Katja Seipel1, Christian Messerli2, Gertrud Wiedemann3, Ulrike Bacher3, Thomas Pabst4. 1. Department for Biomedical Research (DBMR), University of Bern, Bern, Switzerland; Department of Medical Oncology, University Hospital, Inselspital, Bern, Switzerland. Electronic address: katja.seipel@dbmr.unibe.ch. 2. Department for Biomedical Research (DBMR), University of Bern, Bern, Switzerland. 3. Department of Hematology, University Hospital, Inselspital, Bern, Switzerland; Center of Laboratory Medicine (ZLM), University Hospital, Inselspital, Bern, Switzerland. 4. Department of Medical Oncology, University Hospital, Inselspital, Bern, Switzerland. Electronic address: thomas.pabst@insel.ch.
Abstract
BACKGROUND: The meningioma-1 (MN1) gene is expressed in hematopoietic CD34+ cells and down-regulated during myeloid differentiation. MN1 overexpression has been linked to shorter overall and disease free survival in AML patients treated with intensive induction chemotherapy. MN1 overexpression may still be an adverse prognostic marker in AML patients treated with autologous stem cell transplant (auto-SCT) after intensive induction chemotherapy. METHODS: We retrospectively analysed 54 peripheral blood mononuclear cell (PBMC) samples of AML patients who received auto-SCT at remission (CR1) after intensive induction chemotherapy. MN1 and putative MN1-associated mRNAs, as well as MN1-associated micro-RNAs were assessed at diagnosis in peripheral blood mononuclear cells using Taqman gene expression assays. RESULTS: AML patients with elevated MN1 or FoxP1 gene expression at diagnosis had a significantly shorter progression-free and overall survival after intensive induction chemo-therapy and auto-SCT. The presence of the favourable risk NPM1 mutation associated with reduced MN1 gene expression. In contrast to MN1 and FOXP1, elevated expression of the putative tumor suppressive micro-RNA hsa-miR-181a-5p was predictive for positive outcome. Correlation analysis of MN1 with myeloid gene expression levels revealed association of MN1 and BMI-1, CD34, FOXP1 and MDM2 expression. Analysis of non-coding RNAs revealed an inverse correlation of MN1 with hsa-miR-20a-5p and hsa-miR-181b-5p expression. CONCLUSIONS: MN1, FOXP1 and hsa-miR-181a-5p are prognostic markers in AML patients treated with intensive induction chemotherapy and auto-SCT. While MDM2 is a validated therapeutic target, the transcription factors MN1 and FOXP1, and the chromatin modulator BMI-1 are potential therapeutic targets in the treatment of AML. The tumor suppressor hsa-miR-181a-5p may be a candidate miRNA mimic for therapeutic use.
BACKGROUND: The meningioma-1 (MN1) gene is expressed in hematopoietic CD34+ cells and down-regulated during myeloid differentiation. MN1 overexpression has been linked to shorter overall and disease free survival in AMLpatients treated with intensive induction chemotherapy. MN1 overexpression may still be an adverse prognostic marker in AMLpatients treated with autologous stem cell transplant (auto-SCT) after intensive induction chemotherapy. METHODS: We retrospectively analysed 54 peripheral blood mononuclear cell (PBMC) samples of AMLpatients who received auto-SCT at remission (CR1) after intensive induction chemotherapy. MN1 and putative MN1-associated mRNAs, as well as MN1-associated micro-RNAs were assessed at diagnosis in peripheral blood mononuclear cells using Taqman gene expression assays. RESULTS:AMLpatients with elevated MN1 or FoxP1 gene expression at diagnosis had a significantly shorter progression-free and overall survival after intensive induction chemo-therapy and auto-SCT. The presence of the favourable risk NPM1 mutation associated with reduced MN1 gene expression. In contrast to MN1 and FOXP1, elevated expression of the putative tumor suppressive micro-RNA hsa-miR-181a-5p was predictive for positive outcome. Correlation analysis of MN1 with myeloid gene expression levels revealed association of MN1 and BMI-1, CD34, FOXP1 and MDM2 expression. Analysis of non-coding RNAs revealed an inverse correlation of MN1 with hsa-miR-20a-5p and hsa-miR-181b-5p expression. CONCLUSIONS:MN1, FOXP1 and hsa-miR-181a-5p are prognostic markers in AMLpatients treated with intensive induction chemotherapy and auto-SCT. While MDM2 is a validated therapeutic target, the transcription factors MN1 and FOXP1, and the chromatin modulator BMI-1 are potential therapeutic targets in the treatment of AML. The tumor suppressor hsa-miR-181a-5p may be a candidate miRNA mimic for therapeutic use.
Authors: Amanda G Davis; Daniel T Johnson; Dinghai Zheng; Ruijia Wang; Nathan D Jayne; Mengdan Liu; Jihae Shin; Luyang Wang; Samuel A Stoner; Jie-Hua Zhou; Edward D Ball; Bin Tian; Dong-Er Zhang Journal: Blood Date: 2022-01-20 Impact factor: 25.476