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Hierarchical Lineage Tracing Reveals Diverse Pathways of AML Treatment Resistance
Rachel Saxe1,2, Hannah Stuart1,3, Abigail Marshall1,2
1Molecular and Systems Biology, Dartmouth College, Hanover, NH.
Abstract:
Cancer cells adapt to treatment, leading to the emergence of clones that are more aggressive and resistant to anti-cancer therapies. We have a limited understanding of the development of treatment resistance as we lack technologies to map the evolution of cancer under the selective pressure of treatment. To address this, we developed a hierarchical, dynamic lineage tracing method called FLARE (Following Lineage Adaptation and Resistance Evolution). We use this technique to track the progression of acute myeloid leukemia (AML) cell lines through exposure to Cytarabine (AraC), a front-line treatment in AML, in vitro and in vivo. We map distinct cellular lineages in murine and human AML cell lines predisposed to AraC persistence and/or resistance via the upregulation of cell adhesion and motility pathways. Additionally, we highlight the heritable expression of immunoproteasome 11S regulatory cap subunits as a potential mechanism aiding AML cell survival, proliferation, and immune escape in vivo. Finally, we validate the clinical relevance of these signatures in the TARGET-AML cohort, with a bisected response in blood and bone marrow. Our findings reveal a broad spectrum of resistance signatures attributed to significant cell transcriptional changes. To our knowledge, this is the first application of dynamic lineage tracing to unravel treatment response and resistance in cancer, and we expect FLARE to be a valuable tool in dissecting the evolution of resistance in a wide range of tumor types.
Insights
Cancer cells evolve resistance to therapy by adapting their genetic makeup. A new dynamic lineage tracing method, FLARE, reveals specific AML cell adaptations and resistance mechanisms.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Cancer cells develop resistance to anti-cancer therapies, leading to treatment failure.
- Understanding the evolution of treatment resistance is crucial for developing effective cancer therapies.
- Current technologies are limited in mapping cancer evolution under treatment pressure.
Purpose of the Study:
- To develop and apply a novel dynamic lineage tracing method, FLARE, to map cancer evolution during treatment.
- To investigate the mechanisms of Cytarabine (AraC) resistance in acute myeloid leukemia (AML).
- To identify cellular lineages and molecular signatures associated with treatment resistance in AML.
Main Methods:
- Developed FLARE (Following Lineage Adaptation and Resistance Evolution), a hierarchical, dynamic lineage tracing technique.
- Tracked AML cell line progression in vitro and in vivo under Cytarabine (AraC) exposure.
- Analyzed murine and human AML cell lines, validating findings in the TARGET-AML cohort.
Main Results:
- Mapped distinct cellular lineages in AML exhibiting AraC persistence and/or resistance.
- Identified upregulation of cell adhesion and motility pathways in resistant AML cells.
- Highlighted heritable expression of immunoproteasome 11S regulatory cap subunits as a survival mechanism.
- Validated resistance signatures in the TARGET-AML cohort, showing differential responses in blood and bone marrow.
Conclusions:
- FLARE is a novel tool for dissecting cancer evolution and treatment resistance.
- Identified specific molecular and cellular adaptations driving AML resistance to AraC.
- Findings provide insights into AML cell survival, proliferation, and immune escape mechanisms.
- Revealed a broad spectrum of resistance signatures linked to significant transcriptional changes in cancer cells.
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