Drug resistance in myeloproliferative disorders can be overcome

NEW YORK (Reuters Health) - A newly identified apoptosis pathway is inhibited in cancerous myeloid cells, making them resistant to treatment. However, the researchers who identified this pathway have also discovered how to override its inhibition and restore the cells' susceptibility to chemotherapy.

They describe their findings in the December 25th issue of The New England Journal of Medicine.

The investigators, led by Dr. Denis R. Alexander at The Babraham Institute in Cambridge, UK, studied cells from patients with chronic myeloid leukemia (CML) or polycythemia vera. A press release from the Institute explains that in normal cells, DNA damage increases the activity of a proton pump in the cell membrane known as sodium-hydrogen exchanger isoform 1 (NHE-1). Activating NHE-1 raises cellular pH, which in turn triggers a deamidation process in which the prosurvival protein Bcl-xL is converted into a form that permits the damaged cells to die.

"In our study, we found that the signaling pathway leading from DNA damage to Bcl-xL deamidation and consequent apoptosis is inhibited" in myeloid cells in patients with CML or polycythemia vera, the authors report. "This is the first demonstration of a role for deamidation in human malignancy," according to the press release.

The researchers discovered further that in myeloproliferative cancer cells, the Bcl-xL deamidation pathway is being blocked by tyrosine kinases - BCR-ABL in CML and JAK-2 in polycythemia vera.

Furthermore, the researchers discovered that by "enforced alkalinization or overexpression of NHE-1" they could reverse inhibition of the Bcl-xL deamidation pathway and restore apoptosis.

In fact, in cells from a patient with CML who developed resistance to the BCR-ABL inhibitor imatinib, "the effects of imatinib resistance could be bypassed by NHE-1 overexpression, which caused increased intracellular pH and apoptosis, or by enforced alkalinization, which caused increased Bcl-xL deamidation and apoptosis."

"It is...notable that an increase in the expression of NHE-1 by a factor of 2 to 3 was sufficient to increase Bcl-xL deamidation and triple the level of apoptosis in imatinib-resistant CML cells," the researchers write. "Therefore, targeted stimulation of Bcl-xL deamidation provides a potential route for circumventing resistance to tyrosine kinase inhibitors and perhaps also for eradicating leukemic stem cells."

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