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Mitochondria: A Galaxy in the Hematopoietic and Leukemic Stem Cell Universe.

ABSTRACT: Mitochondria are the main fascinating energetic source into the cells. Their number, shape, and dynamism are controlled by the cell's type and current behavior. The perturbation of the mitochondrial inward system via stress response and/or oncogenic insults could activate several trafficking molecular mechanisms with the intention to solve the problem. In this review, we aimed to clarify the crucial pathways in the mitochondrial system, dissecting the different metabolic defects, with a special emphasis on hematological malignancies. We investigated the pivotal role of mitochondria in the maintenance of hematopoietic stem cells (HSCs) and their main alterations that could induce malignant transformation, culminating in the generation of leukemic stem cells (LSCs). In addition, we presented an overview of LSCs mitochondrial dysregulated mechanisms in terms of (1) increasing in oxidative phosphorylation program (OXPHOS), as a crucial process for survival and self-renewal of LSCs,(2) low levels of reactive oxygen species (ROS), and (3) aberrant expression of B-cell lymphoma 2 (Bcl-2) with sustained mitophagy. Furthermore, these peculiarities may represent attractive new "hot spots" for mitochondrial-targeted therapy. Finally, we remark the potential of the LCS metabolic effectors to be exploited as novel therapeutic targets.

SUBMITTER: Panuzzo C

PROVIDER: S-EPMC7312164 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Mitochondria: A Galaxy in the Hematopoietic and Leukemic Stem Cell Universe.

Panuzzo Cristina C Jovanovski Aleksandar A Pergolizzi Barbara B Pironi Lucrezia L Stanga Serena S Fava Carmen C Cilloni Daniela D

International journal of molecular sciences 20200530 11

Mitochondria are the main fascinating energetic source into the cells. Their number, shape, and dynamism are controlled by the cell's type and current behavior. The perturbation of the mitochondrial inward system via stress response and/or oncogenic insults could activate several trafficking molecular mechanisms with the intention to solve the problem. In this review, we aimed to clarify the crucial pathways in the mitochondrial system, dissecting the different metabolic defects, with a special ...[more]

PMID: 32486249

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Project description:Hematopoietic stem cells (HSCs) are rare, multipotent cells that generate via progenitor and precursor cells of all blood lineages. Similar to normal hematopoiesis, leukemia is also hierarchically organized and a subpopulation of leukemic cells, the leukemic stem cells (LSCs), is responsible for disease initiation and maintenance and gives rise to more differentiated malignant cells. Although genetically abnormal, LSCs share many characteristics with normal HSCs, including quiescence, multipotency and self-renewal. Normal HSCs reside in a specialized microenvironment in the bone marrow (BM), the so-called HSC niche that crucially regulates HSC survival and function. Many cell types including osteoblastic, perivascular, endothelial and mesenchymal cells contribute to the HSC niche. In addition, the BM functions as primary and secondary lymphoid organ and hosts various mature immune cell types, including T and B cells, dendritic cells and macrophages that contribute to the HSC niche. Signals derived from the HSC niche are necessary to regulate demand-adapted responses of HSCs and progenitor cells after BM stress or during infection. LSCs occupy similar niches and depend on signals from the BM microenvironment. However, in addition to the cell types that constitute the HSC niche during homeostasis, in leukemia the BM is infiltrated by activated leukemia-specific immune cells. Leukemic cells express different antigens that are able to activate CD4(+) and CD8(+) T cells. It is well documented that activated T cells can contribute to the control of leukemic cells and it was hoped that these cells may be able to target and eliminate the therapy-resistant LSCs. However, the actual interaction of leukemia-specific T cells with LSCs remains ill-defined. Paradoxically, many immune mechanisms that evolved to activate emergency hematopoiesis during infection may actually contribute to the expansion and differentiation of LSCs, promoting leukemia progression. In this review, we summarize mechanisms by which the immune system regulates HSCs and LSCs.

Project description:BackgroundDuring aging, hematopoietic stem cells (HSC) lose progressively both their self-renewal and differentiation potential. The precise molecular mechanisms of this phenomenon are not well established. To uncover the molecular events underlying this event, we have performed a bioinformatics analysis of 650 single-cell transcriptomes.MethodsSingle-cell transcriptome analyses of expression heterogeneity, cell cycle, and cell trajectory in human cell compartment enriched in hematopoietic stem cell compartment were investigated in the bone marrow according to the age of the donors. Identification of aging-related nodules was identified by weighted correlation network analysis in this primitive compartment.ResultsThe analysis of single-cell transcriptomes allowed to uncover a major upregulation of EGR1 in human-aged lineage-CD34+CD38- cells which present cell cycle dysregulation with reduction of G2/M phase according to less expression of CCND2 during S phase. EGR1 upregulation in aging hematopoietic stem cells was found to be independent of cell cycle phases and gender. EGR1 expression trajectory in aged HSC highlighted a signature enriched in hematopoietic and immune disorders with the best induction of AP-1 complex and quiescence regulators such as EGR1, BTG2, JUNB, and NR41A. Sonic Hedgehog-related TMEM107 transmembrane molecule followed also EGR1 cell trajectory. EGR1-dependent gene weighted network analysis in human HSC-associated IER2 target protein-specific regulators of PP2A activity, IL1B, TNFSF10 ligands, and CD69, SELP membrane molecules in old HSC module with immune and leukemogenic signature. In contrast, for young HSC which were found with different cell cycle phase progression, its specific module highlighted upregulation of HIF1A hypoxic factor, PDE4B immune marker, DRAK2 (STK17B) T cell apoptosis regulator, and MYADM myeloid-associated marker.ConclusionEGR1 was found to be connected to the aging of human HSC and highlighted a specific cell trajectory contributing to the dysregulation of an inflammatory and leukemia-related transcriptional program in aged human HSCs. EGR1 and its program were found to be connected to the aging of human HSC with dissociation of quiescence property and cell cycle phase progression in this primitive hematopoietic compartment.

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Mitochondria: A Galaxy in the Hematopoietic and Leukemic Stem Cell Universe.

Publications

Mitochondria: A Galaxy in the Hematopoietic and Leukemic Stem Cell Universe.

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