Emergence of clonal cytogenetic abnormalities in Ph- cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority
Emergence of clonal cytogenetic abnormalities in Ph- cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority
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DOI：
10.1182/blood-2002-07-2053
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发表时间：
2003-03-01
期刊：
影响因子：
20.3
通讯作者：
Deininger, MWN
中科院分区：
文献类型：
--
作者：
Bumm, T;M端ller, C;Deininger, MWN
慢性粒细胞白血病（CML）的特征是存在一种Bcr-Abl融合蛋白，该融合蛋白具有维持恶性表型所需的失调的酪氨酸激酶活性。伊马替尼是一种选择性Bcr-Abl抑制剂，在大多数慢性期CML患者中诱导主要细胞遗传学缓解（MCR）或完全细胞遗传学缓解（CCR）。然而，在MCR或CCR患者队列中对细胞遗传学进行的全面重新评价表明，超过10%的病例存在克隆核型异常，其中一些病例与骨髓增生异常综合征（MDS）临床相关。进一步分析发现，既往暴露于阿糖胞苷和依达拉奉是随后发生费城染色体阴性（Ph-）细胞异常的显著风险因素。为了研究细胞遗传学正常，但克隆造血可能存在于其他患者的细胞遗传学缓解，我们研究了X-染色体失活作为克隆性的标记，通过聚合酶链反应分析的人雄激素受体（HUMARA）。我们发现伊马替尼在CCR和MCR的大多数患者中恢复了多克隆模式。尽管如此，我们的研究结果与伊马替尼靶向治疗CML有利于某些患者表现为Ph-克隆性疾病的观点一致。他们指出，即使在诱导CCR后，也应对接受伊马替尼治疗的患者进行常规细胞遗传学随访。
Chronic myelogenous leukemia (CML) is characterized by the presence of a Bcr-Abl fusion protein with deregulated tyrosine kinase activity that is required for maintaining the malignant phenotype. Imatinib, a selective inhibitor of Bcr-Abl, induces major cytogenetic remission (MCR) or complete cytogenetic remission (CCR) in the majority of patients with CML in first chronic phase. However, thorough re-evaluation of cytogenetics in a cohort of patients in MCR or CCR demonstrated clonal karyotypic abnormalities in more than 10% of cases, some of which were clinically associated with a myelodysplastic syndrome (MDS). Further analysis identified previous exposure to cytarabine and idarubicin as significant risk factors for the subsequent occurrence of abnormalities in Philadelphia chromosome-negative (Ph-) cells. To investigate if cytogenetically normal but clonal hematopoiesis might be present in other patients in cytogenetic remission, we studied X-chromosome inactivation as a marker of clonality by polymerase chain reaction analysis of the human androgen receptor (HUMARA). We find that imatinib restores a polyclonal pattern in most patients in CCR and MCR. Nonetheless, our results are consistent with the notion that targeted therapy of CML with imatinib favors the manifestation of Ph- clonal disorders in some patients. They indicate that patients on imatinib should be followed with conventional cytogenetics, even after induction of CCR.