A murine model of CML blast crisis induced by cooperation between BCR/ABL and NUP98/HOXA9
A murine model of CML blast crisis induced by cooperation between BCR/ABL and NUP98/HOXA9
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DOI：
10.1073/pnas.102583199
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发表时间：
2002-05-28
影响因子：
11.1
通讯作者：
Gilliland, DG
中科院分区：
文献类型：
--
作者：
Dash, AB;Williams, IR;Gilliland, DG
酪氨酸激酶的组成性激活，例如与t(9;22)(q34;q22)相关的BCR/ABL融合，是人类慢性髓系白血病（CML）综合征的一个标志。在小鼠骨髓移植模型中，BCR/ABL的表达对于引起慢性骨髓增殖性综合征既是必要的也是充分的，并且绝对依赖于激酶活性。人类慢性髓系白血病进展为急性白血病（急变期）与获得继发性染色体易位有关，包括导致NUP98/HOXA9融合蛋白的t(7;11)(p15;p15)。我们证明在小鼠模型中BCR/ABL与NUP98/HOXA9协同作用导致急变期。该表型既取决于BCR/ABL和NUP98/HOXA9的表达，但肿瘤在体外和体内对ABL抑制剂STI571仍保持敏感性。这种模式适用于其他组成性激活的酪氨酸激酶，如TEL/PDGFβR。这些实验记录了组成性激活的酪氨酸激酶之间的协同作用，这些激酶赋予造血细胞增殖和存活特性，以及损害分化的突变，如NUP98/HOXA9，产生急性髓系白血病（AML）表型。此外，这些数据表明，尽管获得了额外的突变，慢性髓系白血病急变期细胞在增殖和存活方面仍然依赖于BCR/ABL。
Constitutive activation of tyrosine kinases, such as the BCR/ABL fusion associated with t(9;22)(q34;q22), is a hallmark of chronic myeloid leukemia (CML) syndromes in humans. Expression of BCR/ABL is both necessary and sufficient to cause a chronic myeloproliferative syndrome in murine bone marrow transplantation models, and absolutely depends on kinase activity. Progression of CML to acute leukemia (blast crisis) in humans has been associated with acquisition of secondary chromosomal translocations, including the t(7;11)(p15;p15) resulting in the NUP98/HOXA9 fusion protein. We demonstrate that BCR/ABL cooperates with NUP98/HOXA9 to cause blast crisis in a murine model. The phenotype depends both on expression of BCR/ABL and NUP98/HOXA9, but tumors retain sensitivity to the ABL inhibitor STI571 in vitro and in vivo. This paradigm is applicable to other constitutively activated tyrosine kinases such as TEL/PDGFbetaR, These experiments document cooperative effects between constitutively activated tyrosine kinases, which confer proliferative and survival properties to hematopoietic cells, with mutations that impair differentiation, such as the NUP98/HOXA9, giving rise to the acute myeloid leukemia (AML) phenotype. Furthermore, these data indicate that despite acquisition of additional mutations, CIVIL blast crisis cells retain their dependence on BCR/ABL for proliferation and survival.