JAK2 Inhibition of FLT3 Mutated Acute Myeloid Leukemia Cells to Induce Apoptosis and Differentiation
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Issue Date
2024-04-26
Authors
Sharp, Jonathan
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Kadmiel, Mahita
Additional Readers
Humphreys, Tricia L.
Duriancik, David
Duriancik, David
Keywords
Leukemia , JAK/STAT , JAK2 , FLT3 , Acute Myeloid Leukemia , BMS-911543
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Abstract
Acute myeloid leukemia is the most common type of leukemia among cancer patients. Within acute myeloid leukemia, the FLT3 receptor located on myeloid progenitor cells which is normally responsible for healthy cell proliferation, differentiation and communication can become mutated. An insertion mutation called ITD in FLT3 is common in patients with this leukemia, and results in constitutive activation of the FLT3 receptor. This activation results in the unregulated proliferation of cancerous myeloid blast cells in the bone marrow, impairs hematopoiesis, and creates a poor prognosis in patients. Commonly used FLT3 inhibitors may not always be the best therapy for acute myeloid leukemia because resistant mutants that contain an upregulated JAK2 protein, which will drive further proliferation of cancer cells, can develop. The highly selective JAK2 inhibitor, BMS-911543, was investigated in this study as a potential alternative to FLT3 inhibitors. An IC50 for BMS-911543 regarding the MV4-11 cell line was established at 4.5μM, and this inhibitor seemed to induce modest differentiation in FLT3-ITD mutated acute myeloid leukemia cell line; however, apoptosis was not observed. The differentiation observed is promising for the future of acute myeloid leukemia therapies, but subsequent experiments with flow cytometry and more imaging analysis are needed to further explain how the FLT3 and JAK/STAT pathways affect this type of cancer.
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Biology
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Biology
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Biology, 2024