Ongoing Projects

The Rao lab studies the biology of hematopoietic stem cells (HSCs) in normal and malignant hematopoiesis to identify leukemic stem cell specific dependencies and vulnerabilities for therapeutic targeting. HSCs are responsible for life-long production of all mature blood cell lineages, but also a cellular target of transforming events in hematologic malignancies. Consequently, leukemic (mutant) HSCs constitute ideal cellular targets for future therapeutic strategies. We are investigating the roles of metabolism, inflammation and age-associated changes in leukemic HSCs in driving leukemia initiation and progression. We use mouse models and primary patient samples of myeloproliferative neoplasms (MPNs), myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), and employ multi-omics approaches.

Mechanisms of myeloid leukemia Initiation and Progression

What are the rate-limiting events in leukemia initiation and progression? Why does cancer risk increase as we age?
The major focus of our research lays in unraveling the early events and factors contributing to clonal expansion and myeloid leukemia initiation and progression. Since the incidence and prevalence of myeloid leukemias increase with age, we are investigating the underlying age-associated factors (inflammation) and mechanisms that trigger clonal expansion and disease manifestation in myeloid leukemias. Acquisition of a somatic driver gene mutation (e.g. JAK2, TET2 or DNMT3a) in a single hematopoietic stem cell (HSC) is the initial event in clonal hematopoiesis leading to the emergence of a mutant HSC clone (marked in red, Figure 1), which if not eliminated by the immunosurveillance mechanisms persists in small numbers. At this stage many of the affected individuals do not show signs of hematological malignancies, a phenomenon known as ‘clonal hematopoiesis of indeterminate potential’ (CHIP). Therefore, CHIP might represent a pre-leukemic state. This also suggests that additional factors determine whether hematopoietic stem cells carrying somatic gene mutations can expand and reach a critical clonal size that becomes self-sustaining and disease-initiating. We are investigating the roles of metabolism and inflammation in driving clonal expansion, leukemia progression and therapy resistance. This knowledge will help to develop strategies aiming to improve early detection of leukemic clones and to define novel therapies to delay or target the onset of myeloid leukemias in aging individuals.

Metabolism and biomarkers of myeloid Leukemias

How do leukemic (mutant) stem cells meet their bioenergetic and biosynthetic demands associated with increased proliferation and/or differentiation? How do driver mutations impact metabolic pathways in malignant clones? Is there a therapeutic window for targeting altered metabolism in leukemia?
Irrespective of the type of genetic driver, clonal expansion and aberrant clonal differentiation in myeloid malignancies requires a proliferation and/or survival advantage - an energy dependent process. Therefore, malignant clones must adopt their metabolism. Metabolic aberrancies in cancers are increasingly recognized as potential therapeutic targets. To unravel the metabolic basis of myeloid leukemia pathogenesis, we are studying the metabolic liabilities of leukemic stem cells. We recently uncovered that metabolic rewiring in hematopoietic cells is fundamental to the progression of mutant JAK2 driven MPNs. We demonstrated the feasibility and benefits of targeting altered glucose metabolism in MPN cells in vivo (Figure 2). Ongoing studies are focusing on elucidating the roles and therapeutic viability of various other dysregulated metabolic pathways in leukemic stem cells for targeted therapies. Moreover, we are assessing whether altered metabolites can be harnessed as functional biomarkers of leukemias.

Hematopoietic stem cell heterogeneity and drug response and resistance in myeloid leukemias

How do hematopoietic stem cell (HSC) sub-populations (e.g. lineage biased stem cells) contribute to myeloid leukemia pathogenesis and how are these populations perturbed in response to therapies and contribute to drug resistance? How do driver mutations influence lineage fate decisions of HSCs? We recently uncovered that the frequency of the myeloid/megakaryocyte biased CD41high HSC subset was significantly increased in mutant JAK2 expressing mice and in patients with MPN (Figure 3). We are studying lineage fate choices, and functional and therapeutic relevance of lineage biased HSCs in myeloid leukemia pathogenesis.