Acute Myeloid Leukemia (AML) is a heterogeneous disease that originates from diverse genetic alterations. It can be classified into different cytogenetic groups with variable prognosis. Unfortunately, treatment of AML has not improved over the last 30 years and cure rates remain low. Experimental data supports the view that relapse is driven by a specific subpopulation of cells, termed leukemia initiating cells (LICs), which are able to escape cytotoxic therapy and ultimately reboot the disease. LICs have unique properties, some of them shared with normal hematopoietic stem cells (HSCs), such as relative quiescence, resistance to apoptosis and increased drug efflux, which makes them more resilient to chemotherapy. The discovery of molecular pathways that specifically support LICs, while challenging, would represent an important advancement in AML biology.
With the present project, we study the mechanisms leading to LIC quiescence and to exploit them to sensitize LICs to chemotherapy, in the hope of reducing current relapse rates. Quiescence is partially associated with low oxygen levels (hypoxia) in the bone marrow niche where HSCs/LICs reside. Hypoxia maintains cells in a dormant state as a defense mechanism to prevent their exhaustion. In response to hypoxia, cells activate a specific pathway mediated by Hypoxia Inducible Factors (HIFs), which promote the transcription of many hypoxia-regulated target genes and play a key role in regulating numerous biological processes such as cell proliferation, survival and metabolism.
Although the study of HIF inhibition is at its earliest stage, the growing interest for the function of HIF factors in hematological malignancies suggests its important translational value. Therefore, a deeper understanding of the function of HIFs in cells of hematopoietic origin will create a more precise mapping of the complexity of hypoxia signaling in different physiological and pathological conditions.
The data obtained during this project was focused to couple the hypoxia transcriptional signature of LICs with their in vivo function in the most prevalent human AML cytogenetic subgroups in order to assess: i) whether the hypoxia/HIF pathway represents a mechanism for LICs to evade chemotherapy and, ii) LIC heterogeneity in the hypoxic niche. Targeting this pathway in LICs would open new avenues in AML treatment, leading to clinical trials testing HIF-targeting compounds.
