Inducible knockout of GRP78/BiP in the hematopoietic system suppresses Pten-null leukemogenesis and AKT oncogenic signaling.
Inducible knockout of GRP78/BiP in the hematopoietic system suppresses Pten-null leukemogenesis and AKT oncogenic signaling.
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DOI：
10.1182/blood-2011-06-357384
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发表时间：
2012-01
期刊：
影响因子：
20.3
通讯作者：
Shiuan Wey;Biquan Luo;Chun-Chih Tseng;Min Ni;Hui Zhou;Yong Fu;D. Bhojwani;W. Carroll;Amy S. Lee
中科院分区：
文献类型：
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作者：
Shiuan Wey;Biquan Luo;Chun-Chih Tseng;Min Ni;Hui Zhou;Yong Fu;D. Bhojwani;W. Carroll;Amy S. Lee
传统上，GRP 78被认为是对实体瘤微环境中普遍存在的缺氧和营养饥饿的保护;因此，其在血液恶性肿瘤发展中的作用仍有待确定。为了直接阐明GRP 78在白血病发生中的需求，我们建立了造血系统中GRP 78和PTEN的双等位基因条件性敲除小鼠模型。引人注目的是，PTEN缺失小鼠中GRP 78的杂合敲低足以将造血干细胞群体恢复到正常百分比并抑制白血病母细胞扩增。PTEN缺失BM细胞中的AKT/mTOR活化被Grp 78杂合性有效抑制，对应于白血病细胞系中通过GRP 78敲低对PI 3 K/AKT途径的抑制。这是第一次证明GRP 78是白血病进展的关键效应子，至少部分通过调节致癌PI 3 K/AKT信号传导。与PI 3 K/AKT作为急性髓性白血病中阿糖胞苷抗性的效应子一致，GRP 78的过表达使人白血病细胞对阿糖胞苷诱导的凋亡更具抗性，而GRP 78的敲低使其敏感。这些，再加上成人患者白血病原始细胞中GRP 78表达升高与儿童白血病早期复发的新兴关联，表明GRP 78是白血病的新治疗靶点。
Traditionally, GRP78 is regarded as protective against hypoxia and nutrient starvation prevalent in the microenvironment of solid tumors; thus, its role in the development of hematologic malignancies remains to be determined. To directly elucidate the requirement of GRP78 in leukemogenesis, we created a biallelic conditional knockout mouse model of GRP78 and PTEN in the hematopoietic system. Strikingly, heterozygous knockdown of GRP78 in PTEN null mice is sufficient to restore the hematopoietic stem cell population back to the normal percentage and suppress leukemic blast cell expansion. AKT/mTOR activation in PTEN null BM cells is potently inhibited by Grp78 heterozygosity, corresponding with suppression of the PI3K/AKT pathway by GRP78 knockdown in leukemia cell lines. This is the first demonstration that GRP78 is a critical effector of leukemia progression, at least in part through regulation of oncogenic PI3K/AKT signaling. In agreement with PI3K/AKT as an effector for cytosine arabinoside resistance in acute myeloid leukemia, overexpression of GRP78 renders human leukemic cells more resistant to cytosine arabinoside-induced apoptosis, whereas knockdown of GRP78 sensitizes them. These, coupled with the emerging association of elevated GRP78 expression in leukemic blasts of adult patients and early relapse in childhood leukemia, suggest that GRP78 is a novel therapeutic target for leukemia.