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MAT2A as Key Regulator and Therapeutic Target in MLLr Leukemogenesis.
Kathy-Ann Secker1, Bianca Bloechl1, Hildegard Keppeler1
1Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tuebingen, 72076 Tuebingen, Germany.
Cancers
|May 28, 2020
Summary
Methionine adenosyltransferase 2A (MAT2A) is overexpressed in mixed-lineage leukemia (MLL). Inhibiting MAT2A with PF-9366 showed significant anti-leukemic effects in an MLL model, suggesting a new therapeutic strategy.
Area of Science:
- * Oncology
- * Molecular Biology
- * Epigenetics
Background:
- * Epigenetic dysregulation is crucial in mixed-lineage leukemia (MLL) pathogenesis.
- * Methionine adenosyltransferase 2A (MAT2A) synthesizes S-adenosylmethionine (SAM), the universal methyl donor, and is deregulated in cancers.
- * MAT2A's role in MLL pathogenesis was previously unknown.
Purpose of the Study:
- * To investigate the role of MAT2A in MLL pathogenesis.
- * To evaluate the therapeutic potential of MAT2A inhibition in MLL.
Main Methods:
- * Utilized a human CRISPR/Cas9-MLL-rearranged (MLLr) leukemia model.
- * Assessed MAT2A expression in MLLr models and patient data.
- * Evaluated the effects of the MAT2A inhibitor PF-9366 and MAT2A knockdown on leukemia cells.
- * Investigated combination therapies with PF-9366, chemotherapy, and DOT1L/PRMT5 inhibitors.
Main Results:
- * MAT2A was significantly overexpressed in the CRISPR/Cas9-MLLr model compared to controls.
- * MLLr cells exhibited enhanced sensitivity to MAT2A inhibition (PF-9366 and siRNA).
- * MAT2A inhibition altered leukemia cell proliferation, viability, differentiation, apoptosis, cell cycling, and histone methylation.
- * Combination treatments showed more pronounced anti-leukemic effects.
Conclusions:
- * MAT2A is a key regulator in MLL leukemogenesis.
- * MAT2A inhibition demonstrates significant anti-leukemic effects.
- * PF-9366 holds potential for treating poor-prognosis MLLr leukemia.
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