The results of a scientific study, published in the prestigious journal EMBO Molecular Medicine, adds new insights into the molecular mechanisms that suppress differentiation programs in Acute myeloid leukemia (AML). The research - coordinated by Rosa Bernardi, head of the Division of Experimental Oncology and group leader of Preclinical models of cancer Unit at IRCCS Ospedale San Raffaele - proposes a novel therapeutic strategy for leukemia debulking via transcription factor HIF2a inhibition.

The need of a new therapeutic strategy for AML

Acute myeloid leukemia (AML) is an aggressive disease affecting blood cells of the myeloid lineage. It is most likely to affect men over the age of 60, although it can also occur in children. AML patients have a 5-year overall survival rate of less than 30% and new therapeutic strategies are urgently needed to improve this grim prognosis. To date, the most effective therapy for many patients with acute myeloid leukemia consists of chemotherapy and allogeneic hematopoietic cell transplantation for select group of patients.

“In AML, uncontrolled cell proliferation is intertwined with differentiation arrest, which is the inability of cells with a progenitor phenotype to undergo differentiation to mature and self-exhausting myeloid cells. The molecular basis of this differentiation arrest is complex and a matter of ongoing investigation”, explain Rosa Bernardi.

San Raffaele research

San Raffaele researchers found that the transcription factor HIF2a, a gene that evolved to adapt cellular physiology to variations in oxygen tension, partakes to the AML differentiation block. The function of HIF factors has already been widely studied in solid tumors, where they are known to promote cancer progression.

“We identify important transcriptional regulators and suppressors of myeloid differentiation in the HIF2a-regulated transcriptome and demonstrate that inhibiting HIF2a via genetic or pharmacological manipulation prompts AML differentiation, induces leukemia debulking and potentiates the effect of all-trans retinoic acid (ATRA), a compound that has revolutionized the treatment of acute promyelocytic leukemia”, continues Bernardi.

Therapeutic implications of HIF2a silencing

Because a small molecule inhibitor of HIF2a has been recently generated and is entering the clinic for solid cancers, this work sets the basis for extending the use of this compound to another disease in need of additional therapies and with the therapeutic endpoint of cell exhaustion via differentiation, rather than the conventional cytotoxic or cytostatic activity of anticancer agents.