“Sticky” CML Cells Could Mediate Resistance to Treatment

Chronic myeloid leukemia; source: Robert Cardiff, PhD

A subgroup of chronic myeloid leukemia (CML) cells that were “sticky,” or adherent to plastic, showed higher expression levels of BCR-ABL and were more resistant to treatment with the tyrosine kinase inhibitor imatinib. Managing resistance to therapy in CML may eventually involve measurement of this type of property on both the individual cell and bulk level.

CML cells at different stages of maturation may have varying levels of BCR-ABL expression, but the difference in such levels has an unknown effect on actual disease progression or response to treatment. In a laboratory study led by Ehsan Ghayoor Karimiani, MD, PhD, at the Institute of Cancer Sciences at the University of Manchester in the United Kingdom, investigators used a CML-derived cell line known as K562 and analyzed differences between cells that were adherent to plastic-sticky cells-and those that were not. The results were published in the March issue of Experimental Hematology.

“Previous studies have linked high levels of the BCR-ABL mutation with drug resistance,” said Richard Byers, PhD, also of the University of Manchester, who also participated in the work, in a press release. “We wanted to see how expression of BCR-ABL differed across groups of CML cells, and in particular whether there were differences between adherent and non-adherent populations.”

The group found that BCR-ABL was upregulated in the adherent cells compared with non-adherent cells, both when analyzing individual cells and in bulk populations (P < .0001). Phosphorylation of the BCR protein was also upregulated in the adherent cells (63.42% phosphorylated vs 23.1% in non-adherent cells; P = .007).

They then examined whether the difference in protein expression would affect treatment with imatinib. The TKI reduced cell viability more rapidly in the non-adherent, lower BCR-ABL expressed cells than in the adherent cells, again both at the individual cell and bulk levels (P < .005).

This suggests, the authors concluded, that this subset of sticky CML cells could help mediate clinical resistance to imatinib or other TKIs, a problem commonly seen in general practice. And importantly, since it is a relatively small number of cells that show the higher levels of BCR-ABL, this feature may not be detectable only on bulk analysis of CML cells.

“It looks like it is important to look at protein levels in single cells,” Byers said. “In the future, it may be possible to measure BCR-ABL levels in individual cells in the clinic-this will help us identify the resistant, high BCR-ABL cells and better understand how patients develop resistance to imatinib treatment with the aim of combating this resistance to make response more durable and the treatment more effective.”