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Genetic pathways of myeloid transformation and treatment response

Dr. Lindsley

Coleman Lindsley


Dana-Farber Cancer Institute

Project Term: July 1, 2022 - June 30, 2027

Our central goal is to improve clinical outcomes in patients with myeloid malignancies through developing an enhanced mechanistic understanding of disease. We use multiomic analyses of primary patient samples combined with complementary laboratory models using mice and cell lines to generate and test our hypotheses. The results of our studies will help improve patient outcomes by identifying strategies to mitigate risk of disease progression/relapse and treatment toxicity.

Lay Abstract

Our central goal is to improve clinical outcomes in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). We have three primary areas of research focus:

1. ​Allogeneic stem cell transplantation involves the transfer of healthy donor cells to recipients with blood cancers. We study how characteristics of the patient, the disease, and the stem cell donor influence patient outcomes. (1) We use gene sequencing approaches in patients who have undergone transplantation to define groups with distinct disease biology and clinical outcomes. (2) We conduct clinical studies in patients and laboratory studies in mice to discover how short telomere length may increase the risk of transplant toxicity (telomeres regulate a cell’s ability to grow and recover from injury). (3) We study how gene mutations in donor cells can impact the immunologic function of the transplanted cells, thus influencing the risk relapse and graft-versus-host disease in the recipient. Our studies may improve patient outcomes by explaining how features of the patient, disease, and donor can be integrated to enable more precisely tailored transplant strategies.

2. Inherited mutations can predispose to development of MDS/AML. We analyze samples from patients with Shwachman-Diamond syndrome and telomere biology disorders in order to discover what gene mutations are in their leukemias and to develop technologies for early detection. To complement these studies, we have developed mouse models of both diseases in order to study how acquired mutations cooperate to cause leukemia and to understand their impact on blood cell function. These studies have the potential to improve clinical outcomes by (1) defining strategies to identify and intercept precancerous cells before they develop into full blown leukemias and (2) identifying new targets for treatments.

3. BCOR/PRC1.1: MDS and AML are caused by the stepwise acquisition of gene mutations. We study how gene mutations cooperate to drive leukemia progression, with an emphasis on those affecting the BCOR/PRC1.1 complex (a complex that regulates cell identity by coordinating the expression of groups of genes). We combine analyses of patient samples and laboratory models to study how BCOR mutations function on their own and how they work together with other genes to cause leukemia. We have defined how these mutations cause resistance to specific treatments and identified drugs that may target BCOR-mutated leukemias.

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