Hjort Elizabeth E, Huang Weiqi, Hu Liping, Eklund Elizabeth A
The Feinberg School at Northwestern University, Chicago, IL, USA.
Jesse Brown VA Medical Center, Chicago, IL, USA.
Oncotarget. 2016 Nov 22;7(47):77635-77650. doi: 10.18632/oncotarget.12749.
Icsbp/Irf8 is an interferon regulatory transcription factor that functions as a suppressor of myeloid leukemias. Consistent with this activity, Icsbp represses a set of genes encoding proteins that promote cell proliferation/survival. One such gene encodes Gas2, a calpain inhibitor. We previously found that increased Gas2-expression in Bcr-abl+ cells stabilized βcatenin; a Calpain substrate. This was of interest, because βcatenin contributes to disease progression in chronic myeloid leukemia (CML). Calpain has additional substrates implicated in leukemogenesis, including Stat5. In the current study, we hypothesized that Stat5 activity in CML is regulated by Gas2/Calpain. We found that Bcr-abl-induced, Shp2-dependent dephosphorylation of Icsbp impaired repression of GAS2 by this transcription factor. The consequent decrease in Calpain activity stabilized Stat5 protein; increasing the absolute abundance of both phospho and total Stat5. This enhanced repression of the IRF8 promoter by Stat5 in a manner dependent on Icsbp, Gas2 and Calpain, but not Stat5 tyrosine phosphorylation. During normal myelopoiesis, increased expression and phosphorylation of Icsbp inhibits Calpain. In contrast, constitutive activation of Shp2 in Bcr-abl+ cells impairs regulation of Gas2/Calpain by Icsbp, aberrantly stabilizing Stat5 and enhancing IRF8 repression. This novel feedback mechanism enhances leukemogenesis by increasing Stat5 and decreasing Icsbp. Bcr-abl targeted tyrosine kinase inhibitors (TKIs) provide long term disease control, but CML is not cured by these agents. Our studies suggest targeting Calpain might be a rational therapeutic approach to decrease persistent leukemia stem cells (LSCs) during TKI-treatment.
Icsbp/Irf8是一种干扰素调节转录因子，起着抑制髓系白血病的作用。与这种活性一致，Icsbp抑制一组编码促进细胞增殖/存活蛋白的基因。其中一个这样的基因编码Gas2，一种钙蛋白酶抑制剂。我们之前发现，Bcr-abl+细胞中Gas2表达增加会使β-连环蛋白（一种钙蛋白酶底物）稳定。这很有意思，因为β-连环蛋白在慢性髓系白血病（CML）的疾病进展中起作用。钙蛋白酶还有其他与白血病发生有关的底物，包括Stat5。在当前研究中，我们假设CML中的Stat5活性受Gas2/钙蛋白酶调节。我们发现，Bcr-abl诱导的、Shp2依赖的Icsbp去磷酸化会损害该转录因子对GAS2的抑制作用。随之而来的钙蛋白酶活性降低使Stat5蛋白稳定；增加了磷酸化Stat5和总Stat5的绝对丰度。Stat5以依赖Icsbp、Gas2和钙蛋白酶的方式增强对IRF8启动子的抑制作用，但不依赖Stat5酪氨酸磷酸化。在正常髓系造血过程中，Icsbp表达和磷酸化增加会抑制钙蛋白酶。相反，Bcr-abl+细胞中Shp2的组成性激活会损害Icsbp对Gas2/钙蛋白酶的调节，异常稳定Stat5并增强对IRF8的抑制。这种新的反馈机制通过增加Stat5和减少Icsbp来增强白血病发生。Bcr-abl靶向酪氨酸激酶抑制剂（TKIs）可提供长期疾病控制，但这些药物不能治愈CML。我们的研究表明，靶向钙蛋白酶可能是在TKI治疗期间减少持续性白血病干细胞（LSCs）的一种合理治疗方法。
