Related Experiment Videos
Acute monocytic leukemia: a myeloid leukemia subset that may be sensitive to methotrexate
E Göker1, A Kheradpour, M Waltham
1Program of Molecular Pharmacology and Therapeutics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
Abstract:
Impaired polyglutamylation of methotrexate (MTX) and thus poor retention is believed to be the basis of intrinsic resistance in blasts from patients with acute myeloid leukemia (AML) to MTX. We studied additional samples from patients with this disease, and confirmed that polyglutamylation of MTX was poor in ANLL blast cells. However, in one subset of ANLL, acute monocytic leukemia, (M5) leukemia blasts were found to be capable of accumulating and forming long-chain MTX polyglutamates. An acute monocytic leukemia cell line, THP-1 also was found to accumulate high levels of MTX polyglutamates and was relatively sensitive to MTX, strengthening the concept that M5 blasts may be sensitive to this drug. MTX may be an overlooked drug for the treatment of acute monocytic leukemia.
Insights
Methotrexate (MTX) resistance in acute myeloid leukemia (AML) may be overcome in a specific subtype. Acute monocytic leukemia (M5) blasts show MTX polyglutamation, suggesting sensitivity to this overlooked chemotherapy drug.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Methotrexate (MTX) resistance in acute myeloid leukemia (AML) is often attributed to impaired polyglutamylation, affecting drug retention.
- This study investigates MTX polyglutamylation in various subtypes of AML.
Purpose of the Study:
- To determine if MTX polyglutamylation and sensitivity vary across AML subtypes.
- To explore the potential of MTX as a therapeutic agent for specific AML classifications.
Main Methods:
- Analysis of MTX polyglutamylation in patient-derived acute myeloid leukemia (AML) blast cells.
- Evaluation of MTX polyglutamate accumulation and cellular sensitivity in the THP-1 acute monocytic leukemia cell line.
Main Results:
- Confirmed poor MTX polyglutamylation in general AML blasts.
- Identified acute monocytic leukemia (M5) blasts and the THP-1 cell line as capable of accumulating long-chain MTX polyglutamates.
- Demonstrated relative sensitivity of M5 blasts and THP-1 cells to MTX.
Conclusions:
- MTX polyglutamylation capacity is not uniformly impaired across all AML subtypes.
- Acute monocytic leukemia (M5) blasts exhibit MTX polyglutamation and sensitivity, suggesting potential therapeutic value.
- Methotrexate (MTX) may be an underutilized treatment option for acute monocytic leukemia.