Fellows’ research: How acute myeloid leukaemia cells are protected against chemotherapy by their neighbouring bone marrow cells
28 Nov 2019
Dr Vikram Mathews, Senior Fellow, Christian Medical College
Dr Neha Vyas, Early Career Fellow, St. John's Research Institute
In our recently published work, we identify the mechanism underlying the therapy resistance provided by the bone-marrow microenvironment via normal stromal cells to cells of acute myeloid leukaemia (AML)—a kind of blood cancer originating in the bone marrow.
Management of AML remains a clinical challenge with majority of the patients having disease recurrence post conventional therapy. It is known that the bone marrow, in which the AML cells reside, provides a protective and nurturing environment to these malignant cells. This protection allows cancer cells to thrive even in the presence of chemotherapeutic agents. Our team is interested in unravelling the cellular processes underlying therapy-resistance in leukaemia and identifying therapeutic options to overcome them.
We used cell-based assays, mouse models of leukaemia as well as patient samples to understand the mechanism by which the normal cells in bone-marrow microenvironment shield the cancer cells from the toxic effects of the chemotherapy.
We identified that bone marrow stromal cells change the expression of a specific regulatory non-coding RNA, miR-23a-5p, in the cancer cells. This complex process has a positive feedback mechanism that enhances its effect in the bone marrow microenvironment when AML cells interact with the normal stromal cells. This, in turn, activates a protective mechanism (protective autophagy) in AML cells by which the cells can recycle their damaged organelles efficiently to overcome the toxic effects of the drugs. This is a dynamic process and is context specific—happens within the microenvironment, a location where minimal residual disease is known to reside. Additionally, the process is probably an important mechanism that can explain the presence of minimal measurable disease in the bone marrow after completion of conventional chemotherapy.
This mechanism of protection identified by us can be correlated with clinical outcomes in patients with AML. We also propose a therapeutic approach, tested in mouse model, which can be used to overcome such protective effects of bone-marrow stromal cells. We propose that known autophagy inhibitors can be used with chemotherapeutic agents (combinatorial therapy) to overcome resistance to therapy. We suggest that identifying and targeting such molecular crosstalk can have important clinical implications in the treatment of AML.
Stromal cells downregulate miR-23a-5p to activate protective autophagy in acute myeloid leukemia. Saravanan Ganesan, Hamenth Kumar Palani, Vairavan Lakshmanan, Nithya Balasundaram, Ansu Abu Alex, Sachin David, Arvind Venkatraman, Anu Korula, Biju George, Poonkuzhali Balasubramanian, Dasaradhi Palakodeti, Neha Vyas, and Vikram Mathews. Cell Death & Disease. September 2019.
Banner Image Credits: The Armed Forces Institute of Pathology (AFIP)