GM-CSF-dependent pSTAT5 sensitivity is a feature with therapeutic potential in chronic myelomonocytic leukemia
GM-CSF-dependent pSTAT5 sensitivity is a feature with therapeutic potential in chronic myelomonocytic leukemia
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DOI：
10.1182/blood-2012-10-460170
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发表时间：
2013-06-20
期刊：
影响因子：
20.3
通讯作者：
Epling-Burnette, Pearlie K.
中科院分区：
文献类型：
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作者：
Padron, Eric;Painter, Jeffrey S.;Epling-Burnette, Pearlie K.
粒细胞-巨噬细胞集落刺激因子(GM-CSF)超敏反应是幼年型粒-单核细胞白血病(JMML)的一个特征，但在与其相关的人类疾病慢性粒-单核细胞白血病(CMML)中尚未有系统的表现。通过造血祖细胞集落形成试验和磷酸化STAT5(PSTAT5)流式细胞术，我们发现原代CMML样本与健康供者相比表现出GM-CSF依赖的超敏反应。在CMML患者中，pSTAT5超敏反应与高危疾病、外周血白细胞、单核细胞和信号相关突变呈正相关。与IL-3和G-CSF相比，GM-CSF超敏反应是细胞因子特异性的，因此可能是CMML干预的靶点。为了探索这种可能性，我们用一种新型的抗GM-CSF的单抗KB003和JAK2抑制剂处理原代CMML细胞。我们发现，未成熟的GM-CSF受体-a(R)亚单位表达细胞在CMML的骨髓髓系中比例较高。在存活分析中，我们发现髓系祖细胞和单核细胞祖细胞对GM-CSF信号抑制敏感。我们的数据表明，表达CD38的承诺髓系前体可能代表了CMML对GM-CSF依赖性增强的祖细胞群体，这与JMML的结果一致。这些临床前数据表明，GM-CSF信号抑制物值得在CMML中进一步研究，而且GM-CSFR在髓系祖细胞上的表达可能是该疗法的一个生物标志物。
Granulocyte-macrophage-colony-stimulating factor (GM-CSF) hypersensitivity is a hallmark of juvenile myelomonocytic leukemia (JMML) but has not been systematically shown in the related human disease chronic myelomonocytic leukemia (CMML). We find that primary CMML samples demonstrate GM-CSF-dependent hypersensitivity by hematopoietic colony formation assays and phospho-STAT5 (pSTAT5) flow cytometry compared with healthy donors. Among CMML patients, the pSTAT5 hypersensitive response positively correlated with high-risk disease, peripheral leukocytes, monocytes, and signaling-associated mutations. When compared with IL-3 and G-CSF, GM-CSF hypersensitivity was cytokine specific and thus a possible target for intervention in CMML. To explore this possibility, we treated primary CMML cells with KB003, a novel monoclonal anti-GM-CSF antibody, and JAK2 inhibitors. We found that an elevated proportion of immature GM-CSF receptor-a(R) subunit-expressing cells were present in the bone marrow myeloid compartment of CMML. In survival assays, we found that myeloid and monocytic progenitors were sensitive to GM-CSF signal inhibition. Our data indicate that a committed myeloid precursor expressing CD38 may represent the progenitor population with enhanced GM-CSF dependence in CMML, consistent with results in JMML. These preclinical data indicate that GM-CSF signaling inhibitors merit further investigation in CMML and that GM-CSFR expression on myeloid progenitors may be a biomarker for this therapy.