Mechanisms and Therapeutic Vulnerabilities of Erythroid-Biased Complex Karyotype AML

Complex karyotype acute myeloid leukemia (CK-AML) is an aggressive and often fatal blood cancer that resists current treatments. This form of leukemia is characterized by widespread abnormalities in the chromosomes and frequent mutations in the gene TP53, the most commonly mutated gene in cancer, and a gene that has been the focus of our lab’s research for the past 30 years. Despite advancements in AML treatment, CK-AML patients face poor outcomes due to the disease’s ability to adapt and develop resistance to standard chemotherapy and targeted therapies.

Through our research, we have discovered that CK-AML is not uniform, but rather consists of multiple types of cancer cells, some of which are more resistant to treatment than others. This diversity within the leukemia, known as tumor heterogeneity, makes it difficult to target all cancerous cells effectively. While some cells respond initially to therapy, others persist and drive disease relapse. Understanding why certain cancer cells are resistant to treatment is critical for developing better therapies.

Our research focuses on identifying the key factors that allow these resistant CK-AML cells to survive and grow. Specifically, we have found that CK-AML, unlike other forms of AML, harbors a population of cells that resemble precursor cells to red blood cells—erythroid precursors—but are cancerous. We find that these cells are inherently resistant to cancer treatments and are capable of causing disease relapse. Based on these findings, we believe that designing drugs to specifically eliminate the erythroid CK-AML cells is critical to improving outcomes to treatment.

Here, we propose several lines of complementary experiments that combine analyzing human leukemia cells with unique animal models and gene manipulation tools developed in our group to pinpoint the genes and molecular wiring that shape therapy resistance in CK-AML. We further test our hypothesis that eliminating the erythroid CK-AML cells could provide clinical benefit by informing design of therapies, and we take this one step further by evaluating TRIM28—a regulatory protein linked to repressing remnants of ancient viruses in our genomes—as a promising therapeutic target to eliminate resistant CK-AML cells. Returning to our patients, we will use advanced imaging techniques to understand, at unprecedented molecular detail, how different cell types within CK-AML respond and evolve in the context of treatment, both to confirm our findings in mouse models and to discover novel mechanisms to prevent resistance from emerging.

Our proposed research has the potential to transform how we treat CK-AML by providing new therapeutic targets that directly address the major cause of lethality in patients: the rapid emergence of drug resistance. By understanding how CK-AML cells survive and evade treatment, we can develop more effective and personalized therapies to improve survival and quality of life for patients with this devastating disease.