BRCA1 and TP53 codeficiency causes a PARP inhibitor-sensitive erythroproliferative neoplasm.
BRCA1 and TP53 codeficiency causes a PARP inhibitor-sensitive erythroproliferative neoplasm.
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DOI：
10.1172/jci.insight.158257
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发表时间：
2022-12-22
期刊：
影响因子：
8
通讯作者：
Ross, Theodora S.
中科院分区：
文献类型：
--
作者：
Lopez-Perez, Gerardo;Wijayatunge, Ranjula;McCrum, Kelly B.;Holmstrom, Sam R.;Mgbemena, Victoria E.;Ross, Theodora S.
BRCA 1肿瘤抑制基因的突变，如5382 insC（BRCA 1 insC），使携带者患乳腺癌、卵巢癌、前列腺癌和胰腺癌的风险增加。我们以前曾报道过，在小鼠中，Brca 1在造血系统中的缺陷会导致全血细胞减少，因此，早期致死。我们探讨了Brca 1-null和BRCA 1 insC等位基因与Trp 53缺陷相结合在小鼠造血系统中的细胞后果。我们发现，Brca 1和Trp 53共同缺乏导致一个高度渗透性的红细胞增殖性疾病，其特征是肝脾肿大和扩大的巨核细胞红系祖细胞（MEP）和未成熟的红系母细胞群体。骨髓和脾脏中扩增的红系祖细胞群体有能力将疾病传播到第二代小鼠受体中，这表明Brca 1和Trp 53共缺陷提供了造血肿瘤的小鼠模型。该Brca 1/Trp 53模型复制了在现有Brca 1/Trp 53乳腺癌模型中观察到的聚（ADP-核糖）聚合酶（PARP）抑制剂奥拉帕尼敏感性，并且具有通过外周血分析监测疾病进展和药物反应而不牺牲实验动物的益处。此外，这种红系肿瘤的发展速度比小鼠乳腺癌快得多，从而提高了未来临床前研究的效率。
Mutations in the BRCA1 tumor suppressor gene, such as 5382insC (BRCA1insC), give carriers an increased risk for breast, ovarian, prostate, and pancreatic cancers. We have previously reported that, in mice, Brca1 deficiency in the hematopoietic system leads to pancytopenia and, as a result, early lethality. We explored the cellular consequences of Brca1-null and BRCA1insC alleles in combination with Trp53 deficiency in the murine hematopoietic system. We found that Brca1 and Trp53 codeficiency led to a highly penetrant erythroproliferative disorder that is characterized by hepatosplenomegaly and by expanded megakaryocyte erythroid progenitor (MEP) and immature erythroid blast populations. The expanded erythroid progenitor populations in both BM and spleen had the capacity to transmit the disease into secondary mouse recipients, suggesting that Brca1 and Trp53 codeficiency provides a murine model of hematopoietic neoplasia. This Brca1/Trp53 model replicated Poly (ADP-ribose) polymerase (PARP) inhibitor olaparib sensitivity seen in existing Brca1/Trp53 breast cancer models and had the benefits of monitoring disease progression and drug responses via peripheral blood analyses without sacrificing experimental animals. In addition, this erythroid neoplasia developed much faster than murine breast cancer, allowing for increased efficiency of future preclinical studies.
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影响因子：
--
作者：
Karami F;Mehdipour P
通讯作者：
Mehdipour P
通过使用BRCA1和BRCA2同源模型的ABT-888（PARP抑制剂）和卡铂的组合增强合成致死性。
影响因子：
5.7
作者：
Clark CC;Weitzel JN;O'Connor TR
通讯作者：
O'Connor TR
影响因子：
5.8
作者：
Holmstrom, Sam R.;Wijayatunge, Ranjula;Ross, Theodora S.
通讯作者：
Ross, Theodora S.
影响因子：
64.8
作者：
DONEHOWER, LA;HARVEY, M;BRADLEY, A
通讯作者：
BRADLEY, A
影响因子：
1.5
作者：
Georgiades, P;Ogilvy, S;Print, CG
通讯作者：
Print, CG