Submitted March 3, 2008
Accepted October 23, 2008
Activity of the BH3 mimetic ABT-737 on polycythemia vera erythroid precursor cells
Ann Zeuner*, Francesca Pedini, Federica Francescangeli, Michele Signore, Gabriella Girelli, Agostino Tafuri, and Ruggero De Maria
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanita, Rome, Italy
Department of Cellular Biotechnology and Hematology, University La Sapienza, Rome, Italy
* Corresponding author; email: a.zeuner{at}iss.it.
An increased expression of anti-apoptotic molecules is often found in malignant cells, where it contributes to their clonal expansion by conferring an improved survival ability. We found that erythroid precurors derived from polycythemia vera (PV) patients with medium and high JAK2V617F mutation rates often express elevated levels of the anti-apoptotic molecules Bcl-2 and Bcl-XL (5/12 patients with 3-7 times Bcl-2 and 3/12 patients with 4-7 times Bcl-XL than average normal controls) and are more resistant to myelosuppressive drugs than normal erythroblasts. ABT-737, a small-molecule inhibitor of Bcl-2, Bcl-XL and Bcl-W, induced apoptosis preferentially in JAK2V617F-high PV erythroid precursors as compared to JAK2V617F-low or normal erythroblasts. ABT-737 inhibited also the proliferation of PV erythroblasts and interfered with the formation of endogenous erythroid colonies by PV hematopoietic progenitors. Altogether, these results suggest that small-molecule inhibitors of Bcl-2/Bcl-XL may be employed in the treatment of PV patients with high JAK2V617F allele burden.
