Loss of p19Arf in a Rag1−/− B-cell precursor population initiates acute B-lymphoblastic leukemia

Abstract

In human B-acute lymphoblastic leukemia (B-ALL), RAG1-induced genomic alterations are important for disease progression. However, given that biallelic loss of the RAG1 locus is observed in a subset of cases, RAG1's role in the development of B-ALL remains unclear. We chose a p19Arf ؊/؊ Rag1 ؊/؊ mouse model to confirm the previously published results concerning the contribution of CDKN2A (p19ARF /INK4a) and RAG1 copy number alterations in precursor B cells to the initiation and/or progression to B-acute lymphoblastic leukemia (B-ALL). In this murine model, we identified a new, Rag1-independent leukemiainitiating mechanism originating from a Sca1 ؉ CD19 ؉ precursor cell population and showed that Notch1 expression accelerates the cells' self-renewal capacity in vitro. In human RAG1-deficient BM, a similar CD34 ؉ CD19 ؉ population expressed p19ARF. These findings suggest that combined loss of p19Arf and Rag1 results in B-cell precursor leukemia in mice and may contribute to the progression of precursor B-ALL in humans. (Blood. 2011;118(3):544-553)

Depletion of Cytotoxic T-Cells Does Not Protect NUP98-HOXD13 Mice from Myelodysplastic Syndrome but Reveals a Modest Tumor Immunosurveillance Effect

“…However, given that the survival advantage was only two months, the effect is modest. Of note, a similar moderate survival advantage was observed in crosses of Rag1 KO mice to other oncogenic backgrounds, such as those described above[41], [42], [43]. Interestingly, a RAG1 −/− genotype also denotes a high-risk group with poorer survival in human B-ALL, again supporting the hypothesis that immune-mediated surveillance may be important in the elimination of fully transformed malignant cells [45], [46].…”

The mechanism of B cell acute lymphoblastic leukemia development

“…证明IKZF1可以加速BCR-ABL始发的B-ALL发生进 程 [205] . 例如, p19Arf −/− 小鼠与Rag1 −/− 小鼠杂交得到小 鼠诱发B-ALL, 其中Sca-1 + CD19 + 细胞群含有受Notch 信号调控的LSC [206] . 在研究基因突变协同E2A-PBX1 诱导的B-ALL中, 可以事先将E2A-PBX1小鼠和CD3ε −/− 小 鼠杂交, 在通过外部施进癌变的因素的方式研究Hoxa 协同E2A-PBX1的发病机制 [207] .…”

Activation-induced cytidine deaminase prevents pro-B cell acute lymphoblastic leukemia by functioning as a negative regulator in Rag1 deficient pro-B cells

“…In order to elucidate whether Aid is indeed functional prior to pre-BCR expression, we developed an Aid-deficient mouse model with a tumor prone Rag1 -/- background ( p19Arf -/- Rag1 -/- Aid -/- ARA). Utilizing this model, we were able to assess the influence of Aid at the pro-B cell stage [ 29 ], in the context of pro-B ALL development [ 30 ] and in the absence of Rag1 induced alterations. Here, we present in vivo evidence, that the combined absence of Aid and Rag1 in tumor prone murine pro-B cells accelerates pro-B ALL incidence, which suggests a functional role of Aid in Rag1 deficient BM pro-B-cells even before the expression of a pre-BCR.…”