Zeuner Ann, Pedini Francesca, Francescangeli Federica, Signore Michele, Girelli Gabriella, Tafuri Agostino, De Maria Ruggero
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
Blood. 2009 Feb 12;113(7):1522-5. doi: 10.1182/blood-2008-03-143321. Epub 2008 Dec 5.
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.
抗凋亡分子的表达增加在恶性细胞中经常可见，它通过赋予更好的生存能力促进其克隆性扩增。我们发现，真性红细胞增多症（PV）患者中JAK2V617F突变率中等和高的红系前体细胞通常表达高水平的抗凋亡分子Bcl-2和Bcl-X(L)（12例患者中有5例Bcl-2比正常对照平均水平高3至7倍，12例患者中有3例Bcl-X(L)比正常对照平均水平高4至7倍），并且比正常成红细胞对骨髓抑制药物更具抗性。ABT-737是一种Bcl-2、Bcl-X(L)和Bcl-W的小分子抑制剂，与JAK2V617F低表达或正常成红细胞相比，它优先诱导JAK2V617F高表达的PV红系前体细胞凋亡。ABT-737还抑制PV成红细胞的增殖，并干扰PV造血祖细胞内源性红系集落的形成。总之，这些结果表明，Bcl-2/Bcl-X(L)的小分子抑制剂可用于治疗JAK2V617F等位基因负荷高的PV患者。
