Activity of the BH3 mimetic ABT-737 on polycythemia vera erythroid precursor cells.
An increased expression of antiapoptotic 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 patients with polycythemia vera (PV) with medium and high JAK2V617F mutation rates often express elevated levels of the antiapoptotic molecules Bcl-2 and Bcl-X(L) (5 of 12 patients with 3 to 7 times Bcl-2 and 3 of 12 patients with 4 to 7 times Bcl-X(L) than average normal controls) and are more resistant to myelosuppressive drugs than normal erythroblasts. ABT-737, a small-molecule inhibitor of Bcl-2, Bcl-X(L), and Bcl-W, induced apoptosis preferentially in JAK2V617F-high PV erythroid precursors as compared with 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-X(L) may be used in the treatment of patients with PV with high JAK2V617F allele burden.
Zeuner
Ann
A
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy. a.zeuner@iss.it
Pedini
Francesca
F
Francescangeli
Federica
F
Signore
Michele
M
Girelli
Gabriella
G
Tafuri
Agostino
A
De Maria
Ruggero
R
D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects*; D004920:Erythropoiesis / Q000187:drug effects*; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D018716:Molecular Mimicry; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011087:Polycythemia Vera / Q000188:drug therapy* / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology*; D051020:bcl-X Protein / Q000235:genetics
C501332:ABT-737; C494811:BCL2L1 protein, human; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051020:bcl-X Protein