Investigating the role of preleukemia duration and clonal burden in progression to AML
Cailin Collins
MD PhDStanford University
Project Term: July 1, 2023 - June 30, 2026
The development of acute myeloid leukemia (AML) is preceded by a “preleukemic” phase in which mutated hematopoietic stem cells expand due to a fitness advantage. Our work uses prospective models and analysis of patient samples to study how the duration of preleukemia and how the preleukemic clonal burden affect progression to AML. Results of our studies will shed new light on AML pathogenesis and help guide clinical management of preleukemic conditions such as clonal hematopoiesis.
Acute myeloid leukemia (AML) is an aggressive blood cancer that develops when healthy hematopoietic stem cells sequentially gain mutations that lead to uncontrolled cell growth. Studies have demonstrated that mutations occurring early in this process are acquired in ‘preleukemic’ stem cells years, and sometimes decades, prior to AML diagnosis. Interestingly, the genes that are most commonly mutated in preleukemic stem cells are the same as those seen in a condition called clonal hematopoiesis (CH), which affects nearly 20% of elderly individuals. Patients with CH are at a 10-fold increased risk of developing a hematologic malignancy, and thus CH represents a preleukemic state in some individuals. Importantly, for patients with CH who progress to leukemia, the presence of a higher proportion of preleukemic cells at the time of AML diagnosis portends a worse overall survival. Despite their importance in the pathogenesis and prognosis of AML, the process through which preleukemic cells transform into leukemia and how the length of the preleukemic phase affects AML biology is currently unknown. Our work aims to investigate these questions prospectively using genetically engineered cells, as well as with retrospective analysis of preleukemic cells isolated from patient samples. We have recently generated a model of the transition from preleukemia to leukemia through sequential introduction of mutations into human hematopoietic stem cells. Using this model, we will test how the duration of preleukemia and the proportion of preleukemic cells affects progression to leukemia and disease severity. We will then validate these findings by estimating the time between the preleukemic mutation and leukemia diagnosis in patient samples, and determine if this time correlates with prognosis and other clinical features of AML. The results of our work will serve as a significant advancement in our understanding of preleukemic stem cell biology and will be critical to help guide the management of preleukemic conditions like clonal hematopoiesis.