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

Abstract

Myelodysplastic syndrome (MDS) and aplastic anemia (AA) patients both present with symptoms of bone marrow failure. In many AA patients, these features are thought to result from an oligoclonal expansion of cytotoxic T-cells that destroy haematopoietic stem or progenitor cells. This notion is supported by the observation that AA patients respond to immunosuppressive therapy. A fraction of MDS patients also respond well to immunosuppressive therapy suggesting a similar role for cytotoxic T-cells in the etiology of MDS, however the role of cytotoxic T-cells in MDS remains unclear. Mice that express a NUP98-HOXD13 (NHD13) transgene develop a MDS that closely mimics the human condition in terms of dysplasia, ineffective hematopoiesis, and transformation to acute myeloid leukemia (AML). We followed a cohort of NHD13 mice lacking the Rag1 protein (NHD13/Rag1KO) to determine if the absence of lymphocytes might 1) delay the onset and/or diminish the severity of the MDS, or 2) effect malignant transformation and survival of the NHD13 mice. No difference was seen in the onset or severity of MDS between the NHD13 and NHD13/Rag1KO mice. However, NHD13/Rag1KO mice had decreased survival and showed a trend toward increased incidence of transformation to AML compared to the NHD13 mice, suggesting protection from AML transformation by a modest immuno-surveillance effect. In the absence of functional Tcrb signaling in the NHD13/Rag1KO T-cell tumors, Pak7 was identified as a potential Tcrb surrogate survival signal.

A unique mutator phenotype reveals complementary oncogenic lesions leading to acute leukemia

“…Previous reports had demonstrated that Mcm2 cre/wt mice were not predisposed to malignancy (6). To determine whether they had a subtle predisposition toward myeloid malignancy that could be uncovered by the NHD13 transgene, we compared the median survival of Mcm2 cre/wt NHD13 + to Mcm2 wt/wt NHD13 + ; the median survival was not significantly different (259 vs. 324 days) ( Figure 1A) and was similar to our previous reports with NHD13 + mice (14,18). In summary, these results showed that the NHD13 transgene did not accelerate the onset of disease in heterozygous Table 2) and infiltration of parenchymal organs, such as the liver, kidney, and lung, with CD3 + lymphoblasts (Supplemental Figure 2).…”

NUP98–PHF23 Is a Chromatin-Modifying Oncoprotein That Causes a Wide Array of Leukemias Sensitive to Inhibition of PHD Histone Reader Function

“…This range of leukemic subtypes was identified in six founders and their offspring, indicating that the leukemias were not caused by a unique transgene insertion site. The AMLs were typically Mac1 + /Gr1 + /B220 dim , similar to those described for the NUP98-HOXD13 and CALM-AF10 murine models (17, 18, 26). Clonal DJ Igh gene rearrangements were detected in a small proportion (4/26) of the Mac1 + /B220 + AMLs, which has also been seen in patients with biphenotypic leukemia (27) and in the CALM-AF10 murine model (18).…”

Identification of latent core genes and pathways associated with myelodysplastic syndromes based on integrated bioinformatics analysis

“…RAG1/2, the recombination activating gene protein complex, regulates cell cycle progression through phosphorylation of RAG2 mediated by the complex called cyclin Acyclin- dependent kinase 2 (CDK2) [33,34]. In addition, conditional deletion of RAG1 in MDS mouse models has also increased the incidence of transformation into AML [35]. Hence, it may be regarded as a valuable biomarker for the diagnosis, treatment and prognosis of MDS.…”