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Prof. Dr. Sylwia Flis

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Center for Translational Medicine, Warsaw University of Life Sciences, 100 Nowoursynowska St., 02-797 Warsaw, Poland
Interests: apoptosis; cytotoxicity; molecular cell biology; cancer cells; cancer research; chronic myeloid leukemia; leukemia

Prof. Dr. Mirosława Koronkiewicz

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Department of Biomedical Research, National Medicines Institute, 30/34 Chelmska St., 00-725 Warsaw, Poland
Interests: protein kinase inhibitors; apoptosis; cytotoxicity; cancer biology; leukemia; molecular cell biology

Special Issue Information

Dear Colleagues,

Hematooncology is a field that dynamically uses new technologies in both diagnosis and treatment. The highest increase in the use of new therapies is observed in patients with blood cancers. The high effectiveness of targeted therapies and immunotherapy is associated with limiting the use of traditional chemotherapy. A personalized therapeutic approach in the treatment of leukemia is associated with a better cure/survival ratio, but it also has its limitations. Should traditional therapeutic approaches be abandoned? How can we improve the diagnosis and treatment efficiency of leukemia patients? How can we effectively eliminate leukemic stem cells? These and other questions will be answered in this Special Issue, which aims to present research in the field of pathophysiology, treatment strategies, and outcomes of leukemia, with a focus on the following:

The molecular mechanisms involved in leukemia;
Novel biomarkers for early leukemia diagnosis;
New therapeutic approaches (target therapies including drug design and development).

Prof. Dr. Sylwia Flis
Prof. Dr. Mirosława Koronkiewicz
Guest Editors

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Keywords

chronic leukemia
acute leukemia
T-cell prolymphocytic leukemia
BCR-ABL1
tyrosine kinase inhibitors
Philadelphia chromosome
biomarkers

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15 pages, 5275 KiB

Open AccessArticle

FLT3 and IRAK4 Inhibitor Emavusertib in Combination with BH3-Mimetics in the Treatment of Acute Myeloid Leukemia

by Katja Seipel, Harpreet Mandhair, Ulrike Bacher and Thomas Pabst

Curr. Issues Mol. Biol. 2024, 46(4), 2946-2960; https://doi.org/10.3390/cimb46040184 - 29 Mar 2024

Viewed by 527

Abstract

Targeting the FLT3 receptor and the IL-1R associated kinase 4 as well as the anti-apoptotic proteins MCL1 and BCL2 may be a promising novel approach in the treatment of acute myeloid leukemia (AML). The FLT3 and IRAK4 inhibitor emavusertib (CA4948), the MCL1 inhibitor S63845, the BCL2 inhibitor venetoclax, and the HSP90 inhibitor PU-H71 were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells in vitro. AML cells represented all major morphologic and molecular subtypes, including FLT3-ITD and NPM1 mutant AML cell lines and a variety of patient-derived AML cells. Emavusertib in combination with MCL1 inhibitor S63845 or BCL2 inhibitor venetoclax induced cell cycle arrest and apoptosis in MOLM-13 cells. In primary AML cells, the response to emavusertib was associated with the presence of the FLT3 gene mutation with an allelic ratio >0.5 and the presence of NPM1 gene mutations. S63845 was effective in all tested AML cell lines and primary AML samples. Blast cell percentage was positively associated with the response to CA4948, S63845, and venetoclax, with elevated susceptibility of primary AML with blast cell fraction >80%. Biomarkers of the response to venetoclax included the blast cell percentage and bone marrow infiltration rate, as well as the expression levels of CD11b, CD64, and CD117. Elevated susceptibility to CA4948 combination treatments with S63845 or PU-H71 was associated with FLT3-mutated AML and CD34 < 30%. The combination of CA4948 and BH3-mimetics may be effective in the treatment in FLT3-mutated AML with differential target specificity for MCL1 and BCL2 inhibitors. Moreover, the combination of CA4948 and PU-H71 may be a candidate combination treatment in FLT3-mutated AML. Full article

(This article belongs to the Special Issue Molecular Research and Pathological Mechanism of Leukemia)

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