Truncated RUNX1 generated from the fusion of RUNX1 to antisense GRIK2 via a cryptic chromosome translocation enhances sensitivity to granulocyte colony-stimulating factor
Truncated RUNX1 generated from the fusion of RUNX1 to antisense GRIK2 via a cryptic chromosome translocation enhances sensitivity to granulocyte colony-stimulating factor
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RUNX1通过隐性染色体易位与反义GRIK2融合产生的截短RUNX1增强了对粒细胞集落刺激因子的敏感性
DOI：
10.1159/000508012
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发表时间：
2020
影响因子：
1.7
通讯作者：
Tomita A.
中科院分区：
文献类型：
--
作者：
Abe A;Yamamoto Y;Katsumi A;Yamamoto H;Okamoto A;Inaguma Y;Iriyama C;Tokuda M;Okamoto M;Emi N;Tomita A.
Runt相关转录因子1（RUNX 1）与不同伴侣基因的融合与各种血液疾病相关。有趣的是，RUNX 1和RUNX 1融合蛋白的C-末端截短形式同样被认为是白血病发生的重要贡献者。在这里，我们描述了一个59岁的男性患者谁最初被诊断为急性髓性白血病，inv（16）（p13; q22）/CBFB-MYH 11（FAB分类M4 Eo）。他在柔红霉素/阿糖胞苷联合化疗后获得完全缓解和阴性CBFB-MYH 11状态，但3年后复发。复发性白血病细胞的细胞遗传学分析显示CBFB-MYH 11阴性和复杂的染色体异常，无inv（16）（p13; q22）。在这种情况下，RNA-seq鉴定了6 q16上的谷氨酸受体离子型激酶2（GRIK 2）基因作为RUNX 1的新型融合伴侣。具体地，RUNX 1与GRIK 2反义链的融合（RUNX 1-GRIK 2as）产生多个错剪接转录物。由于在白血病细胞中检测到极低水平的野生型GRIK 2，因此认为RUNX 1-GRIK 2as驱动与RUNX 1-GRIK 2融合相关的发病机制。从RUNX 1-GRIK 2as产生的截短的RUNX 1诱导32 D髓性白血病细胞上的粒细胞集落刺激因子（G-CSF）受体的表达，并增强响应于G-CSF的增殖。总之，RUNX 1-GRIK 2as融合强调了异常截短的RUNX 1在白血病发生中的重要性。
Fusions of the Runt-related transcription factor 1 (RUNX1) with different partner genes have been associated with various hematological disorders. Interestingly, the C-terminally truncated form of RUNX1 and RUNX1 fusion proteins are similarly considered important contributors to leukemogenesis. Here, we describe a 59-year-old male patient who was initially diagnosed with acute myeloid leukemia, inv (16)(p13; q22)/CBFB-MYH11 (FAB classification M4Eo). He achieved complete remission and negative CBFB-MYH11 status with daunorubicin/cytarabine combination chemotherapy but relapsed 3 years later. Cytogenetic analysis of relapsed leukemia cells revealed CBFB-MYH11 negativity and complex chromosomal abnormalities without inv (16)(p13; q22). RNA-seq identified the glutamate receptor, ionotropic, kinase 2 (GRIK2) gene on 6q16 as a novel fusion partner for RUNX1 in this case. Specifically, the fusion of RUNX1 to the GRIK2 antisense strand (RUNX1-GRIK2as) generated multiple missplicing transcripts. Because extremely low levels of wild-type GRIK2 were detected in leukemia cells, RUNX1-GRIK2as was thought to drive the pathogenesis associated with the RUNX1-GRIK2 fusion. The truncated RUNX1 generated from RUNX1-GRIK2as induced the expression of the granulocyte colony-stimulating factor (G-CSF) receptor on 32D myeloid leukemia cells and enhanced proliferation in response to G-CSF. In summary, the RUNX1-GRIK2as fusion emphasizes the importance of aberrantly truncated RUNX1 in leukemogenesis.