Gunby Rosalind Helen, Cazzaniga Giovanni, Tassi Elena, Le Coutre Philipp, Pogliani Enrico, Specchia Giorgina, Biondi Andrea, Gambacorti-Passerini Carlo
Oncogenic Fusion Protein Unit, Department of Experimental Oncology, Istituto Nazionale Tumori, 20133 Milan, Italy.
Haematologica. 2003 Apr;88(4):408-15.
Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome that has been associated with the expression of platelet-derived growth factor b receptor (PDGFRbeta) fusion proteins, namely TEL/PDGFRbeta. These fusion proteins possess a constitutive PDGFRbeta tyrosine kinase activity, leading to aberrant PDGFRbeta signaling and cellular transformation. The expression of PDGFRbeta fusions in CMML could have therapeutic relevance, as PDGFRb is inhibited by the selective tyrosine kinase inhibitor, imatinib. Here, we investigated the possibility of employing imatinib to treat CMML.
We assessed the effect of imatinib on TEL/PDGFRbeta transformed cells in terms of proliferation, by trypan blue exclusion and 3H-thymidine uptake, and TEL/PDGFRbeta autophosphorylation by anti-phosphotyrosine immunoblotting. TEL/PDGFRbeta expression in mononuclear cells from the peripheral blood of 27 clinically diagnosed CMML patients was determined by reverse transcriptase-polymerase chain reaction.
Imatinib potently inhibited the proliferation of TEL/PDGFRbeta transformed cells (IC50=7.5 nM), and TEL/PDGFRbeta kinase activity. However, TEL/PDGFRbeta expression was detected in only 1 of 27 CMML patients (4%, confidence intervals: 0-13%). Additionally, another PDGFRbeta fusion protein, Hip1/PDGFRbeta, had a similarly low incidence in the same samples: 1 of 25 (4%, confidence intervals: 0-14%).
Although imatinib represents an attractive therapeutic agent for neoplasias associated with abnormal PDGFRbeta signaling, the low frequency of the TEL/PDGFRbeta and Hip1/PDGFRbeta fusion proteins in CMML suggests that its application to this disease maybe limited. Detection of PDGFRbeta fusion genes in individual patients is necessary in order to employ this drug rationally in CMML.
慢性粒单核细胞白血病（CMML）是一种骨髓增生异常综合征，与血小板衍生生长因子b受体（PDGFRβ）融合蛋白即TEL/PDGFRβ的表达相关。这些融合蛋白具有组成性PDGFRβ酪氨酸激酶活性，导致异常的PDGFRβ信号传导和细胞转化。CMML中PDGFRβ融合蛋白的表达可能具有治疗意义，因为PDGFRβ可被选择性酪氨酸激酶抑制剂伊马替尼抑制。在此，我们研究了使用伊马替尼治疗CMML的可能性。
我们通过台盼蓝排斥法和³H-胸腺嘧啶摄取评估伊马替尼对TEL/PDGFRβ转化细胞增殖的影响，并通过抗磷酸酪氨酸免疫印迹法评估TEL/PDGFRβ自身磷酸化情况。采用逆转录聚合酶链反应测定27例临床诊断的CMML患者外周血单个核细胞中TEL/PDGFRβ的表达。
伊马替尼有效抑制TEL/PDGFRβ转化细胞的增殖（IC50 = 7.5 nM）以及TEL/PDGFRβ激酶活性。然而，27例CMML患者中仅1例检测到TEL/PDGFRβ表达（4%，置信区间：0 - 13%）。此外，另一种PDGFRβ融合蛋白Hip1/PDGFRβ在相同样本中的发生率同样较低：25例中有1例（4%，置信区间：0 - 14%）。
尽管伊马替尼是与异常PDGFRβ信号传导相关肿瘤的一种有吸引力的治疗药物，但CMML中TEL/PDGFRβ和Hip1/PDGFRβ融合蛋白的低频率表明其在该疾病中的应用可能有限。为了在CMML中合理使用这种药物，有必要检测个体患者的PDGFRβ融合基因。
