Meydan N, Grunberger T, Dadi H, Shahar M, Arpaia E, Lapidot Z, Leeder J S, Freedman M, Cohen A, Gazit A, Levitzki A, Roifman C M
Division of Immunology/Allergy, Hospital for Sick Children, Toronto, Canada.
Nature. 1996 Feb 15;379(6566):645-8. doi: 10.1038/379645a0.
Acute lymphoblastic leukaemia (ALL) is the most common cancer of childhood. Despite the progress achieved in its treatment, 20% of cases relapse and no longer respond to chemotherapy. The most common phenotype of ALL cells share surface antigens with very early precursors of B cells and are therefore believed to originate from this lineage. Characterization of the growth requirement of ALL cells indicated that they were dependent on various cytokines, suggesting paracrine and/or autocrine growth regulation. Because many cytokines induce tyrosine phosphorylation in lymphoid progenitor cells, and constitutive tyrosine phosphorylation is commonly observed in B-lineage leukaemias, attempts have been made to develop protein tyrosine kinase (PTK) blockers of leukaemia cell growth. Here we show that leukaemic cells from patients in relapse have constitutively activated Jak-2 PTK. Inhibition of Jak-2 activity by a specific tyrosine kinase blocker, AG-490, selectively blocks leukaemic cell growth in vitro and in vivo by inducing programmed cell death, with no deleterious effect on normal haematopoiesis.
急性淋巴细胞白血病（ALL）是儿童期最常见的癌症。尽管在其治疗方面取得了进展，但仍有20%的病例复发且不再对化疗有反应。ALL细胞最常见的表型与B细胞的极早期前体共享表面抗原，因此被认为起源于该谱系。ALL细胞生长需求的特征表明它们依赖于多种细胞因子，提示旁分泌和/或自分泌生长调节。由于许多细胞因子在淋巴祖细胞中诱导酪氨酸磷酸化，并且在B系白血病中通常观察到组成型酪氨酸磷酸化，因此人们试图开发白血病细胞生长的蛋白酪氨酸激酶（PTK）阻滞剂。在此我们表明，复发患者的白血病细胞具有组成型激活的Jak-2 PTK。一种特异性酪氨酸激酶阻滞剂AG-490对Jak-2活性的抑制通过诱导程序性细胞死亡在体外和体内选择性地阻断白血病细胞生长，对正常造血没有有害影响。
