bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2024–09–29
fiveteen papers selected by
William Grey, University of York
  1. Metabolic regulation in normal and leukemic stem cells.
  2. Spermidine metabolism regulates leukemia stem and progenitor cell function through KAT7 expression in patient-derived mouse models.
  3. Leukemia-derived apelin selects endothelial niche clones to promote tumorigenesis.
  4. Sirens and sphingolipids: What lures hematopoietic stem cells to the nervous system?
  5. Inflammation perturbs hematopoiesis by remodeling specific compartments of the bone marrow niche.
  6. Combinations of HDAC inhibitor and PPAR agonist induce ferroptosis of leukemic stem cell-like cells in acute myeloid leukemia.
  7. Single-cell multi-omics map of human fetal blood in Down syndrome.
  8. Enhanced feature matching in single-cell proteomics characterizes IFN-γ response and co-existence of cell states.
  9. Distinct pathway activities are associated with prognosis and response to bortezomib-containing treatment in MCL1-M based molecular subtypes of multiple myeloma.
  10. Geranylgeranylated SCFFBXO10 regulates selective outer mitochondrial membrane proteostasis and function.
  11. Endothelial cell elongation and alignment in response to shear stress requires acetylation of microtubules.
  12. Transferrin receptor targeting chimeras for membrane protein degradation.
  13. Designed endocytosis-inducing proteins degrade targets and amplify signals.
  14. Further biological characterization of small molecules UM171 and SR1: In vitro effects on three hematopoietic cell populations from human cord blood.
  15. Can PROTACs cure Leukemia?
  1. Trends Pharmacol Sci. 2024 Sep 20. pii: S0165-6147(24)00166-4. [Epub ahead of print]
    Metabolic regulation in normal and leukemic stem cells.
    Cheuk-Him Man, Changzheng Li, Xi Xu, Meng Zhao.
      Hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs) are crucial for ensuring hematopoietic homeostasis and driving leukemia progression, respectively. Recent research has revealed that metabolic adaptations significantly regulate the function and survival of these stem cells. In this review, we provide an overview of how metabolic pathways regulate oxidative and proteostatic stresses in HSCs during homeostasis and aging. Furthermore, we highlight targetable metabolic pathways and explore their interactions with epigenetics and the microenvironment in addressing the chemoresistance and immune evasion capacities of LSCs. The metabolic differences between HSCs and LSCs have profound implications for therapeutic strategies.
    Keywords:  bone marrow microenvironment; drug resistance; epigenetic; hematopoietic stem cell; leukemic stem cell; metabolism; oxidative stress; proteostatic stress
    DOI:  https://doi.org/10.1016/j.tips.2024.08.004
  2. Sci Transl Med. 2024 Sep 25. 16(766): eadn1285
    Spermidine metabolism regulates leukemia stem and progenitor cell function through KAT7 expression in patient-derived mouse models.
    Vincent Rondeau, Jacob M Berman, Tianyi Ling, Cristiana O'Brien, Rachel Culp-Hill, Julie A Reisz, Mark Wunderlich, Yun Chueh, Karina E Jiménez-Camacho, Christina Sexton, Katharine M Carter, Cody Stillwell, Jonathan St-Germain, Duhan Yendi, Aarushi Gupta, Mary Shi, Aleksandra Bourdine, Vikram R Paralkar, Soheil Jahangiri, Kristin J Hope, Anastasia N Tikhonova, Andrea Arruda, Mark D Minden, Brian Raught, Angelo D'Alessandro, Courtney L Jones.
      Acute myeloid leukemia (AML) is a devastating disease initiated and maintained by a rare subset of cells called leukemia stem cells (LSCs). LSCs are responsible for driving disease relapse, making the development of new therapeutic strategies to target LSCs urgently needed. The use of mass spectrometry-based metabolomics profiling has enabled the discovery of unique and targetable metabolic properties in LSCs. However, we do not have a comprehensive understanding of metabolite differences between LSCs and their normal counterparts, hematopoietic stem and progenitor cells (HSPCs). In this study, we used an unbiased mass spectrometry-based metabolomics analysis to define differences in metabolites between primary human LSCs and HSPCs, which revealed that LSCs have a distinct metabolome. Spermidine was the most enriched metabolite in LSCs compared with HSPCs. Pharmacological reduction of spermidine concentrations decreased LSC function but spared normal HSPCs. Polyamine depletion also decreased leukemic burden in patient-derived xenografts. Mechanistically, spermidine depletion induced LSC myeloid differentiation by decreasing eIF5A-dependent protein synthesis, resulting in reduced expression of a select subset of proteins. KAT7, a histone acetyltransferase, was one of the top candidates identified to be down-regulated by spermidine depletion. Overexpression of KAT7 partially rescued polyamine depletion-induced decreased colony-forming ability, demonstrating that loss of KAT7 is an essential part of the mechanism by which spermidine depletion targets AML clonogenic potential. Together, we identified and mechanistically dissected a metabolic vulnerability of LSCs that has the potential to be rapidly translated into clinical trials to improve outcomes for patients with AML.
    DOI:  https://doi.org/10.1126/scitranslmed.adn1285
  3. bioRxiv. 2024 Sep 13. pii: 2024.09.09.612077. [Epub ahead of print]
    Leukemia-derived apelin selects endothelial niche clones to promote tumorigenesis.
    Chloe S Baron, Olivia Mitchell, Serine Avagyan, Romain Menard, Song Yang, Anne L Robertson, Rajiv Potluri, Jay Shendure, Romain Madelaine, Aaron McKenna, Leonard I Zon.
      Hematopoietic stem cells are regulated by endothelial and mesenchymal stromal cells in the marrow niche1-3. Leukemogenesis was long believed to be solely driven by genetic perturbations in hematopoietic cells but introduction of genetic mutations in the microenvironment demonstrated the ability of niche cells to drive disease progression4-8. The mechanisms by which the stem cell niche induces leukemia remain poorly understood. Here, using cellular barcoding in zebrafish, we found that clones of niche endothelial and stromal cells are significantly expanded in leukemic marrows. The pro-angiogenic peptide apelin secreted by leukemic cells induced sinusoidal endothelial cell clonal selection and transcriptional reprogramming towards an angiogenic state to promote leukemogenesis in vivo. Overexpression of apelin in normal hematopoietic stem cells led to clonal amplification of the niche endothelial cells and promotes clonal dominance of blood cells. Knock-out of apelin in leukemic zebrafish resulted in a significant reduction in disease progression. Our results demonstrate that leukemic cells remodel the clonal and transcriptional landscape of the marrow niche to promote leukemogenesis and provide a potential therapeutic opportunity for anti-apelin treatment.
    DOI:  https://doi.org/10.1101/2024.09.09.612077
  4. Mol Ther. 2024 Sep 19. pii: S1525-0016(24)00603-8. [Epub ahead of print]
    Sirens and sphingolipids: What lures hematopoietic stem cells to the nervous system?
    Yedda Li, Florian S Eichler.
      
    DOI:  https://doi.org/10.1016/j.ymthe.2024.09.017
  5. bioRxiv. 2024 Sep 12. pii: 2024.09.12.612751. [Epub ahead of print]
    Inflammation perturbs hematopoiesis by remodeling specific compartments of the bone marrow niche.
    James W Swann, Ruiyuan Zhang, Evgenia V Verovskaya, Fernando J Calero-Nieto, Xiaonan Wang, Melissa A Proven, Peter T Shyu, X Edward Guo, Berthold Göttgens, Emmanuelle Passegué.
      Hematopoietic stem and progenitor cells (HSPC) are regulated by interactions with stromal cells in the bone marrow (BM) cavity, which can be segregated into two spatially defined central marrow (CM) and endosteal (Endo) compartments. However, the importance of this spatial compartmentalization for BM responses to inflammation and neoplasia remains largely unknown. Here, we extensively validate a combination of scRNA-seq profiling and matching flow cytometry isolation that reproducibly identifies 7 key CM and Endo populations across mouse strains and accurately surveys both niche locations. We demonstrate that different perturbations exert specific effects on different compartments, with type I interferon responses causing CM mesenchymal stromal cells to adopt an inflammatory phenotype associated with overproduction of chemokines modulating local monocyte dynamics in the surrounding microenvironment. Our results provide a comprehensive method for molecular and functional stromal characterization and highlight the importance of altered stomal cell activity in regulating hematopoietic responses to inflammatory challenges.
    DOI:  https://doi.org/10.1101/2024.09.12.612751
  6. Clin Cancer Res. 2024 Sep 25.
    Combinations of HDAC inhibitor and PPAR agonist induce ferroptosis of leukemic stem cell-like cells in acute myeloid leukemia.
    Hui Zhou, Dongmei Qin, Chendi Xie, Jie Zhou, Shuman Jia, Ziwei Zhou, Yi Qiu, Bing Xu, Jie Zha.
       PURPOSE: Leukemia stem cells (LSCs) are responsible for leukemia initiation, relapse, and therapeutic resistance. Therefore, the development of novel therapeutic approaches targeting LSCs is urgently needed for patients with AML.
    METHODS: The LSCs-like cell lines (KG-1α and Kasumi-1), CD34+ primary AML cells purified from AML patients (n=23) treated with CS055 and/or chiglitazar and were analyzed for viability, death, and colony formation assay. We performed RNA-seq, Glutamate-Release, Intracellular-GSH, Lipid-ROS, transmission-electron-microscopy, Western-Blotting assay, and confirmed ferroptosis in LSCs-like cells. The luciferase-reporter, co-immunoprecipitation, HDAC3-shRNA/HDAC3/deacetylase-deficient LSCs-like cell lines, His-pull-down, and chromatin-immunoprecipitation assays performed to clarify the molecular mechanism of CS055/chiglitazar in LSCs-like cells. We also established CDX and PDX mouse models to evaluate the therapeutic efficacy of CS055/chiglitazar against-AML in vivo.
    RESULTS: We report that the histone deacetylase inhibitor CS055, in combination with peroxisome proliferator-activated receptor (PPAR) pan-agonist (chiglitazar), synergistically targets leukemia stem-like cells from leukemia cell lines and patient samples, while sparing normal hematopoietic progenitor cells. Mechanistically, chiglitazar enhances the inhibitory effect of CS055 on HDAC3 and induces ferroptosis in LSCs-like cells by down-regulating the expression of ferroptosis suppressor SLC7A11. In fact, the inhibition of HDAC3 increases H3K27AC levels in the promoter region of activating transcription factor 3 (ATF3), a transcriptional repressor of the SLC7A11 gene, and upregulates the expression of ATF3. In contrast, ATF4, a SLC7A11 activator, is suppressed by HDAC3 inhibition.
    CONCLUSIONS: Our findings suggest that treatment with CS055 combined with chiglitazar, will target LSCs by inducing ferroptosis and may confer an effective approach for the treatment of AML.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-0796
  7. Nature. 2024 Sep 25.
    Single-cell multi-omics map of human fetal blood in Down syndrome.
    Andrew R Marderstein, Marco De Zuani, Rebecca Moeller, Jon Bezney, Evin M Padhi, Shuo Wong, Tim H H Coorens, Yilin Xie, Haoliang Xue, Stephen B Montgomery, Ana Cvejic.
      Down syndrome predisposes individuals to haematological abnormalities, such as increased number of erythrocytes and leukaemia in a process that is initiated before birth and is not entirely understood1-3. Here, to understand dysregulated haematopoiesis in Down syndrome, we integrated single-cell transcriptomics of over 1.1 million cells with chromatin accessibility and spatial transcriptomics datasets using human fetal liver and bone marrow samples from 3 fetuses with disomy and 15 fetuses with trisomy. We found that differences in gene expression in Down syndrome were dependent on both cell type and environment. Furthermore, we found multiple lines of evidence that haematopoietic stem cells (HSCs) in Down syndrome are 'primed' to differentiate. We subsequently established a Down syndrome-specific map linking non-coding elements to genes in disomic and trisomic HSCs using 10X multiome data. By integrating this map with genetic variants associated with blood cell counts, we discovered that trisomy restructured regulatory interactions to dysregulate enhancer activity and gene expression critical to erythroid lineage differentiation. Furthermore, as mutations in Down syndrome display a signature of oxidative stress4,5, we validated both increased mitochondrial mass and oxidative stress in Down syndrome, and observed that these mutations preferentially fell into regulatory regions of expressed genes in HSCs. Together, our single-cell, multi-omic resource provides a high-resolution molecular map of fetal haematopoiesis in Down syndrome and indicates significant regulatory restructuring giving rise to co-occurring haematological conditions.
    DOI:  https://doi.org/10.1038/s41586-024-07946-4
  8. Nat Commun. 2024 Sep 26. 15(1): 8262
    Enhanced feature matching in single-cell proteomics characterizes IFN-γ response and co-existence of cell states.
    Karl K Krull, Syed Azmal Ali, Jeroen Krijgsveld.
      Proteome analysis by data-independent acquisition (DIA) has become a powerful approach to obtain deep proteome coverage, and has gained recent traction for label-free analysis of single cells. However, optimal experimental design for DIA-based single-cell proteomics has not been fully explored, and performance metrics of subsequent data analysis tools remain to be evaluated. Therefore, we here formalize and comprehensively evaluate a DIA data analysis strategy that exploits the co-analysis of low-input samples with a so-called matching enhancer (ME) of higher input, to increase sensitivity, proteome coverage, and data completeness. We assess the matching specificity of DIA-ME by a two-proteome model, and demonstrate that false discovery and false transfer are maintained at low levels when using DIA-NN software, while preserving quantification accuracy. We apply DIA-ME to investigate the proteome response of U-2 OS cells to interferon gamma (IFN-γ) in single cells, and recapitulate the time-resolved induction of IFN-γ response proteins as observed in bulk material. Moreover, we uncover co- and anti-correlating patterns of protein expression within the same cell, indicating mutually exclusive protein modules and the co-existence of different cell states. Collectively our data show that DIA-ME is a powerful, scalable, and easy-to-implement strategy for single-cell proteomics.
    DOI:  https://doi.org/10.1038/s41467-024-52605-x
  9. Ann Hematol. 2024 Sep 21.
    Distinct pathway activities are associated with prognosis and response to bortezomib-containing treatment in MCL1-M based molecular subtypes of multiple myeloma.
    Yuan Yang, Sitao Jiang, Hang Du, Jingling Tang, Pengli Xiao, Yin Wu, Jiuyi Li, Jing Feng, Yanfei Wei, Ayaz Ali Samo, Xuzhang Lu, Xiaolong Fan.
      Multiple myeloma (MM) is the second most prevalent hematological malignancy and remains incurable with remarkable heterogeneity in prognosis and treatment response across the patients. Clinical diagnosis and the existing molecular classification systems are inadequate for predicting treatment responses. Based on the convergence between plasma cell development and MM pathogenesis, we identified a gene co-expression module centered on the plasma cell survival regulator MCL1 (MCL1 module, MCL1-M) in the transcriptomes of pre-treated MM, which enabled stratification of MM patients into MCL1-M high and MCL1-M low molecular subtypes with subtype-specific prognosis and response to bortezomib-containing treatment. Here, we aimed to examine the mechanism underlying the disparate prognosis and treatment responses between the two molecular subtypes. Our findings reveal that MCL1-M high MM displays significant activation of pathways associated with cell proliferation, while MCL1-M low MM exhibits activation of immune-related signaling pathways. The relative enrichment of immune cells within the bone marrow microenvironment of MCL1-M low MM, particularly plasmacytoid dendritic cells, likely contributes to the activation of immune-related signaling pathways in this subset of myeloma cells. Using phase III trial data, we show that responses to bortezomib-containing treatment are associated with the extent of unfolded protein response (UPR) signaling activity. Further, bortezomib-mediated killing of MM cells could be enhanced or inhibited by in vitro manipulation of UPR activities in representative cell lines. In conclusion, MCL1-M based molecular subtypes of MM are characterized by distinct signaling activities from both malignant cells and bone marrow microenvironment, which may drive distinct prognosis and treatment responses.
    Keywords:  Bortezomib; MCL1-M based classification; Microenvironment; Multiple myeloma; Signaling pathway
    DOI:  https://doi.org/10.1007/s00277-024-06009-y
  10. Cell Rep. 2024 Sep 21. pii: S2211-1247(24)01134-3. [Epub ahead of print]43(10): 114783
    Geranylgeranylated SCFFBXO10 regulates selective outer mitochondrial membrane proteostasis and function.
    Sameer Ahmed Bhat, Zahra Vasi, Liping Jiang, Shruthi Selvaraj, Rachel Ferguson, Sanaz Salarvand, Anish Gudur, Ritika Adhikari, Veronica Castillo, Hagar Ismail, Avantika Dhabaria, Beatrix Ueberheide, Shafi Kuchay.
      Compartment-specific cellular membrane protein turnover is not well understood. We show that FBXO10, the interchangeable component of the cullin-RING-ligase 1 complex, undergoes lipid modification with geranylgeranyl isoprenoid at cysteine953, facilitating its dynamic trafficking to the outer mitochondrial membrane (OMM). FBXO10 polypeptide lacks a canonical mitochondrial targeting sequence (MTS); instead, its geranylgeranylation at C953 and interaction with two cytosolic factors, cytosolic factor-like δ subunit of type 6 phosphodiesterase (PDE6δ; a prenyl-group-binding protein) and heat shock protein 90 (HSP90; a chaperone), orchestrate specific OMM targeting of prenyl-FBXO10. The FBXO10(C953S) mutant redistributes away from the OMM, impairs mitochondrial ATP production and membrane potential, and increases fragmentation. Phosphoglycerate mutase-5 (PGAM5) was identified as a potential substrate of FBXO10 at the OMM using comparative quantitative proteomics of enriched mitochondria. FBXO10 loss or expression of prenylation-deficient FBXO10(C953S) inhibited PGAM5 degradation, disrupted mitochondrial homeostasis, and impaired myogenic differentiation of human induced pluripotent stem cells (iPSCs) and murine myoblasts. Our studies identify a mechanism for FBXO10-mediated regulation of selective mitochondrial proteostasis potentially amenable to therapeutic intervention.
    Keywords:  CP: Metabolism; CP: Molecular biology; E3-ligase; F-box protein; FBXO10; HSP90; PDE6δ; mitochondria; prenylation; trafficking; ubiquitination
    DOI:  https://doi.org/10.1016/j.celrep.2024.114783
  11. Front Physiol. 2024 ;15 1425620
    Endothelial cell elongation and alignment in response to shear stress requires acetylation of microtubules.
    Katiannah Moise, Keerthana M Arun, Maalavika Pillai, Jocelynda Salvador, Aarya S Mehta, Yogesh Goyal, M Luisa Iruela-Arispe.
      The innermost layer of the vessel wall is constantly subjected to recurring and relenting mechanical forces by virtue of their direct contact with blood flow. Endothelial cells of the vessel are exposed to distension, pressure, and shear stress; adaptation to these hemodynamic forces requires significant remodeling of the cytoskeleton which includes changes in actin, intermediate filaments, and microtubules. While much is known about the effect of shear stress on the endothelial actin cytoskeleton; the impact of hemodynamic forces on the microtubule network has not been investigated in depth. Here we used imaging techniques and protein expression analysis to characterize how pharmacological and genetic perturbations of microtubule properties alter endothelial responses to laminar shear stress. Our findings revealed that pharmacological suppression of microtubule dynamics blocked two typical responses to laminar shear stress: endothelial elongation and alignment. The findings demonstrate the essential contribution of the microtubule network to changes in cell shape driven by mechanical forces. Furthermore, we observed a flow-dependent increase in microtubule acetylation that occurred early in the process of cell elongation. Pharmacological manipulation of microtubule acetylation showed a direct and causal relationship between acetylation and endothelial elongation. Finally, genetic inactivation of aTAT1, a microtubule acetylase, led to significant loss of acetylation as well as inhibition of cell elongation in response to flow. In contrast, loss of HDAC6, a microtubule deacetylase, resulted in robust microtubule acetylation with cells displaying faster kinetics of elongation and alignment. Taken together, our findings uncovered the critical contributions of HDAC6 and aTAT1, that through their roles in the regulation of microtubule acetylation, are key mediators of endothelial mechanotransduction.
    Keywords:  cytoskeleton; hemodynamics; mechanosensing; mechanotransduction; vascular biology
    DOI:  https://doi.org/10.3389/fphys.2024.1425620
  12. Nature. 2024 Sep 25.
    Transferrin receptor targeting chimeras for membrane protein degradation.
    Dingpeng Zhang, Jhoely Duque-Jimenez, Francesco Facchinetti, Garyk Brixi, Kaitlin Rhee, William W Feng, Pasi A Jänne, Xin Zhou.
      Cancer cells require high levels of iron for rapid proliferation, leading to significant upregulation of cell-surface transferrin receptor 1 (TfR1), which mediates iron uptake by binding to the iron-carrying protein transferrin1-3. Leveraging this phenomenon and the fast endocytosis rate of TfR1 (refs. 4,5), we developed transferrin receptor targeting chimeras (TransTACs), a heterobispecific antibody modality for membrane protein degradation. TransTACs are engineered to drive rapid co-internalization of a target protein of interest and TfR1 from the cell surface, and to enable target protein entry into the lysosomal degradation pathway. We show that TransTACs can efficiently degrade a diverse range of single-pass, multi-pass, native or synthetic membrane proteins, including epidermal growth factor receptor, programmed cell death 1 ligand 1, cluster of differentiation 20 and chimeric antigen receptor. In example applications, TransTACs enabled the reversible control of human primary chimeric antigen receptor T cells and the targeting of drug-resistant epidermal growth factor receptor-driven lung cancer with the exon 19 deletion/T790M/C797S mutations in a mouse xenograft model. TransTACs represent a promising new family of bifunctional antibodies for precise manipulation of membrane proteins and targeted cancer therapy.
    DOI:  https://doi.org/10.1038/s41586-024-07947-3
  13. Nature. 2024 Sep 25.
    Designed endocytosis-inducing proteins degrade targets and amplify signals.
    Buwei Huang, Mohamad Abedi, Green Ahn, Brian Coventry, Isaac Sappington, Cong Tang, Rong Wang, Thomas Schlichthaerle, Jason Z Zhang, Yujia Wang, Inna Goreshnik, Ching Wen Chiu, Adam Chazin-Gray, Sidney Chan, Stacey Gerben, Analisa Murray, Shunzhi Wang, Jason O'Neill, Li Yi, Ronald Yeh, Ayesha Misquith, Anitra Wolf, Luke M Tomasovic, Dan I Piraner, Maria J Duran Gonzalez, Nathaniel R Bennett, Preetham Venkatesh, Maggie Ahlrichs, Craig Dobbins, Wei Yang, Xinru Wang, Danny D Sahtoe, Dionne Vafeados, Rubul Mout, Shirin Shivaei, Longxing Cao, Lauren Carter, Lance Stewart, Jamie B Spangler, Kole T Roybal, Per Jr Greisen, Xiaochun Li, Gonçalo J L Bernardes, Carolyn R Bertozzi, David Baker.
      Endocytosis and lysosomal trafficking of cell surface receptors can be triggered by endogenous ligands. Therapeutic approaches such as lysosome-targeting chimaeras1,2 (LYTACs) and cytokine receptor-targeting chimeras3 (KineTACs) have used this to target specific proteins for degradation by fusing modified native ligands to target binding proteins. Although powerful, these approaches can be limited by competition with native ligands and requirements for chemical modification that limit genetic encodability and can complicate manufacturing, and, more generally, there may be no native ligands that stimulate endocytosis through a given receptor. Here we describe computational design approaches for endocytosis-triggering binding proteins (EndoTags) that overcome these challenges. We present EndoTags for insulin-like growth factor 2 receptor (IGF2R) and asialoglycoprotein receptor (ASGPR), sortilin and transferrin receptors, and show that fusing these tags to soluble or transmembrane target protein binders leads to lysosomal trafficking and target degradation. As these receptors have different tissue distributions, the different EndoTags could enable targeting of degradation to different tissues. EndoTag fusion to a PD-L1 antibody considerably increases efficacy in a mouse tumour model compared to antibody alone. The modularity and genetic encodability of EndoTags enables AND gate control for higher-specificity targeted degradation, and the localized secretion of degraders from engineered cells. By promoting endocytosis, EndoTag fusion increases signalling through an engineered ligand-receptor system by nearly 100-fold. EndoTags have considerable therapeutic potential as targeted degradation inducers, signalling activators for endocytosis-dependent pathways, and cellular uptake inducers for targeted antibody-drug and antibody-RNA conjugates.
    DOI:  https://doi.org/10.1038/s41586-024-07948-2
  14. Blood Cells Mol Dis. 2024 Sep 18. pii: S1079-9796(24)00073-1. [Epub ahead of print]110 102895
    Further biological characterization of small molecules UM171 and SR1: In vitro effects on three hematopoietic cell populations from human cord blood.
    Patricia Flores-Guzman, Aranxa Torres-Caballero, Hector Mayani.
      Small molecules UM171 and SR1 have already been taken into clinically-oriented protocols for the ex vivo expansion of hematopoietic stem (HSCs) and progenitor (HPCs) cells. In order to gain further insight into their biology, in the present study we have assessed their effects, both individually and in combination, on the in vitro long-term proliferation and expansion of HSCs and HPCs contained within three different cord blood-derived cell populations: MNCs (CD34+ cells = 0.8 %), LIN- cells (CD34+ cells = 41 %), and CD34+ cells (CD34+ cells >98 %). Our results show that when added to cultures in the absence of recombinant stimulatory cytokines, neither molecule had any effect. In contrast, when added in the presence of hematopoietic cytokines, UM171 and SR1 had significant stimulatory effects on cell proliferation and expansion in cultures of LIN- and CD34+ cells. No significant effects were observed in cultures of MNCs. The effects of both molecules were more pronounced in cultures with the highest proportion of CD34+ cells, and the greatest effects were observed when both molecules were added in combination. In the absence of small molecules, cell numbers reached a peak by days 25-30, and then declined; whereas in the presence of UM171 or/and SR1 cell numbers were sustained up to day 45 of culture. Our results indicate that besides CD34+ cells, LIN- cells could also be used as input cells in clinically-oriented expansion protocols, and that using both molecules simultaneously would be a better approach than using only one of them.
    Keywords:  Cell expansion; Cell proliferation; Hematopoietic stem/progenitor cells; In vitro; SR1; UM171
    DOI:  https://doi.org/10.1016/j.bcmd.2024.102895
  15. Leukemia. 2024 Sep 26.
    Can PROTACs cure Leukemia?
    Kathleen M Sakamoto.
      
    DOI:  https://doi.org/10.1038/s41375-024-02427-z
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