October 07, 2019
Ramesh Balusu, PhD, a researcher at The University of Kansas Cancer Center, is working to uncover what happens behind the scenes that leads to the development of certain types of blood cancers like acute myeloid leukemia.
Key cells behind the scenes
Hematopoietic progenitor cells are responsible for the production and replenishment of all blood cell types. They are born as “unassigned” young stem cells and their lineage (myeloid or lymphoid) is determined as they mature.
- Myeloid cells include red blood cells, white blood cells, platelets and monocytes.
- Lymphoid cells include T cells and B cells.
After lineage is determined, their maturation doesn’t stop there. The cells continue differentiating (becoming more specialized), moving through the various phases of cell life before dying.
“The life of a healthy cell follows more than a dozen different steps to mature,” says Dr. Balusu. “If a lymphoid or myeloid cell does not differentiate correctly at any point during this process, it creates a traffic jam. Undifferentiated cells start accumulating in the bone marrow and the cancer develops.”
If lymphoid or myeloid cells fail to differentiate, lymphoma or leukemia occurs, respectively.
Balusu’s research primarily focuses on the NPM1 protein, the most frequently mutated gene in up to 50% of adult acute myeloid leukemia cases.
If the cells responsible for the production of blood cells don't mature correctly at any point, the process may repeat. These faulty cells will accumulate in the blood marrow and cancer develops.
On/off switch failure
“In a healthy environment, there is a defined lifespan for each cell. The mutated NPM1 halts the normal differentiation process in myeloid cells, preventing the cells from moving on to the next phase of life,” points out Dr. Balusu. “Instead, the activated mutant gene reprograms the cell to continuously multiply.”
He compares this constant activation of the mutated gene to a malfunctioning light switch that is stuck in the “ON” position.
"This continuous proliferation of undifferentiated cells interrupts the development of white blood cells, red blood cells and platelets," he says. "Without these essential immune cells, patients with AML will typically experience weakness, bruising and increased risk of infection."
AML patients are also usually older with an average age of 67. The standard treatment includes chemotherapy and a bone marrow transplant. However, older patients often cannot tolerate the high-dose chemotherapy. Consequently, treatment options are very limited.
Dr. Balusu is working to develop less toxic novel drug combinations that may work for older AML patients. By better understanding the pathways and mechanisms of AML, his laboratory can refine and pinpoint the molecules that play a role in cancer, and then design and screen specific small molecule inhibitors to use in targeted cancer therapy.