Ludwig Boltzmann Cluster Oncology, and.
Department of Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria;
Blood. 2014 Jun 19;123(25):3951-62. doi: 10.1182/blood-2013-10-536078. Epub 2014 Apr 28.
Chronic myeloid leukemia (CML) is a stem cell (SC) neoplasm characterized by the BCR/ABL1 oncogene. Although mechanisms of BCR/ABL1-induced transformation are well-defined, little is known about effector-molecules contributing to malignant expansion and the extramedullary spread of leukemic SC (LSC) in CML. We have identified the cytokine-targeting surface enzyme dipeptidylpeptidase-IV (DPPIV/CD26) as a novel, specific and pathogenetically relevant biomarker of CD34(+)/CD38(─) CML LSC. In functional assays, CD26 was identified as target enzyme disrupting the SDF-1-CXCR4-axis by cleaving SDF-1, a chemotaxin recruiting CXCR4(+) SC. CD26 was not detected on normal SC or LSC in other hematopoietic malignancies. Correspondingly, CD26(+) LSC decreased to low or undetectable levels during successful treatment with imatinib. CD26(+) CML LSC engrafted NOD-SCID-IL-2Rγ(-/-) (NSG) mice with BCR/ABL1(+) cells, whereas CD26(─) SC from the same patients produced multilineage BCR/ABL1(-) engraftment. Finally, targeting of CD26 by gliptins suppressed the expansion of BCR/ABL1(+) cells. Together, CD26 is a new biomarker and target of CML LSC. CD26 expression may explain the abnormal extramedullary spread of CML LSC, and inhibition of CD26 may revert abnormal LSC function and support curative treatment approaches in this malignancy.
慢性髓性白血病（CML）是一种以 BCR/ABL1 癌基因为特征的干细胞（SC）肿瘤。虽然 BCR/ABL1 诱导转化的机制已经得到很好的定义，但对于导致 CML 中白血病 SC（LSC）恶性扩张和骨髓外扩散的效应分子知之甚少。我们已经确定细胞因子靶向表面酶二肽基肽酶-IV（DPPIV/CD26）是 CD34(+)/CD38(─) CML LSC 的一种新的、特异的和与发病机制相关的生物标志物。在功能测定中，CD26 被鉴定为通过切割趋化因子 SDF-1 来破坏 SDF-1-CXCR4 轴的靶酶，SDF-1 招募 CXCR4(+) SC。在其他血液恶性肿瘤中，正常 SC 或 LSC 上未检测到 CD26。相应地，在成功接受伊马替尼治疗期间，CD26(+) CML LSC 减少到低水平或无法检测到的水平。CD26(+) CML LSC 用 BCR/ABL1(+) 细胞植入 NOD-SCID-IL-2Rγ(-/-)（NSG）小鼠，而来自同一患者的 CD26(─) SC 产生多谱系 BCR/ABL1(-) 植入。最后，gliptins 靶向 CD26 抑制了 BCR/ABL1(+)细胞的扩增。总之，CD26 是 CML LSC 的一个新的生物标志物和靶点。CD26 表达可能解释了 CML LSC 的异常骨髓外扩散，抑制 CD26 可能逆转异常 LSC 功能，并支持这种恶性肿瘤的治愈治疗方法。
