CXCR4-SERINE339 regulates cellular adhesion, retention and mobilization, and is a marker for poor prognosis in acute myeloid leukemia
CXCR4-SERINE339 regulates cellular adhesion, retention and mobilization, and is a marker for poor prognosis in acute myeloid leukemia
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DOI：
10.1038/leu.2013.201
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发表时间：
2014-03-01
期刊：
影响因子：
11.4
通讯作者：
Schwaller, J.
中科院分区：
文献类型：
--
作者：
Brault, L.;Rovo, A.;Schwaller, J.
CXCR4受体是造血细胞迁移的主要调节因子。CXCR4过表达与急性髓性白血病（AML）的不良预后相关。我们之前已经证明，PIM1介导的配体介导的细胞内结构域丝氨酸339 （CXCR4-S339）残基磷酸化与该受体的表面再表达有关。在此，我们报告了骨髓活检中CXCR4-S339的磷酸化与AML患者预后不良相关。为了从功能上解决CXCR4- s339磷酸化的影响，我们产生了表达CXCR4突变体的细胞系，这些突变体可以模拟组成性磷酸化（S339E）或消除磷酸化（S339A）。虽然CXCR4的表达显著增加，但CXCR4- s339e和CXCR4- s339a突变体在免疫缺陷小鼠中显著降低了Kasumi-1 AML细胞的BM归巢和植入。相比之下，仅表达CXCR4-S339E突变体增加了细胞的BM保留率和对阿糖胞苷治疗的抗性，损害了移植白血病细胞的脱离能力和amd3100诱导的动员。这些观察结果表明，显示CXCR4-S339磷酸化的AML患者预后不良可能是与白血病细胞化疗耐药性增强相关的BM潴留增加的结果。因此，CXCR4-S339磷酸化可以作为人类AML的一种新的预后标志物。
The CXCR4 receptor is a major regulator of hematopoietic cell migration. Overexpression of CXCR4 has been associated with poor prognosis in acute myelogenous leukemia (AML). We have previously shown that ligand-mediated phosphorylation of the Serine339 (CXCR4-S339) residue of the intracellular domain by PIM1 is implicated in surface re-expression of this receptor. Here, we report that phosphorylation of CXCR4-S339 in bone marrow (BM) biopsies correlated with poor prognosis in a cohort of AML patients. To functionally address the impact of CXCR4-S339 phosphorylation, we generated cell lines-expressing CXCR4 mutants that mimic constitutive phosphorylation (S339E) or abrogate phosphorylation (S339A). Whereas the expression of CXCR4 significantly increased, both CXCR4-S339E and the CXCR4-S339A mutants significantly reduced the BM homing and engraftment of Kasumi-1 AML cells in immunodeficient mice. In contrast, only expression of the CXCR4-S339E mutant increased the BM retention of the cells and resistance to cytarabine treatment, and impaired detachment capacity and AMD3100-induced mobilization of engrafted leukemic cells. These observations suggest that the poor prognosis in AML patients displaying CXCR4-S339 phosphorylation can be the consequence of an increased retention to the BM associated with an enhanced chemoresistance of leukemic cells. Therefore, CXCR4-S339 phosphorylation could serve as a novel prognostic marker in human AML.