Researchers in Sweden have identified a gene that is essential for the survival of acute myeloid leukemia (AML) stem cells.
AML is characterized by the accumulation of immature, abnormally differentiated myeloid cells in the bone marrow. Myeloid cells are the precursors to myeloblasts (white blood cells), red blood cells, and platelets. The abnormal myeloid cells mutate into leukemic blasts, which do not function correctly. Over time, the lack of functioning white blood cells means the body cannot fight infections, the lack of functional platelets means the blood doesn’t clot properly, and lower numbers of functional red blood cells reduces the capacity of the blood to carry oxygen.
AML is often fatal. Only 27.4% of adult patients diagnosed with the disease survive longer than 5 years after diagnosis according to the National Cancer Institute and only 24% according to the American Cancer Society. The survival rate in children is around 60%-70%. AML is sustained by a small population of leukemia stem cells (LSCs) that have self-renewing capabilities. Treatment for AML is usually chemotherapy, but if the LSCs are not wiped out, the disease will return.
The research team at Lund University in Sweden identified a gene that is essential to the survival of LSCs. The researchers were able to switch off genes to identify the role each plays in AML in mice. This was achieved using a CRISPR-Cas9 screen that targeted cell surface genes. This allowed the researchers to study approximately 100 genes at the same time.
They found the protein encoded by the gene CXCR4 was essential to the survival of the LSCs. The researchers report that the lack of the protein caused oxidative stress, and while the LSCs matured, the cells had a limited lifespan as the buildup of waste products in the cells resulted in toxicity that led to cell death. “Deletion of Cxcr4 in AML cells eradicates leukemia cells in vivo without impairing their homing to the bone marrow,” explained the researchers.
The researchers report that in healthy blood cells, the interactions between the CXCR4 protein and the protein CXCL12 is important, but LSCs did not require CXCL12, highlighting an important difference in how normal and abnormal cells are regulated. The findings of the study could help with the development of new drugs for treating AML.
You can read more about the study in the paper – CXCR4 Signaling Has a CXCL12-Independent Essential Role in Murine MLL-AF9-Driven Acute Myeloid Leukemia – which was recently published in the journal Cell Reports. DOI: 10.1016/j.celrep.2020.107684