NOTCH1 pathway activating mutations and clonal evolution in pediatric T-cell acute lymphoblastic leukemia.
NOTCH1 pathway activating mutations and clonal evolution in pediatric T-cell acute lymphoblastic leukemia.
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DOI：
10.1111/cas.13859
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发表时间：
2019-03
期刊：
影响因子：
5.7
通讯作者：
Takita J
中科院分区：
文献类型：
--
作者：
Kimura S;Seki M;Yoshida K;Shiraishi Y;Akiyama M;Koh K;Imamura T;Manabe A;Hayashi Y;Kobayashi M;Oka A;Miyano S;Ogawa S;Takita J
尽管由于 NOTCH1/FBXW7 改变而激活 NOTCH1 信号传导是主要的致癌驱动因素，但涉及 T 细胞急性淋巴细胞白血病 (T-ALL) 复发的分子机制尚不完全清楚。为了揭示 NOTCH1/FBXW7 突变与复发的相关性，我们对 30 例儿童 T-ALL 病例进行了全外显子组测序，其中进一步研究了 11 例诊断-复发配对病例，以使用基于扩增子的深度测序追踪复发的克隆进化。在 73.3%（诊断）和 72.7%（复发）的病例中检测到 NOTCH1/FBXW7 改变。异二聚化结构域中的单核苷酸变异在诊断时最常见（40.0%），而脯氨酸、谷氨酸、丝氨酸、富含苏氨酸（PEST）结构域改变在复发时最常见（54.5%）。诊断时非复发病例和复发病例之间的比较显示，复发病例中 PEST 改变占主导地位 (P = .045)，尽管我们未能在 TARGET 队列中验证这一点。基于对诊断-复发样本的克隆分析，我们在分析的 11 个诊断-复发配对病例中，有 2 个发现了 NOTCH1“转换”，其特征是诊断和复发样本之间的主要克隆中存在不同的 NOTCH1 突变。我们在先前报道的柏林-法兰克福-明斯特队列（n = 13）中发现了另一个 NOTCH1“转换”病例，表明 NOTCH1 在 T-ALL 的发生和进展中的重要性。尽管样本量小和基于非微小残留病的方案存在局限性，但我们的结果表明 NOTCH1 突变的存在可能会导致 T-ALL 疾病复发。
Molecular mechanisms involved in the relapse of T‐cell acute lymphoblastic leukemia (T‐ALL) are not fully understood, although activating NOTCH1 signaling due to NOTCH1/FBXW7 alterations is a major oncogenic driver. To unravel the relevance of NOTCH1/FBXW7 mutations associated with relapse, we performed whole–exome sequencing in 30 pediatric T‐ALL cases, among which 11 diagnosis‐relapse paired cases were further investigated to track the clonal evolution of relapse using amplicon–based deep sequencing. NOTCH1/FBXW7 alterations were detected in 73.3% (diagnosis) and 72.7% (relapse) of cases. Single nucleotide variations in the heterodimerization domain were the most frequent (40.0%) at diagnosis, whereas proline, glutamic acid, serine, threonine–rich (PEST) domain alterations were the most frequent at relapse (54.5%). Comparison between non–relapsed and relapsed cases at diagnosis showed a predominance of PEST alterations in relapsed cases (P = .045), although we failed to validate this in the TARGET cohort. Based on the clonal analysis of diagnosis‐relapse samples, we identified NOTCH1 “switching” characterized by different NOTCH1 mutations in a major clone between diagnosis and relapse samples in 2 out of 11 diagnosis‐relapse paired cases analyzed. We found another NOTCH1 “switching” case in a previously reported Berlin‐Frankfurt‐Münster cohort (n = 13), indicating NOTCH1 importance in both the development and progression of T‐ALL. Despite the limitations of having a small sample size and a non–minimal residual disease–based protocol, our results suggest that the presence of NOTCH1 mutations might contribute to the disease relapse of T‐ALL.
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影响因子：
30.8
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Meyer, Julia A.;Wang, Jinhua;Hogan, Laura E.;Yang, Jun J.;Dandekar, Smita;Patel, Jay P.;Tang, Zuojian;Zumbo, Paul;Li, Sheng;Zavadil, Jiri;Levine, Ross L.;Cardozo, Timothy;Hunger, Stephen P.;Raetz, Elizabeth A.;Evans, William E.;Morrison, Debra J.;Mason, Christopher E.;Carroll, William L.
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Liu Y;Easton J;Shao Y;Maciaszek J;Wang Z;Wilkinson MR;McCastlain K;Edmonson M;Pounds SB;Shi L;Zhou X;Ma X;Sioson E;Li Y;Rusch M;Gupta P;Pei D;Cheng C;Smith MA;Auvil JG;Gerhard DS;Relling MV;Winick NJ;Carroll AJ;Heerema NA;Raetz E;Devidas M;Willman CL;Harvey RC;Carroll WL;Dunsmore KP;Winter SS;Wood BL;Sorrentino BP;Downing JR;Loh ML;Hunger SP;Zhang J;Mullighan CG
通讯作者：
Mullighan CG
影响因子：
30.8
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Makishima H;Yoshizato T;Yoshida K;Sekeres MA;Radivoyevitch T;Suzuki H;Przychodzen B;Nagata Y;Meggendorfer M;Sanada M;Okuno Y;Hirsch C;Kuzmanovic T;Sato Y;Sato-Otsubo A;LaFramboise T;Hosono N;Shiraishi Y;Chiba K;Haferlach C;Kern W;Tanaka H;Shiozawa Y;Gómez-Seguí I;Husseinzadeh HD;Thota S;Guinta KM;Dienes B;Nakamaki T;Miyawaki S;Saunthararajah Y;Chiba S;Miyano S;Shih LY;Haferlach T;Ogawa S;Maciejewski JP
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Maciejewski JP
影响因子：
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Cave, H.