Feldhahn Niklas, Klein Florian, Mooster Jana L, Hadweh Paul, Sprangers Mieke, Wartenberg Maria, Bekhite Mohamed M, Hofmann Wolf-Karsten, Herzog Sebastian, Jumaa Hassan, Rowley Janet D, Müschen Markus
Laboratory for Molecular Stem Cell Biology, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany.
J Exp Med. 2005 Jun 6;201(11):1837-52. doi: 10.1084/jem.20042101.
Pre-B cells undergo apoptosis unless they are rescued by pre-B cell receptor-dependent survival signals. We previously showed that the BCR-ABL1 kinase that is expressed in pre-B lymphoblastic leukemia bypasses selection for pre-B cell receptor-dependent survival signals. Investigating possible interference of BCR-ABL1 with pre-B cell receptor signaling, we found that neither SYK nor SLP65 can be phosphorylated in response to pre-B cell receptor engagement. Instead, Bruton's tyrosine kinase (BTK) is constitutively phosphorylated by BCR-ABL1. Activated BTK is essential for survival signals that otherwise would arise from the pre-B cell receptor, including activation of PLCgamma1, autonomous Ca2+ signaling, STAT5-phosphorylation, and up-regulation of BCLX(L). Inhibition of BTK activity specifically induces apoptosis in BCR-ABL1+ leukemia cells to a similar extent as inhibition of BCR-ABL1 kinase activity itself. However, BCR-ABL1 cannot directly bind to full-length BTK. Instead, BCR-ABL1 induces the expression of a truncated splice variant of BTK that acts as a linker between the two kinases. As opposed to full-length BTK, truncated BTK lacks kinase activity yet can bind to BCR-ABL1 through its SRC-homology domain 3. Acting as a linker, truncated BTK enables BCR-ABL1-dependent activation of full-length BTK, which initiates downstream survival signals and mimics a constitutively active pre-B cell receptor.
前B细胞会发生凋亡，除非它们被前B细胞受体依赖性存活信号挽救。我们之前表明，在前B淋巴细胞白血病中表达的BCR-ABL1激酶绕过了对前B细胞受体依赖性存活信号的选择。在研究BCR-ABL1对前B细胞受体信号传导的可能干扰时，我们发现，在前B细胞受体结合后，SYK和SLP65均不能被磷酸化。相反，布鲁顿酪氨酸激酶（BTK）被BCR-ABL1组成性磷酸化。活化的BTK对于原本由前B细胞受体产生的存活信号至关重要，包括PLCγ1的激活、自主Ca2+信号传导、STAT5磷酸化以及BCLX(L)的上调。抑制BTK活性特异性地诱导BCR-ABL1+白血病细胞凋亡，其程度与抑制BCR-ABL1激酶活性本身相似。然而，BCR-ABL1不能直接与全长BTK结合。相反，BCR-ABL1诱导BTK的一种截短剪接变体的表达，该变体充当两种激酶之间的连接物。与全长BTK不同，截短的BTK缺乏激酶活性，但可通过其SRC同源结构域3与BCR-ABL1结合。截短的BTK作为连接物，使BCR-ABL1能够依赖性地激活全长BTK，从而启动下游存活信号并模拟组成性激活的前B细胞受体。
