bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2024–01–28
seven papers selected by
William Grey, University of York
  1. PI3Kγ maintains the self-renewal of acute myeloid leukemia stem cells by regulating the pentose phosphate pathway.
  2. IDH1-Mutant Preleukemic Hematopoietic Stem Cells Can Be Eliminated by Inhibition of Oxidative Phosphorylation.
  3. Deciphering cell states and genealogies of human hematopoiesis.
  4. Chromatin accessibility and cell cycle progression are controlled by the HDAC-associated Sin3B protein in murine hematopoietic stem cells.
  5. Activating p53 abolishes self-renewal of quiescent leukaemic stem cells in residual CML disease.
  6. Generation of a new therapeutic D-peptide that induces the differentiation of acute myeloid leukemia cells through A TLR-2 signaling pathway.
  7. LUBAC-mediated M1 Ub regulates necroptosis by segregating the cellular distribution of active MLKL.
  1. Blood. 2024 Jan 25. pii: blood.2023022202. [Epub ahead of print]
    PI3Kγ maintains the self-renewal of acute myeloid leukemia stem cells by regulating the pentose phosphate pathway.
    Hao Gu, Chiqi Chen, Zhi-Shuai Hou, Xia-Di He, Shaozhen Xie, Jing Ni, Changli Qian, Xin Cheng, Tao Jiang, Ce Yang, Thomas M Roberts, Junke Zheng, Judith A Varner, Scott A Armstrong, Jean J Zhao.
      Acute myeloid leukemia (AML) is an aggressive hematological malignancy originating from transformed hematopoietic stem/progenitor cells. AML prognosis remains poor, due to resistance and relapse driven by leukemia stem cells (LSCs). Targeting molecules essential for LSC function is a promising therapeutic approach. The PI3K/AKT pathway is often dysregulated in AML. We found while that PI3Kγ is highly enriched in LSCs and critical for self-renewal, it was dispensable for normal hematopoietic stem cells. Mechanistically, PI3Kγ-AKT signaling promotes NRF2 nuclear accumulation, which induces PGD and the pentose phosphate pathway, thereby maintaining LSC stemness. Importantly, genetic or pharmacological inhibition of PI3Kγ impaired expansion and stemness of murine and human AML cells in vitro and in vivo. Together, our findings reveal a key role for PI3Kγ in selectively maintaining LSC function by regulating AKT-NRF2-PGD metabolic pathway. Targeting the PI3Kγ pathway may therefore eliminate LSCs without damaging normal hematopoiesis, providing a promising therapeutic strategy for AML.
    DOI:  https://doi.org/10.1182/blood.2023022202
  2. Blood Cancer Discov. 2024 Jan 23. OF1-OF18
    IDH1-Mutant Preleukemic Hematopoietic Stem Cells Can Be Eliminated by Inhibition of Oxidative Phosphorylation.
    Niklas Landberg, Thomas Köhnke, Yang Feng, Yusuke Nakauchi, Amy C Fan, Miles H Linde, Daiki Karigane, Kelly Lim, Rahul Sinha, Luca Malcovati, Daniel Thomas, Ravindra Majeti.
      Rare preleukemic hematopoietic stem cells (pHSC) harboring only the initiating mutations can be detected at the time of acute myeloid leukemia (AML) diagnosis. pHSCs are the origin of leukemia and a potential reservoir for relapse. Using primary human samples and gene editing to model isocitrate dehydrogenase 1 (IDH1) mutant pHSCs, we show epigenetic, transcriptional, and metabolic differences between pHSCs and healthy hematopoietic stem cells (HSC). We confirm that IDH1-driven clonal hematopoiesis is associated with cytopenia, suggesting an inherent defect to fully reconstitute hematopoiesis. Despite giving rise to multilineage engraftment, IDH1-mutant pHSCs exhibited reduced proliferation, blocked differentiation, downregulation of MHC class II genes, and reprogramming of oxidative phosphorylation metabolism. Critically, inhibition of oxidative phosphorylation resulted in the complete eradication of IDH1-mutant pHSCs but not IDH2-mutant pHSCs or wild-type HSCs. Our results indicate that IDH1-mutant preleukemic clones can be targeted with complex I inhibitors, offering a potential strategy to prevent the development and relapse of leukemia.
    SIGNIFICANCE: A high burden of pHSCs is associated with worse overall survival in AML. Using single-cell sequencing, metabolic assessment, and gene-edited human models, we find human pHSCs with IDH1 mutations to be metabolically vulnerable and sensitive to eradication by complex I inhibition. See related commentary by Steensma.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-23-0195
  3. Nature. 2024 Jan 22.
    Deciphering cell states and genealogies of human hematopoiesis.
    Chen Weng, Fulong Yu, Dian Yang, Michael Poeschla, L Alexander Liggett, Matthew G Jones, Xiaojie Qiu, Lara Wahlster, Alexis Caulier, Jeffrey A Hussmann, Alexandra Schnell, Kathryn E Yost, Luke Koblan, Jorge D Martin-Rufino, Joseph Min, Alessandro Hammond, Daniel Ssozi, Raphael Bueno, Hari Mallidi, Antonia Kreso, Javier Escabi, William M Rideout, Tyler Jacks, Sahand Hormoz, Peter van Galen, Jonathan S Weissman, Vijay G Sankaran.
      The human blood system is maintained through the differentiation and massive amplification of a limited number of long-lived hematopoietic stem cells (HSCs)1. Perturbations to this process underlie diverse diseases, but the clonal contributions to human hematopoiesis and how this changes with age remain incompletely understood. While recent insights have emerged from barcoding studies in model systems4,5,16,17, simultaneous detection of cell states and phylogenies from natural barcodes in humans has been challenging. Here, we introduce an improved single-cell lineage tracing system based on deep detection of naturally-occurring mitochondrial DNA (mtDNA) mutations with simultaneous readout of transcriptional states and chromatin accessibility. We use this system to define the clonal architecture of HSCs and map the physiological state and output of clones. We uncover functional heterogeneity in HSC clones, which is stable over months and manifests as differences in total HSC output as well as biases toward the production of different mature cell types. We also find that the diversity of HSC clones decreases dramatically with age leading to an oligoclonal structure with multiple distinct clonal expansions. Our study thus provides the first clonally-resolved and cell-state aware atlas of human hematopoiesis at single-cell resolution revealing an unappreciated functional diversity of human HSC clones and more broadly paves the way for refined studies of clonal dynamics across a range of tissues in human health and disease.
    DOI:  https://doi.org/10.1038/s41586-024-07066-z
  4. Epigenetics Chromatin. 2024 Jan 23. 17(1): 2
    Chromatin accessibility and cell cycle progression are controlled by the HDAC-associated Sin3B protein in murine hematopoietic stem cells.
    Alexander Calderon, Tamara Mestvirishvili, Francesco Boccalatte, Kelly V Ruggles, Gregory David.
       BACKGROUND: Blood homeostasis requires the daily production of millions of terminally differentiated effector cells that all originate from hematopoietic stem cells (HSCs). HSCs are rare and exhibit unique self-renewal and multipotent properties, which depend on their ability to maintain quiescence through ill-defined processes. Defective control of cell cycle progression can eventually lead to bone marrow failure or malignancy. In particular, the molecular mechanisms tying cell cycle re-entry to cell fate commitment in HSCs remain elusive. Previous studies have identified chromatin coordination as a key regulator of differentiation in embryonic stem cells.
    RESULTS: Here, we utilized genetic inactivation of the chromatin-associated Sin3B protein to manipulate cell cycle control and found dysregulated chromatin accessibility and cell cycle progression in HSCs. Single cell transcriptional profiling of hematopoietic stem and progenitor cells (HSPCs) inactivated for Sin3B reveals aberrant progression through the G1 phase of the cell cycle, which correlates with the engagement of specific signaling pathways, including aberrant expression of cell adhesion molecules and the interferon signaling program in LT-HSCs. In addition, we uncover the Sin3B-dependent accessibility of genomic elements controlling HSC differentiation, which points to cell cycle progression possibly dictating the priming of HSCs for differentiation.
    CONCLUSIONS: Our findings provide new insights into controlled cell cycle progression as a potential regulator of HSC lineage commitment through the modulation of chromatin features.
    Keywords:  Cell cycle; Chromatin; Differentiation; Hematopoiesis; Stem cells
    DOI:  https://doi.org/10.1186/s13072-024-00526-w
  5. Nat Commun. 2024 Jan 22. 15(1): 651
    Activating p53 abolishes self-renewal of quiescent leukaemic stem cells in residual CML disease.
    Mary T Scott, Wei Liu, Rebecca Mitchell, Cassie J Clarke, Ross Kinstrie, Felix Warren, Hassan Almasoudi, Thomas Stevens, Karen Dunn, John Pritchard, Mark E Drotar, Alison M Michie, Heather G Jørgensen, Brian Higgins, Mhairi Copland, David Vetrie.
      Whilst it is recognised that targeting self-renewal is an effective way to functionally impair the quiescent leukaemic stem cells (LSC) that persist as residual disease in chronic myeloid leukaemia (CML), developing therapeutic strategies to achieve this have proved challenging. We demonstrate that the regulatory programmes of quiescent LSC in chronic phase CML are similar to that of embryonic stem cells, pointing to a role for wild type p53 in LSC self-renewal. In support of this, increasing p53 activity in primitive CML cells using an MDM2 inhibitor in combination with a tyrosine kinase inhibitor resulted in reduced CFC outputs and engraftment potential, followed by loss of multilineage priming potential and LSC exhaustion when combination treatment was discontinued. Our work provides evidence that targeting LSC self-renewal is exploitable in the clinic to irreversibly impair quiescent LSC function in CML residual disease - with the potential to enable more CML patients to discontinue therapy and remain in therapy-free remission.
    DOI:  https://doi.org/10.1038/s41467-024-44771-9
  6. Cell Death Discov. 2024 Jan 26. 10(1): 51
    Generation of a new therapeutic D-peptide that induces the differentiation of acute myeloid leukemia cells through A TLR-2 signaling pathway.
    Fei Yu, Yingshi Chen, Mo Zhou, Lingling Liu, Bingfeng Liu, Jun Liu, Ting Pan, Yuewen Luo, Xu Zhang, Hailan Ou, Wenjing Huang, Xi Lv, Zhihui Xi, Ruozhi Xiao, Wenyu Li, Lixue Cao, Xiancai Ma, Jingwen Zhang, Lijuan Lu, Hui Zhang.
      Acute myeloid leukemia (AML) is caused by clonal disorders of hematopoietic stem cells. Differentiation therapy is emerging as an important treatment modality for leukemia, given its less toxicity and wider applicable population, but the arsenal of differentiation-inducing agents is still very limited. In this study, we adapted a competitive peptide phage display platform to search for candidate peptides that could functionally induce human leukemia cell differentiation. A monoclonal phage (P6) and the corresponding peptide (pep-P6) were identified. Both L- and D-chirality of pep-P6 showed potent efficiency in inducing AML cell line differentiation, driving their morphologic maturation and upregulating the expression of macrophage markers and cytokines, including CD11b, CD14, IL-6, IL-1β, and TNF-α. In the THP-1 xenograft animal model, administration of D-pep-P6 was effective in inhibiting disease progression. Importantly, exposure to D-pep-P6 induced the differentiation of primary human leukemia cells isolated AML patients in a similar manner to the AML cell lines. Further mechanism study suggested that D-pep-P6 induced human leukemia cell differentiation by directly activating a TLR-2 signaling pathway. These findings identify a novel D-peptide that may promote leukemia differentiation therapy.
    DOI:  https://doi.org/10.1038/s41420-024-01822-w
  7. Cell Death Dis. 2024 01 20. 15(1): 77
    LUBAC-mediated M1 Ub regulates necroptosis by segregating the cellular distribution of active MLKL.
    Nadine Weinelt, Kaja Nicole Wächtershäuser, Gulustan Celik, Birte Jeiler, Isabelle Gollin, Laura Zein, Sonja Smith, Geoffroy Andrieux, Tonmoy Das, Jens Roedig, Leonard Feist, Björn Rotter, Melanie Boerries, Francesco Pampaloni, Sjoerd J L van Wijk.
      Plasma membrane accumulation of phosphorylated mixed lineage kinase domain-like (MLKL) is a hallmark of necroptosis, leading to membrane rupture and inflammatory cell death. Pro-death functions of MLKL are tightly controlled by several checkpoints, including phosphorylation. Endo- and exocytosis limit MLKL membrane accumulation and counteract necroptosis, but the exact mechanisms remain poorly understood. Here, we identify linear ubiquitin chain assembly complex (LUBAC)-mediated M1 poly-ubiquitination (poly-Ub) as novel checkpoint for necroptosis regulation downstream of activated MLKL in cells of human origin. Loss of LUBAC activity inhibits tumor necrosis factor α (TNFα)-mediated necroptosis, not by affecting necroptotic signaling, but by preventing membrane accumulation of activated MLKL. Finally, we confirm LUBAC-dependent activation of necroptosis in primary human pancreatic organoids. Our findings identify LUBAC as novel regulator of necroptosis which promotes MLKL membrane accumulation in human cells and pioneer primary human organoids to model necroptosis in near-physiological settings.
    DOI:  https://doi.org/10.1038/s41419-024-06447-6
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:28.