Inflammation-driven deaminase deregulation fuels human pre-leukemia stem cell evolution.
Inflammation-driven deaminase deregulation fuels human pre-leukemia stem cell evolution.
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DOI：
10.1016/j.celrep.2020.108670
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发表时间：
2021-01-26
期刊：
影响因子：
8.8
通讯作者：
Jamieson C
中科院分区：
文献类型：
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作者：
Jiang Q;Isquith J;Ladel L;Mark A;Holm F;Mason C;He Y;Mondala P;Oliver I;Pham J;Ma W;Reynoso E;Ali S;Morris IJ;Diep R;Nasamran C;Xu G;Sasik R;Rosenthal SB;Birmingham A;Coso S;Pineda G;Crews L;Donohoe ME;Venter JC;Whisenant T;Mesa RA;Alexandrov LB;Fisch KM;Jamieson C
炎症依赖性碱性脱氨酶促进许多恶性肿瘤的治疗抗性。然而，它们在人白血病前干细胞（pre-LSC）向急性髓性白血病干细胞（LSC）进化中的作用尚未阐明。来自骨髓增生性肿瘤（MPN）患者的FACS纯化的前LSC的比较性全基因组和全转录组测序分析揭示了进展期间APOBEC 3C上调、C至T突变负荷增加以及造血干细胞和祖细胞（HSPC）增殖，这可以通过慢病毒APOBEC 3C过表达来重现。在pre-LSC中，炎性剪接异构体过表达与APOBEC 3C上调和ADAR 1 p150诱导的A-to-I RNA超编辑一致。Pre-LSC进化为LSC的标志是STAT 3编辑、STAT 3 β亚型转换、磷酸化STAT 3升高和ADAR 1 p150表达增加，这可以通过鲁索利替尼或fedratinib抑制JAK 2/STAT 3或慢病毒ADAR 1 shRNA敲减来预防。相反，慢病毒ADAR 1 p150表达增强前LSC再铺板和STAT 3剪接亚型转换。因此，前LSC进化为LSC是由灵长类特异性APOBEC 3C诱导的前LSC增殖和ADAR 1介导的剪接失调推动的。Jiang等人鉴定了双重APOBEC 3C和ADAR 1碱基脱氨酶失调作为骨髓增殖性肿瘤干细胞进化为自我更新白血病干细胞的炎症反应驱动因子，其促进继发性急性髓性白血病转化。
Inflammation-dependent base deaminases promote therapeutic resistance in many malignancies. However, their roles in human pre-leukemia stem cell (pre-LSC) evolution to acute myeloid leukemia stem cells (LSCs) had not been elucidated. Comparative whole genome and whole transcriptome sequencing analyses of FACS-purified pre-LSC from myeloproliferative neoplasm (MPN) patients reveals APOBEC3C upregulation, an increased C-to-T mutational burden, and hematopoietic stem and progenitor cell (HSPC) proliferation during progression, which can be recapitulated by lentiviral APOBEC3C overexpression. In pre-LSC, inflammatory splice isoform overexpression coincides with APOBEC3C upregulation and ADAR1p150-induced A-to-I RNA hyper-editing. Pre-LSC evolution to LSC is marked by STAT3 editing, STAT3β isoform switching, elevated phospho-STAT3, and increased ADAR1p150 expression, which can be prevented by JAK2/STAT3 inhibition with ruxolitinib or fedratinib or lentiviral ADAR1 shRNA knockdown. Conversely, lentiviral ADAR1p150 expression enhances pre-LSC replating and STAT3 splice isoform switching. Thus, pre-LSC evolution to LSC is fueled by primate-specific APOBEC3C induced pre-LSC proliferation and ADAR1-mediated splicing deregulation. Jiang et al. identify dual APOBEC3C and ADAR1 base deaminase deregulation as an inflammation-responsive driver of myeloproliferative neoplasm stem cell evolution to self-renewing leukemia stem cells that fuel secondary acute myeloid leukemia transformation.
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影响因子：
30.8
作者：
Burns, Michael B.;Temiz, Nuri A.;Harris, Reuben S.
通讯作者：
Harris, Reuben S.
DOI：
10.1073/pnas.90.8.3755
发表时间：
1993-04-15
影响因子：
11.1
作者：
GISHIZKY, ML;JOHNSONWHITE, J;WITTE, ON
通讯作者：
WITTE, ON
影响因子：
13.6
作者：
Di Giorgio, Salvatore;Martignano, Filippo;Conticello, Silvestro G.
通讯作者：
Conticello, Silvestro G.
影响因子：
46.9
作者：
通讯作者：
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AZIN1 的重新编码 RNA 编辑易诱发肝细胞癌。
影响因子：
82.9
作者：
通讯作者：
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