Wittwer Nicole L, Brumatti Gabriela, Marchant Ceilidh, Sandow Jarrod J, Pudney Melanie K, Dottore Mara, D'Andrea Richard J, Lopez Angel F, Ekert Paul G, Ramshaw Hayley S
Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, SA, Australia.
Walter and Eliza Hall Institute, Parkville, VIC, Australia.
Blood Adv. 2017 Jun 20;1(15):1067-1079. doi: 10.1182/bloodadvances.2016002931. eCollection 2017 Jun 27.
High expression of the α chain of the interleukin-3 receptor (IL-3Rα; CD123) is a hallmark of acute myeloid leukemia (AML) leukemic stem cells (LSCs). Elevated CD123 expression is part of the diagnostic immunophenotyping of myeloid leukemia, and higher expression is associated with poor prognosis. However, the biological basis of the poorer prognosis is unclear, and may include heightened IL-3 signaling and non-cell autonomous interactions with the bone marrow (BM) microenvironment. We used TF-1 cells expressing different levels of CD123 and found elevated CD123 levels amplified the proliferative response to exogenous IL-3 and maintained viability in reducing IL-3 concentrations. This was associated with stronger activation of STAT5, Akt, and extracellular signal-regulated kinase 1/2 in vitro. Surprisingly, in vivo e14.5 fetal liver cells transduced with retroviral constructs to express high CD123 failed to engraft in syngeneic recipients. In exploring the underlying mechanism for this, we found that CXCR4, a key molecule involved in LSC/BM interactions, was specifically downregulated in CD123 overexpressing cells in a manner dependent on IL-3 signaling. CXCR4 downregulation was sufficient to alter the chemotactic response of hematopoietic cells to stromal derived factor-1 (SDF-1). Thus, we propose that the overexpression of CD123 in AML LSC dictates their location by altering CXCR4/SDF-1 interaction in the BM, raising the possibility that this mechanism underpins the egress of BM AML LSC and more mature cells into the circulation.
白细胞介素-3受体α链（IL-3Rα；CD123）的高表达是急性髓系白血病（AML）白血病干细胞（LSCs）的一个标志。CD123表达升高是髓系白血病诊断性免疫表型分析的一部分，且更高的表达与不良预后相关。然而，预后较差的生物学基础尚不清楚，可能包括IL-3信号增强以及与骨髓（BM）微环境的非细胞自主相互作用。我们使用表达不同水平CD123的TF-1细胞，发现CD123水平升高放大了对外源性IL-3的增殖反应，并在降低IL-3浓度的情况下维持细胞活力。这与体外更强的信号转导及转录激活因子5（STAT5）、蛋白激酶B（Akt）和细胞外信号调节激酶1/2（ERK1/2）激活相关。令人惊讶的是，用逆转录病毒构建体转导以表达高CD123的体内e14.5胎肝细胞未能在同基因受体中植入。在探索其潜在机制时，我们发现CXCR4（一种参与LSC/BM相互作用的关键分子）在CD123过表达细胞中以依赖IL-3信号的方式特异性下调。CXCR4下调足以改变造血细胞对基质衍生因子-1（SDF-1）的趋化反应。因此，我们提出AML LSC中CD123的过表达通过改变BM中CXCR4/SDF-1相互作用来决定其位置，这增加了这种机制是BM AML LSC和更成熟细胞进入循环的基础的可能性。
