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Molecular basis and new therapeutic strategies in lineage ambiguous leukemia

Dr. Montefiori

Lindsey Montefiori


St. Jude Children's Research Hospital

Project Term: July 1, 2023 - June 30, 2025

Lineage-ambiguous leukemias are high-risk blood cancers with unclear biologic basis and suboptimal treatment options. Here, I will identify the cell of origin of lineage ambiguous leukemia and investigate new therapeutic strategies through in vitro and in vivo experimental modeling approaches and preclinical drug studies in patient-derived xenografts. These studies will clarify the cellular and molecular alterations driving lineage ambiguity and advance a new, rational therapeutic approach.

Lay Abstract

Acute leukemia is a cancer of blood cells and typically comes in one of two forms, either acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). The distinction is important because it directs choice of therapy and informs on the cell type where the leukemia originated (myeloid cells for AML, B or T cells for ALL). However, a rare form of leukemia that has features of both AML and ALL is called “lineage ambiguous” leukemia and these patients face increased rates of treatment failure and relapse due to unclear guidelines regarding optimal treatment and uncertain cellular origins. The goal of my proposed research is to identify how lineage ambiguous leukemia arises and identify more effective therapeutic approaches that are tailored to this specific disease. My prior research identified a genetic alteration in a gene called BCL11B that causes some forms of lineage ambiguous leukemia. BCL11B is a transcription factor, which are proteins that bind specific DNA sequences to regulate the activity of other genes in our genomes. All of our cells contain the same genes, but transcription factors help coordinate which ones are active at any given time and it is the mis-regulation of this activity that often drives cancer-causing processes, particularly in pediatric cancers. I hypothesize that BCL11B is inappropriately activated in a specific blood cell type, likely a stem cell, where it corrupts normal developmental processes that result in lineage ambiguous leukemia. In my first Aim, I will identify how BCL11B corrupts normal gene processes to cause a normal cell to become a leukemia cell using a technique to enforce BCL11B activity in specific blood cell types. The other major goal of my proposal is to identify more effective therapy approaches. BCL11B-driven leukemias have high levels of two genes that can be targeted with FDA approved drugs. My preliminary research showed that when these drugs are combined, they are highly effective in a preclinical mouse model. Here, I will identify why this drug combination is successful, including whether it is unique to this form of leukemia, and investigate possible routes of treatment resistance which will help prevent relapses in future patient populations. In summary, my proposed studies will identify new routes of leukemia formation which may directly lead to new targeted treatment options and will advance a new drug combination as a rational choice of therapy in this difficult to treat disease.

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