of investigations.

This Special Issue of Cancers (“Novel Combination Therapies for Acute Leukemias” ) focuses on novel therapeutical approaches in acute leukemias and related diseases, and aims to collect original papers and commentaries in several areas of investigations concerning AML and ALL, including preclinical, clinical, and biological studies.

Prof. Dr. Francesco Lanza
Prof. Dr. Attilio Olivieri
Guest Editors

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• acute myeloid leukemia
• acute lymphoblastic leukemia
• molecular aberrations
• novel therapies
• druggable genetic lesions

Title: Synergistic effects of the RARalpha agonist tamibarotene and the Menin inhibitor revumenib in acute myeloid leukemia cells with KMT2A rearrangement or NPM1 mutation
Authors: Maximilian Fleischmann; Julia Bechwar; Diana Voigtlaender; Mike Fischer; Ulf Schnetzke; Andreas Hochhaus; Sebastian Scholl
Affiliation: Universitätsklinikum Jena, Klinik für Innere Medizin II, Jena, Germany
Abstract: Inhibition of Menin in acute myeloid leukemia (AML) harboring histone-lysine-N-methyltransferase 2A rearrangement (KMT2Ar) or mutated Nucleophosmin gene (NPM1c) is considered a novel and effective treatment approach in these patients. However, rapid acquisition of resistance mutations can impair treatment success. In patients with elevated retinoic acid receptor alpha (RARA) expression levels, promising effects are demonstrated by the next-generation RARalpha agonist tamibarotene, which restores differentiation or induces apoptosis. In this study, the combination of revumenib and tamibarotene was investigated in various KMT2Ar or NPM1c AML cell lines and patient-derived blasts, focusing on the potential synergistic induction of differentiation or apoptosis. Both effects were analyzed by flow cytometry and validated by western blot analysis. Synergy calculations were performed using viability assays. Regulation of relevant key mediators for the MLL-complex were quantified by RT-qPCR. In MV4:11 cells characterized by the highest relative mRNA levels of RARA, highly synergistic induction of apoptosis is demonstrated upon combination treatment. Induction of apoptosis by combined treatment of MV4:11 cells is accompanied by pronounced induction of the pro-apoptotic protein BAX and synergistic reduction of CDK6 mRNA levels. In MOLM13 and OCI-AML3 cells an increase of differentiation markers like PU.1 or decreased ratio of phosphorylated to total CEBPA is demonstrated. In parts corresponding effects were observed patient derived AML cells carrying either KMT2Ar or NPM1c. The impact of revumenib on KMT2Ar or NPM1c AML cells was significantly enhanced when combined with tamibarotene, demonstrating synergistic differentiation or apoptosis initiation. These findings propose promising strategies for relapsed/refractory AML patients with defined molecular characteristics.