Identifying New Vulnerabilities in Treatment-Resistant AML
High-throughput screening finds novel targets
Technology Overview
Shan Lin, PhD
Acute myeloid leukemia (AML) is notoriously difficult to cure, with many cases recurring after remission or becoming resistant to treatment. AML is one of the most common blood cancers in children and has a 5-year survival rate of 65%-70%. In part because of the cancer’s tendency to develop resistance, treatment options for AML have lagged behind those for other blood cancers.
Cancer biologist Shan Lin, PhD, is studying the biology underlying treatment-resistant pediatric AML. The Lin Lab uses mouse models and leukemia cell lines derived from patients and from hematopoietic stem cells to examine leukemia cell survival and drug resistance. Using high-throughput CRISPR-based screens, Dr. Lin and his team have identified several novel pathways involved in these processes and are studying these pathways in more detail.
In one project, Dr. Lin is exploring the biology of receptor proteins known as solute carriers. These membrane proteins enable the transport of specific nutrients or metabolites into cells. The Lin Lab’s CRISPR screens identified two transporter proteins that may possess previously unexplored vulnerabilities in some treatment-resistant AMLs. One of these proteins, SLC5A3, transports myo-inositol, a sugar that is necessary for cellular metabolism. Another protein, FLVCR1, transports choline, which is an essential nutrient that is similar to some B vitamins.
Although myo-inositol and choline are essential for healthy cell functions, non-cancerous cells have redundant systems that either generate the two nutrients internally or take them up from the external environment. For reasons that are not entirely clear, some cancers lose that redundancy. Healthy cells can manufacture their own myo-inositol, for example, but approximately 20% of AML cancers lose that ability and thus rely on environmental sources of the sugar. Dr. Lin is exploring ways to target SLC5A3 and FLVCR1 in leukemia cells to block the critical nutrient transport process in AML cases that have lost transport redundancy, with the goal of eventually translating that work into finding new drug targets for clinical use. He is collaborating with protein engineer Jason Price, PhD, to develop SLC5A3-targeting antibodies for potential therapeutic use.
In another project, Dr. Lin is working on promoting cell death in AML cells. All cells use programmed cell death, a process known as apoptosis, to naturally prune older or diseased cells. Many kinds of cancer, however, block apoptosis, which allows the cancer cells to continue growing and dividing. Several cancer therapies are aimed at triggering apoptosis in cancer cells and AML seems especially sensitive to this form of therapy.
Apoptosis-triggering drugs for AML include BCL-2 inhibitors such as venetoclax, which typically is used in combination with other drugs. Not all patients respond to BCL-2 inhibitors, however, and those who do often relapse. Dr. Lin has identified a protein in AML cells called MARCH5 that, when deleted, further sensitizes the cells to venetoclax treatment. His lab is now working to understand the specific mechanism by which MARCH5 regulates apoptosis in AML.
Dr. Lin has more than 10 years of experience in cancer biology and screening technology development. He is interested in industry partnerships to help develop inhibitors of the potential AML drug targets he has identified and to uncover more therapeutic targets with his high-throughput, CRISPR-based screening platforms.
Stage of Development
- Preclinical in vitro
- Preclinical in vivo
Partnering Opportunities
- Collaborative research and development
- Sponsored research agreement
- Consultation agreement
- Cell line access
- Animal model access
- High-throughput screening
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Publications
- Lin S, Schneider C, Su AH, et al. The UBE2J2/UBE2K-MARCH5 ubiquitination machinery regulates apoptosis in response to venetoclax in acute myeloid leukemia. Leukemia. 2024;38(3):652-656.
- Larrue C, Mouche S, Lin S, et al. Mitochondrial fusion is a therapeutic vulnerability of acute myeloid leukemia. Leukemia. 2023;37(4):765-775.
- Lin S, Larrue C, Scheidegger NK, et al. An in vivo CRISPR screening platform for prioritizing therapeutic targets in AML. Cancer Discov. 2022;12(2):432-449.
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Last updated March 2026