Severe acute graft versus host disease (GvHD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation. Human mesenchymal stromal cells (MSCs) play an important role in endogenous tissue repair and possess strong immune-modulatory properties making them a promising tool for the treatment of steroid-refractory GvHD. To date, a few reports exist on the use of MSCs in treatment of GvHD in children indicating that children tend to respond better than adults, albeit with heterogeneous results.We here present a review of the literature and the clinical course of two instructive pediatric patients with acute steroid-refractory GvHD after haploidentical stem cell transplantation, which exemplify the beneficial effects of third-party transplanted MSCs in treatment of acute steroid-refractory GvHD. Moreover, we provide a meta-analysis of clinical studies addressing the outcome of patients with steroid-refractory GvHD and treatment with MSCs in adults and in children (n = 183; 122 adults, 61 children). Our meta-analysis demonstrates that the overall response-rate is high (73.8%) and confirms, for the first time, that children indeed respond better to treatment of GvHD with MSCs than adults (complete response 57.4% vs. 45.1%, respectively).These data emphasize the significance of this therapeutic approach especially in children and indicate that future prospective studies are needed to assess the reasons for the observed differential response-rates in pediatric and adult patients.
Tumor cells evolve adaptive mechanisms to survive hypoxia, nutrient deprivation, oxidative or genotoxic stress to ultimately drive tumor progression (Sorensen et al. 2015). We previously described MondoA (also known as MLXIP, MAX like protein X interacting protein) as a metabolic stress sensor, required for leukemogenesis. Lymphocytes, in particular B Lymphocytes are adapted to hypoxic environments from their very beginning. They are destined to travel from the hypoxic bone marrow via normoxic peripheral blood to hypoxic lymph nodes. They thus are specialized in glycolysis to compensate the lack of oxidative phosphorylation under hypoxic conditions. Leukemic counterparts of B-lymphocytes exploit these features for their survival. Glucose-derived metabolites control the nuclear activity of the transcription factor MondoA. Here we report on the expression of MondoA in common B-cell acute lymphoblastic leukemia (cALL) compared to other malignancies, its role in malignancy of cALL in vivo, downstream pathways and correlation with relapse risk. Methods. Our human/murine xenotransplantation model with immunodeficient RAG2-/-gc-/- mice was used (Richter et al. 2009). NALM6 and 697 cALL lines were lentivirally transduced with MondoA short hairpin RNA. Upon successful MondoA knock down (KD), KD and control lines were injected into the mice; CD10+ blasts in blood, spleen and marrow were assessed. Results. We found MondoA to be most strongly expressed in pediatric cALL and AML. Moreover MondoA expression was high in gastrointestinal stromal tumors and alveolar rhabdomyosarcoma. MondoA KD in cALL cell lines and their subsequent analysis in xenograft mice resulted in a reduced number of leukemic blasts in blood, marrow and spleen. Spleen size and weight normalized in mice after MondoA KD. Further microarray analysis revealed an enrichment of glycolytic and hypoxia response gene sets by MondoA. Moreover, HIF1a induction under hypoxia required MondoA. We demonstrate that hypoxia facilitates vincristine resistance of cALL. MondoA is induced under hypoxia and confers cALL cells chemotherapeutic resistance. Tied to these results, MondoA overexpression correlated with relapse risk; its expression was 63% higher in the very high-risk group as compared to the non-high-risk group of cALL. In conclusion, our findings demonstrate that MondoA maintains leukemic burden and aggressiveness of cALL in vivo possibly by modulating metabolic and hypoxia stress response, in particular by induction of HIF1a. Citation Format: Alexandra A. Sipol, Thomas G. Grunewald, Juliane Schmaeh, Monique L. den Boer, Rebeca Alba Rubío, Michaela Baldauf, Caroline Wernicke, Martin Horstmann, Gunnar Cario, Günther Richter, Stefan Burdach. Metabolic stress sensor MondoA mediates in vivo aggressiveness of common ALL by induction of HIF1α [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4515. doi:10.1158/1538-7445.AM2017-4515
Oncogene addiction provides ideal targets for immunotherapy. We previously described MondoA (also known as MLXIP, MAX like protein X interacting protein) as a metabolic stress sensor, required for leukemogenesis. Here we report on the expression of MondoA in common acute lymphoblastic leukemia (cALL) compared to other malignancies, its role in malignancy of cALL in vivo, downstream pathways and correlation with relapse risk. Given the non-accessibility of transcription factors by drugs or chimeric antigen receptor transgenic T cells (CARs), we tested the targetability of MondoA by allo-restricted, peptide specific T cells. Our human/murine xenotransplantation model with immunodeficient RAG2-/-gc-/- mice was used (Richter et al. 2009). NALM6 and 697 cALL lines were lentivirally transduced with MondoA short hairpin RNA (shRNA). Upon successful MondoA knock down (KD), KD and control lines were injected into the mice; CD10+ blasts in blood, spleen and marrow were assessed. MondoA specific T cells were generated by priming of donor HLAA0201 negative (A2-) T-cells with A2+ dendritic cells bearing MondoA peptides, multimer-based sorting and subcloning of A2-CD8+ T-cells. For priming of T cells, five MondoA peptides were chosen by SYMPEITHI, BIMAS and NetCTL1.2. analyses. Peptide 428 stabilized best A2 expression on TAP-deficient T2 cells. Specificity and functionality of T cell clones were tested by ELISpot interferon gamma (IFg) and granzyme B assays with six MondoA+ leukemia lines (A2+, A2-). Off target effects of MondoA specific T-cell clones were assessed by IFg reactivity against the MondoA expressing A2+ NALM6 cell line vs. A2+ and A2- EBV immortalized lymphoblastoid cell lines from six donors. Peptide homology was assessed with BLAST algorithms in SWISSPROT. We found MondoA to be most strongly expressed in pediatric cALL and AML. Moreover MondoA expression was high in gastrointestinal stromal tumors and alveolar rabdomyosarcoma. MondoA KD in cALL cell lines and their subsequent analysis in xenograft mice resulted in a reduced number of leukemic blasts in blood, marrow and spleen. Spleen size and weight normalized in treated mice after MondoA KD. Further microarray analysis revealed an induction of aerobic glycolysis switch genes and hypoxia-response by MondoA. Consequently, HIF1A stabilization required MondoA expression and tied to these results, MondoA overexpression correlated with relapse risk; its expression was 63% higher in the very high-risk group as compared to the non-high-risk group of cALL. Therapeutically, MondoA-derived peptide antigens and A2+ cALL lines were successfully recognized and killed by specific, allo-restricted CD8+ T cells. In conclusion, our findings demonstrate that MondoA maintains leukemic burden and aggressiveness of cALL in vivo possibly by modulating metabolic and hypoxia stress response. Moreover, we identified MondoA as a promising target for immunotherapy of cALL. Citation Format: Alexandra Sipol, Thomas G. P. Grunewald, Juliane Schmaeh, David Schirmer, Monique L. den Boer, Rebeca Alba Rubío, Michaela Baldauf, Caroline Wernicke, Hans-Jochem Kolb, Martin Horstmann, Gunnar Cario, Guünther Richter, Stefan Burdach. MondoA mediates in vivo aggressiveness of common ALL and may serve as a T-cell immunotherapy target. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2462.
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