Acute myeloid leukemia (AML) is a highly aggressive cancer with frequent relapse and very poor clinical outcomes for most patients. AML is a genetically heterogenous disease and can be driven by various gene lesions. Currently, genetic classification of AML are routinely used as prognostic markers for risk assessment, therapy responses and patient outcomes. However, the ability to clinically predict resistance and relapse based on genetic subtypes remains limited, where patients with harmonized mutational backgrounds can have distinct outcomes (i.e. early relapse vs long-term remission). This is likely due to an additional level of non-genetically driven intra-patient heterogeneity including transcriptional dynamics, epigenetic regulation, metabolic adaptation or microenvironmental cues. In addition, different cell of origin further contributes to the heterogeneity and complex response to therapies in AML.
AML is usually an age-associated disease. This is because AML transformation occurs when DNA damages accumulate in hematopoietic stem and progenitor cells (HSPC) during their continuous cell proliferation and differentiation over an individual’s life time. HSPC proliferation and differentiation is essential, as this enables continuous supply of new red and white blood cells to maintain normal homeostasis. The HSPC compartment is known to be highly heterogeneous, containing distinct cell populations such as hematopoietic stem cell (HSC) and multipotent progenitor (MPP) cells. Within these populations, some are known to exhibit preferential tendency to develop into myeloid cells, while the others have a bias toward a different lineage such as lymphocytes. Such differential preference could contribute to the pathogenesis of leukemia of different subtype and origins.
The overarching goal of this proposal is to tackle the fundamental lack of understanding in how HPSC heterogeneity contribute to the non-genetic heterogeneity in AML. From the scientific point of view, this project will answer the following questions: Are HSPC populations with a bias towards myeloid differentiation more likely to develop into AML? If so, can we utilize the other population to compensate for such transformation, to rejuvenate the aging process and to delay the onset of AML? Can we understand the molecular mechanism regulating lineage bias, stem cell maintenance and aging? From the translational point of view, given that the global population is developing toward a more aged population overtime, it is of high importance to understand stem cell heterogeneity in normal, aged and leukemic conditions and such knowledge gain can contribute to the potential development of new preventative strategy of age-associated AML onset or therapies targeting different subsets of AMLs.
