Recurrent cyclin D2 mutations in myeloid neoplasms.
Recurrent cyclin D2 mutations in myeloid neoplasms.
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DOI：
10.1038/leu.2017.195
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发表时间：
2017-09
期刊：
影响因子：
11.4
通讯作者：
Tyner JW
中科院分区：
文献类型：
--
作者：
Khanna V;Eide CA;Tognon CE;Maxson JE;Wilmot B;Bottomly D;McWeeney S;Edwards V DK;Druker BJ;Tyner JW
费城阴性嗜中性粒细胞白血病-非典型慢性粒细胞白血病（aCML）、慢性嗜中性粒细胞白血病（CNL）、MDS/MPNu（骨髓增生异常/骨髓增生性肿瘤，无法分类）和MPNu（骨髓增生性肿瘤，无法分类）-是一种罕见的血液学肿瘤，其特征是白细胞增多，骨髓细胞过多，主要由粒细胞组成，缺乏费城染色体（t（9; 22）; BCRABL 1），并且不存在PDGFRA/B或FGFR 1基因重排。CNL 1和MDS/MPNu的偶见病例2以及大多数aCML病例表现出非特异性细胞遗传学异常3或JAK 2 V617 F突变4，揭示了其克隆性质。这些白血病的主要遗传基础是未知的，直到最近的工作由Maxson等人，5，强调了CSF 3R突变是约60% aCML或CNL患者的关键致白血病驱动因素。随后的研究在大多数CNL患者中发现了CSF 3R突变，仅在少数aCML患者中发现了CSF 3R突变，6 aCML的平行研究揭示了复发性SETBP 1和ETNK 1突变的存在。7，8尽管有这些发现，费城阴性嗜中性粒细胞白血病的完整遗传景观的知识仍然不完整。为了鉴定和表征导致这些恶性肿瘤发病机制的其他突变，我们对116例费城阴性嗜酸性白血病样本进行了全外显子组测序（WES）（补充材料和方法）。我们鉴定了4/116个样本中含有CCND 2突变，CCND 2是编码细胞周期调节因子细胞周期蛋白D2的基因。在这四个样本中，一个经病理学证实为MPNu，而另一个经病理学证实为MDS/MPNu（补充表1）。有趣的是，所有突变的样本都在密码子281处携带变体，其中三个样本具有P281 S变体，另一个携带P281 L变体（补充表1）。这些变化似乎以杂合突变形式发生，仅存在于缺乏CSF 3R突变的患者中，其中一份样本（13-00010）含有已知的致病性SETBP 1变体（I871 T），另一份样本（14-00247）含有SRSF 2 P95 H变体。4份样品中有2份含有TET 2突变（补充表2中观察到的其他突变）。通过桑格测序证实了具有额外可用DNA的所有突变（补充图1）。
Philadelphia-negative neutrophilic leukemias—atypical chronic myeloid leukemia (aCML), chronic neutrophilic leukemia (CNL), MDS/MPNu (myelodysplastic/myeloproliferative neoplasm, unclassifiable), and MPNu (myeloproliferative neoplasm, unclassifiable)—are rare hematologic neoplasms characterized by leukocytosis, a hypercellular bone marrow comprised predominantly of granulocytic cells, absence of the Philadelphia chromosome (t (9; 22); BCRABL1), and absence of PDGFRA/B or FGFR1 gene rearrangements. Occasional cases of CNL1 and MDS/MPNu, 2 as well as a majority of aCML cases, exhibit non-specific cytogenetic abnormalities3 or the JAK2 V617F mutation, 4 revealing their clonal nature. The primary genetic basis of these leukemias was unknown until recent work by Maxson et al., 5 which highlighted mutations in CSF3R as key leukemogenic drivers in~ 60% of patients with aCML or CNL. Subsequent studies found CSF3R mutations in a majority of patients with CNL and only in a minority of patients with aCML, 6 with parallel studies of aCML revealing the presence of recurrent SETBP1 and ETNK1 mutations. 7, 8 Despite these discoveries, knowledge of the full genetic landscape of Philadelphia-negative neutrophilic leukemias remains incomplete. To identify and characterize additional mutations contributing to the pathogenesis of these malignancies, we performed whole exome sequencing (WES) on 116 Philadelphia-negative neutrophilic leukemia samples (Supplementary Materials and Methods). We identified 4/116 samples harboring mutations in CCND2, the gene encoding the cell cycle regulator cyclin D2. Of these four samples, one was pathologically confirmed as MPNu, while another was confirmed as MDS/MPNu (Supplementary Table 1). Interestingly, all mutated samples harbored variants in codon 281, with three samples possessing a P281S variant and the other carrying a P281L variant (Supplementary Table 1). These changes appeared to occur as heterozygous mutations and were present only in patients lacking CSF3R mutations, with one sample (13-00010) harboring a known pathogenic SETBP1 variant (I871T), and another (14-00247) possessing an SRSF2 P95H variant. Two out of four samples harbored a TET2 mutation (other observed mutations in Supplementary Table 2). All mutations with additional available DNA were confirmed by Sanger sequencing (Supplementary Figure 1).
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影响因子：
30.8
作者：
Faber ZJ;Chen X;Gedman AL;Boggs K;Cheng J;Ma J;Radtke I;Chao JR;Walsh MP;Song G;Andersson AK;Dang J;Dong L;Liu Y;Huether R;Cai Z;Mulder H;Wu G;Edmonson M;Rusch M;Qu C;Li Y;Vadodaria B;Wang J;Hedlund E;Cao X;Yergeau D;Nakitandwe J;Pounds SB;Shurtleff S;Fulton RS;Fulton LL;Easton J;Parganas E;Pui CH;Rubnitz JE;Ding L;Mardis ER;Wilson RK;Gruber TA;Mullighan CG;Schlenk RF;Paschka P;Döhner K;Döhner H;Bullinger L;Zhang J;Klco JM;Downing JR
通讯作者：
Downing JR
DOI：
10.1056/nejmoa1214514
发表时间：
2013-05-09
期刊：
The New England journal of medicine
影响因子：
--
作者：
Maxson JE;Gotlib J;Pollyea DA;Fleischman AG;Agarwal A;Eide CA;Bottomly D;Wilmot B;McWeeney SK;Tognon CE;Pond JB;Collins RH;Goueli B;Oh ST;Deininger MW;Chang BH;Loriaux MM;Druker BJ;Tyner JW
通讯作者：
Tyner JW
影响因子：
11.4
作者：
Clappier, E;Cuccuini, W;Soulier, J
通讯作者：
Soulier, J
影响因子：
50.5
作者：
Hernández, JM;del Cañizo, MC;San Miguel, JF
通讯作者：
San Miguel, JF
影响因子：
11.4
作者：
Eisfeld AK;Kohlschmidt J;Schwind S;Nicolet D;Blachly JS;Orwick S;Shah C;Bainazar M;Kroll KW;Walker CJ;Carroll AJ;Powell BL;Stone RM;Kolitz JE;Baer MR;de la Chapelle A;Mrózek K;Byrd JC;Bloomfield CD
通讯作者：
Bloomfield CD