Sylvester Researcher Finds a Key Trigger in Myeloid Cancers

When the body is working well, hematopoietic (blood) stem cells in the bone marrow generate healthy red and white blood cells. However, faulty genes can produce abnormal cells, leading to myeloid leukemia and other conditions. Researchers have been working for years to untangle this complicated biology.

Cells with impaired chromatid separation (red arrows) in cultured WT and Asxl1+/- hematopoietic progenitor cells.

But now, Feng-Chun Yang, M.D., Ph.D., a cancer researcher at Sylvester Comprehensive Cancer Center and professor of biochemistry and molecular biology at the University of Miami Miller School of Medicine, and colleagues have shown that one protein — called ASXL1 — plays a major role in hematopoietic stem and progenitor cells. The study was published in the journal Science Advances.

That ASXL1 contributes to myeloid conditions is not a complete surprise – researchers have often found mutated ASXL1 in some aggressive blood cancers. But now the Yang lab has shown how the protein might fit into the molecular puzzle.

“This study helped us identify a novel mechanism through which ASXL1 loss can lead to leukemia development,” said Yang. “This moves us one step further toward identifying the molecular mechanism underlying ASXL1 alterations-mediated myeloid leukemia.”

The research shows that ASXL1 works closely with a group of proteins called cohesin complexes. Cohesins help keep mother and daughter DNA (chromatids) together during cell division. If the separation of two identical strands is impaired, the cells will be damaged. In other words, ASXL1 and cohesins help maintain the genome’s structural integrity.

If ASXL1 is mutated, cohesin function is impaired, chromatids can separate improperly, and gene expression can be altered. As a result, ASXL1 acts as a tumor suppressor, and when that function is lost, cancer can more easily gain a foothold.

Losing ASXL1 has other dramatic impacts on cellular biology, affecting stem cell differentiation, programmed cell death, and other important functions. The researchers identified a set of genes modulated by ASXL1/cohesion axis that have already been linked to hematopoiesis.

Now that scientists better understand how ASXL1 loss can affect hematopoietic stem cell function and myeloid differentiation, the next step is to figure out how to control this dysregulated pathway. Yang is hopeful the disease model she and her team developed for this research can be used to test potential therapeutic compounds.

“This study can provide new insights into the development of therapeutic approaches to abrogate ASXL1-associated myeloid leukemia,” said Yang.

Tags: cohesin complexes, Feng-Chun Yang, hematopoietic stem cells, myeloid cancers, Sylvester Comprehensive Cancer Center