Liran ShlushPhD, MD
Weizmann Institute of Science
Project Term: July 1, 2018 - June 30, 2023
In the current study we propose, based on our preliminary results, that we can reliably identify pre-AML cases out of the many individuals with age related clonal hematopoiesis (ARCH) based on clinical parameters thereby limiting the population that needs to undergo molecular testing. We have also developed a predictive model that can identify pre-AML cases years before diagnosis. We now propose to utilize this knowledge to treat high-risk individuals with ARCH, at a time point before they have developed disease, by targeting the driving alterations most associated with AML development.
Acute myeloid leukemia (AML) is a devastating disease with a 10% five year overall survival for patients above the age of 60. Recent studies identified preleukemic stem cells (pLSC) as the cell of origin in AML. pLSCs acquire leukemia-related mutations years before AML diagnosis; however treatment of preleukemic state is not pursued because patients have no overt clinical signs of disease. Moreover, screening for preleukemic mutations (pLM) among healthy individuals for early identification of AML is currently not feasible for several reasons. First, pLMs are very common among healthy elderly individuals. More than 20% of the general population above the age of 60 carry mutations related to blood malignancies, a phenomenon known as age related clonal hematopoiesis (ARCH). Currently there is no reliable method to identify which patients with ARCH will develop AML. Secondly, even if tools to identify those individuals with ARCH destined to develop AML existed it is not clear whether screening is feasible as AML is a relatively rare disease (incidence 1:10,000). Finally, it also is unclear how this condition should be treated and whether the benefits of treatment would outweigh potential risks of therapy.