Mutations of an E3 ubiquitin ligase c-Cbl but not TET2 mutations are pathogenic in juvenile myelomonocytic leukemia
Mutations of an E3 ubiquitin ligase c-Cbl but not TET2 mutations are pathogenic in juvenile myelomonocytic leukemia
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DOI：
10.1182/blood-2009-06-226340
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发表时间：
2010-03-11
期刊：
影响因子：
20.3
通讯作者：
Maciejewski, Jaroslaw P.
中科院分区：
文献类型：
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作者：
Muramatsu, Hideki;Makishima, Hideki;Maciejewski, Jaroslaw P.
幼年型骨髓单核细胞白血病是一种罕见的小儿骨髓肿瘤，其特征是骨髓单核细胞过度增殖。当我们研究49例JMML患儿中复发性分子病变的存在时，发现2例（4%）患者存在神经纤维瘤病表型（从而存在NF 1突变），而先前描述的PTPN 11、NRAS和KRAS突变分别见于53%、4%和2%的病例。因此，一个显着比例的JMML患者没有明确的发病机制，促使我们寻找其他分子缺陷。当我们将单核苷酸多态性阵列应用于JMML患者时，在49例患者中的4例中检测到体细胞单亲二体11 q;所有这些病例均携带RING指结构域c-Cbl突变。总的来说，在49例患者中的5例（10%）中检测到c-Cbl突变。在Cbl-b和TET 2中未鉴定出突变。c-Cbl和RAS途径突变是相互排斥的。临床表型比较显示c-Cbl突变患者的早期表现和较低的血红蛋白F水平。我们的研究结果表明，c-Cbl突变可能代表JMML患者的关键分子病变没有RAS/PTPN 11病变，这表明类似的发病机制，在慢性粒单核细胞白血病（CMML）患者中观察到的。（血。2010; 115：1969-1975）
Juvenile myelomonocytic leukemia (JMML) is a rare pediatric myeloid neoplasm characterized by excessive proliferation of myelomonocytic cells. When we investigated the presence of recurrent molecular lesions in a cohort of 49 children with JMML, neurofibromatosis phenotype (and thereby NF1 mutation) was present in 2 patients (4%), whereas previously described PTPN11, NRAS, and KRAS mutations were found in 53%, 4%, and 2% of cases, respectively. Consequently, a significant proportion of JMML patients without identifiable pathogenesis prompted our search for other molecular defects. When we applied single nucleotide polymorphism arrays to JMML patients, somatic uniparental disomy 11q was detected in 4 of 49 patients; all of these cases harbored RING finger domain c-Cbl mutations. In total, c-Cbl mutations were detected in 5 (10%) of 49 patients. No mutations were identified in Cbl-b and TET2. c-Cbl and RAS pathway mutations were mutually exclusive. Comparison of clinical phenotypes showed earlier presentation and lower hemoglobin F levels in patients with c-Cbl mutations. Our results indicate that mutations in c-Cbl may represent key molecular lesions in JMML patients without RAS/PTPN11 lesions, suggesting analogous pathogenesis to those observed in chronic myelomonocytic leukemia (CMML) patients. (Blood. 2010; 115: 1969-1975)