Arcangeli A, Fontana L, Crociani O, Cherubini A, Hofmann G, Piccini E, Polvani S, D'Amico M, Carlà M, Olivotto M
Department of Experimental Pathology and Oncology, University of Firenze, Italy.
Leukemia. 2000 Dec;14(12):2112-7. doi: 10.1038/sj.leu.2401936.
Although dephosphorylation of tyrosine containing proteins is considered a necessary step in the induction of leukemia cell differentiation by hybrid polar compounds (HPC), the crucial actors in this step remain unknown. We present evidence that tyrosine phosphorylation of JAK1 and JAK2 is down-regulated in murine erythroleukemia cells (MELC) within the first 6 h of their exposure to the prototype of the HPC family, hexamethylenebisacetamide (HMBA), with full recovery at 14 h. Further evidence that the JAKs-centered signalling pathway is switched off early by HMBA was provided by the demonstration that STAT5, a downstream member of this pathway, turned out to be completely dephosphorylated at 6 h in HMBA-treated cells. This JAKs dephosphorylation did not occur in HMBA-resistant clones, suggesting that JAKs are possible targets of the dephosphorylative process required for leukemia cell commitment to differentiation. These results may have impact on leukemia therapy based on JAKs inhibitors.
尽管含酪氨酸蛋白的去磷酸化被认为是杂合极性化合物（HPC）诱导白血病细胞分化过程中的一个必要步骤，但这一步骤中的关键作用因子仍不清楚。我们提供的证据表明，在小鼠红白血病细胞（MELC）暴露于HPC家族原型六亚甲基双乙酰胺（HMBA）的最初6小时内，JAK1和JAK2的酪氨酸磷酸化被下调，在14小时时完全恢复。通过证明该信号通路的下游成员STAT5在HMBA处理的细胞中6小时时完全去磷酸化，进一步提供了证据表明以JAKs为中心的信号通路被HMBA早期关闭。这种JAKs去磷酸化在HMBA抗性克隆中未发生，表明JAKs可能是白血病细胞定向分化所需去磷酸化过程的靶点。这些结果可能会对基于JAKs抑制剂的白血病治疗产生影响。
