Distinct protein signatures of acute myeloid leukemia bone marrow-derived stromal cells are prognostic for patient survival.
Distinct protein signatures of acute myeloid leukemia bone marrow-derived stromal cells are prognostic for patient survival.
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DOI：
10.3324/haematol.2017.172429
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发表时间：
2018-05
期刊：
影响因子：
10.1
通讯作者：
Andreeff M
中科院分区：
文献类型：
--
作者：
Kornblau SM;Ruvolo PP;Wang RY;Battula VL;Shpall EJ;Ruvolo VR;McQueen T;Qui Y;Zeng Z;Pierce S;Jacamo R;Yoo SY;Le PM;Sun J;Hail N Jr;Konopleva M;Andreeff M
间充质基质细胞（MSC）支持急性髓系白血病（AML）细胞在骨髓（BM）微环境中的存活。aml来源的MSC的蛋白表达谱尚不清楚。通过反相蛋白阵列分析比较AML-MSC （n=106）和健康供者MSC (n=71) 151个蛋白的表达。两组间蛋白表达差异显著，白血病基质细胞中有19种蛋白过表达，正常基质细胞中有9种蛋白过表达。使用这28种蛋白对样品进行无偏分层聚类分析，发现了三个蛋白星座，其表达变化定义了四种MSC蛋白表达特征：1类、2类、3类和4类。这些细胞群似乎具有临床相关性。具体来说，与其他组相比，3类细胞患者的生存期和缓解期更长。白血病骨髓间充质干细胞首次诊断时与挽救期（即复发/难治性）的比较显示，9种蛋白的差异表达反映了向成骨分化的转变。白血病的MSC比正常的MSC更衰老，这可能是由于高β-半乳糖苷酶染色证实了p53/p21轴的过度表达。此外，BCL-XL在白血病MSC中过表达可能在衰老或应激条件下具有生存优势，过表达的半乳糖凝集素-3具有深刻的免疫抑制作用。总之，我们的研究结果表明，AML患者中特定MSC群体的鉴定可能是治疗反应的重要决定因素。
Mesenchymal stromal cells (MSC) support acute myeloid leukemia (AML) cell survival in the bone marrow (BM) microenvironment. Protein expression profiles of AML-derived MSC are unknown. Reverse phase protein array analysis was performed to compare expression of 151 proteins from AML-MSC (n=106) with MSC from healthy donors (n=71). Protein expression differed significantly between the two groups with 19 proteins over-expressed in leukemia stromal cells and 9 over-expressed in normal stromal cells. Unbiased hierarchical clustering analysis of the samples using these 28 proteins revealed three protein constellations whose variation in expression defined four MSC protein expression signatures: Class 1, Class 2, Class 3, and Class 4. These cell populations appear to have clinical relevance. Specifically, patients with Class 3 cells have longer survival and remission duration compared to other groups. Comparison of leukemia MSC at first diagnosis with those obtained at salvage (i.e. relapse/refractory) showed differential expression of 9 proteins reflecting a shift toward osteogenic differentiation. Leukemia MSC are more senescent compared to their normal counterparts, possibly due to the overexpressed p53/p21 axis as confirmed by high β-galactosidase staining. In addition, overexpression of BCL-XL in leukemia MSC might give survival advantage under conditions of senescence or stress and overexpressed galectin-3 exerts profound immunosuppression. Together, our findings suggest that the identification of specific populations of MSC in AML patients may be an important determinant of therapeutic response.
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