Ramírez-Komo J A, Delaney M A, Straign D, Lukin K, Tsang M, Iritani B M, Hagman J
Department of Comparative Medicine, University of Washington, Seattle, WA, USA.
Department of Biomedical Research, National Jewish Health, Denver, CO USA.
Oncogenesis. 2017 Jul 10;6(7):e355. doi: 10.1038/oncsis.2017.55.
Early B-cell factor 1 (EBF1) plays a central role in B-cell lineage specification and commitment. Loss of this critical transcription factor is strongly associated with high-risk, relapsed and therapy-resistant B-cell-acute lymphoblastic leukemia, especially in children. However, Ebf1 haploinsufficient mice exhibit a normal lifespan. To determine whether prolonged survival of B cells would enable tumorigenesis in Ebf1 haploinsufficient animals, we generated Ebf1Bcl-x mice, which express the anti-apoptotic factor Bcl-x in B cells. Approximately half of Ebf1Bcl-x mice develop aggressive oligoclonal leukemia as they age, which engrafts in congenic wild-type recipients without prior conditioning. The neoplastic cells display a pre-B phenotype and express early developmental- and natural killer cell/myeloid-markers inappropriately. In addition, we found tumor cell-specific loss of several transcription factors critical for maintaining differentiation: EBF1, TCF3 and RUNX1. However, in the majority of tumors, loss of Ebf1 expression was not due to loss of heterozygosity. This is the first spontaneous mouse model of pre-B leukemia to demonstrate inappropriate expression of non-B-cell-specific genes associated with loss of Ebf1, Tcf3 and Runx1 expression.
早期B细胞因子1（EBF1）在B细胞谱系的指定和定向分化中起着核心作用。这种关键转录因子的缺失与高危、复发和难治性B细胞急性淋巴细胞白血病密切相关，尤其是在儿童中。然而，Ebf1单倍体不足的小鼠寿命正常。为了确定B细胞的长期存活是否会导致Ebf1单倍体不足动物发生肿瘤，我们构建了Ebf1Bcl-x小鼠，其在B细胞中表达抗凋亡因子Bcl-x。随着年龄的增长，约一半的Ebf1Bcl-x小鼠会发展为侵袭性寡克隆白血病，且无需预先处理即可移植到同基因野生型受体中。肿瘤细胞表现出前B细胞表型，并异常表达早期发育相关标志物以及自然杀伤细胞/髓系标志物。此外，我们发现维持分化所必需的几种转录因子在肿瘤细胞中特异性缺失：EBF1、TCF3和RUNX1。然而，在大多数肿瘤中，Ebf1表达的缺失并非由于杂合性缺失。这是首个前B细胞白血病的自发小鼠模型，该模型显示出与Ebf1、Tcf3和Runx1表达缺失相关的非B细胞特异性基因的异常表达。
