2013 – MESENCHYMAL STROMAL CELL MITOCHONDRIAL TRANSFER FUELS MDS TO AML TRANSFORMATION

In haematological malignancies, dysplastic hematopoietic stem and progenitor cells (HSPCs) can remodel bone marrow mesenchymal stem cells (BMSC) in their favour. However, it is unknown whether BMSCs remodelling occurs during transformation of myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML). Transcriptomic analysis and exome sequencing of BMSCs from bone biopsies of MDS patients before and after AML transformation, showed metabolic dysregulations at the mitochondrial level during transformation. Specifically, BMSCs from AML-transformed patients showed downregulation of mitophagy genes and upregulation of genes encoding mitochondrial proteins. Mitochondrial numbers increased but presented compromised metabolic function as evidenced by MitoStress test and prevalence of donut-shaped mitochondria. Interestingly, expression of mitochondrial trafficking genes was increased in AML as compared to MDS BMSCs. As a result, MSCs and dysplastic HSPCs exchange mitochondria via Tunneling Nanotubes (TNTs). This exchange occurs so that AML cells transfer dysfunctional mitochondria to BMSCs, whereas BMCSs transfer functional mitochondria to AML blasts. Mitochondrial transfer reduces the number of CD45+ AML cells indicating that it alters their profile to a more immature population. Notably, these events, do not occur among healthy BMSCs and HSPCs. Further, inhibition of TNTs formation using Jasplakinolide, reduced mitochondrial transfer and the number of dsRed+ MLL-AF9 cells in the bone marrow and spleen of MLL-injected mice, and maintained tissues architecture. As a resulted, it slowed disease progression and prolonged survival in leukemic mice. These observations demonstrate that BMSCs provide functional mitochondria to MDS cells. The transfer allows malignant cells to overcome their metabolic stress and favour their hyperproliferation as AML blasts. In haematological malignancies, dysplastic hematopoietic stem and progenitor cells (HSPCs) can remodel bone marrow mesenchymal stem cells (BMSC) in their favour. However, it is unknown whether BMSCs remodelling occurs during transformation of myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML). Transcriptomic analysis and exome sequencing of BMSCs from bone biopsies of MDS patients before and after AML transformation, showed metabolic dysregulations at the mitochondrial level during transformation. Specifically, BMSCs from AML-transformed patients showed downregulation of mitophagy genes and upregulation of genes encoding mitochondrial proteins. Mitochondrial numbers increased but presented compromised metabolic function as evidenced by MitoStress test and prevalence of donut-shaped mitochondria. Interestingly, expression of mitochondrial trafficking genes was increased in AML as compared to MDS BMSCs. As a result, MSCs and dysplastic HSPCs exchange mitochondria via Tunneling Nanotubes (TNTs). This exchange occurs so that AML cells transfer dysfunctional mitochondria to BMSCs, whereas BMCSs transfer functional mitochondria to AML blasts. Mitochondrial transfer reduces the number of CD45+ AML cells indicating that it alters their profile to a more immature population. Notably, these events, do not occur among healthy BMSCs and HSPCs. Further, inhibition of TNTs formation using Jasplakinolide, reduced mitochondrial transfer and the number of dsRed+ MLL-AF9 cells in the bone marrow and spleen of MLL-injected mice, and maintained tissues architecture. As a resulted, it slowed disease progression and prolonged survival in leukemic mice. These observations demonstrate that BMSCs provide functional mitochondria to MDS cells. The transfer allows malignant cells to overcome their metabolic stress and favour their hyperproliferation as AML blasts.