bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2024–12–01
thirteen papers selected by
William Grey, University of York
  1. Targeting IL-1/IRAK1/4 signaling in Acute Myeloid Leukemia Stem Cells Following Treatment and Relapse.
  2. Models to study myelodysplastic syndrome and acute myeloid leukaemia.
  3. Quantitative determination of the spatial distribution of components in single cells with CellDetail.
  4. FoxO1 regulates human haematopoietic stem cells self-renewal and engraftment.
  5. RSK1 dependency in FLT3-ITD acute myeloid leukemia.
  6. Single-cell multiomics analysis reveals dynamic clonal evolution and targetable phenotypes in acute myeloid leukemia with complex karyotype.
  7. Genotype-immunophenotype relationships in NPM1 -mutant AML clonal evolution uncovered by single cell multiomic analysis.
  8. Novel techniques to quantitatively assess age-dependent alterations in biophysical properties of HSPCs and bone marrow niche.
  9. RNF38 promotes gilteritinib resistance in acute myeloid leukemia via inducing autophagy by regulating ubiquitination of LMX1A.
  10. Human umbilical cord mesenchymal stem cells improve bone marrow hematopoiesis through regulation of bone marrow adipose tissue.
  11. Oncogenic RTKs sensitize cancer cells to ferroptosis via c-Myc mediated upregulation of ACSL4.
  12. PIEZO-dependent mechanosensing is essential for intestinal stem cell fate decision and maintenance.
  13. Master regulators governing protein abundance across ten human cancer types.
  1. bioRxiv. 2024 Nov 11. pii: 2024.11.09.622796. [Epub ahead of print]
    Targeting IL-1/IRAK1/4 signaling in Acute Myeloid Leukemia Stem Cells Following Treatment and Relapse.
    Tzu-Chieh Ho, Mark W LaMere, Hiroki Kawano, Daniel K Byun, Elizabeth A LaMere, Yu-Chiao Chiu, Chunmo Chen, Jian Wang, Nikolay V Dokholyan, Laura M Calvi, Jane L Liesveld, Craig T Jordan, Reuben Kapur, Rakesh K Singh, Michael W Becker.
      Therapies for acute myeloid leukemia (AML) face formidable challenges due to relapse, often driven by leukemia stem cells (LSCs). Strategies targeting LSCs hold promise for enhancing outcomes, yet paired comparisons of functionally defined LSCs at diagnosis and relapse remain underexplored. We present transcriptome analyses of functionally defined LSC populations at diagnosis and relapse, revealing significant alterations in IL-1 signaling. Interleukin-1 receptor type I (IL1R1) and interleukin-1 receptor accessory protein (IL1RAP) were notably upregulated in leukemia stem and progenitor cells at both diagnosis and relapse. Knockdown of IL1R1 and IL1RAP reduced the clonogenicity and/or engraftment of primary human AML cells. In leukemic MLL-AF9 mice, Il1r1 knockout reduced LSC frequency and extended survival. To target IL-1 signaling at both diagnosis and relapse, we developed UR241-2, a novel interleukin-1 receptor-associated kinase 1 and 4 (IRAK1/4) inhibitor. UR241-2 robustly suppressed IL-1/IRAK1/4 signaling, including NF-κB activation and phosphorylation of p65 and p38, following IL-1 stimulation. UR241-2 selectively inhibited LSC clonogenicity in primary human AML cells at both diagnosis and relapse, while sparing normal hematopoietic stem and progenitor cells. It also reduced AML engraftment in leukemic mice. Our findings highlight the therapeutic potential of UR241-2 in targeting IL-1/IRAK1/4 signaling to eradicate LSCs and improve AML outcomes.
    DOI:  https://doi.org/10.1101/2024.11.09.622796
  2. Curr Opin Hematol. 2024 Nov 28.
    Models to study myelodysplastic syndrome and acute myeloid leukaemia.
    Clifford Chao, Isabella G Martinez, Elvin Wagenblast.
       PURPOSE OF REVIEW: Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are hematological malignancies characterized by complex genetic alterations, leading to poor clinical outcomes. Despite advances in treatment, there is an urgent need for novel therapeutic approaches. This review outlines recent progress in humanized models of MDS and AML and highlight their role in advancing our understanding of these diseases.
    RECENT FINDINGS: Patient derived xenografts (PDXs) were among the first humanized models for studying MDS and AML, allowing researchers to analyze patient-specific cancer properties in vivo. However, they face challenges related to sample availability and consistent engraftment in mice. New methods, including specialized mouse strains and human tissue scaffolds, have been developed to address these issues. Induced pluripotent stem cells (iPSCs) offer the advantage of indefinite expansion and genetic modification, making them valuable for in vitro research, though protocols to enhance their engraftment in vivo are still being refined. Genetically engineered human primary hematopoietic stem and progenitor cells (HSPCs) provide reliable in vivo models with good engraftment in mice, and recent advancements in culture systems and gene-editing techniques are helping to overcome challenges related to ex vivo expansion and genetic modification.
    SUMMARY: PDXs, iPSCs, and genetically engineered HSPCs are crucial models for the study of MDS and AML. This review discusses strengths, limitations, and recent advancements of these humanized models, which provide insights into human-specific disease biology and therapeutic development.
    DOI:  https://doi.org/10.1097/MOH.0000000000000856
  3. Nat Commun. 2024 Nov 26. 15(1): 10250
    Quantitative determination of the spatial distribution of components in single cells with CellDetail.
    Tanja Schuster, Amanda Amoah, Angelika Vollmer, Gina Marka, Julian Niemann, Mehmet Saçma, Vadim Sakk, Karin Soller, Mona Vogel, Ani Grigoryan, Meinhard Wlaschek, Karin Scharffetter-Kochanek, Medhanie Mulaw, Hartmut Geiger.
      The distribution of biomolecules within cells changes upon aging and diseases. To quantitatively determine the spatial distribution of components inside cells, we built the user-friendly open-source 3D-cell-image analysis platform Cell Detection and Analysis of Intensity Lounge (CellDetail). The algorithm within CellDetail is based on the concept of the dipole moment. CellDetail provides quantitative values for the distribution of the polarity proteins Cdc42 and Tubulin in young and aged hematopoietic stem cells (HSCs). Septin proteins form networks within cells that are critical for cell compartmentalization. We uncover a reduced level of organization of the Septin network within aged HSCs and within senescent human fibroblasts. Changes in the Septin network structure might therefore be a common feature of aging. The level of organization of the network of Septin proteins in aged HSCs can be restored to a youthful level by pharmacological attenuation of the activity of the small RhoGTPase Cdc42.
    DOI:  https://doi.org/10.1038/s41467-024-54638-8
  4. Mol Biol Rep. 2024 Nov 30. 52(1): 31
    FoxO1 regulates human haematopoietic stem cells self-renewal and engraftment.
    Lieguang Chen, Qunfang Ge, An Wu, Shasha You, Lixia Sheng, Yanli Lai, Yurong Bao, Congfa Jiang.
       BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is one of the most effective ways to treat hematological malignant diseases, but the traditional culture of hematopoietic stem cells (HSCs) in vitro will soon lose their ability to self-renewal or differentiate into multilineage blood cells.
    METHODS: To determine whether Forkhead boxO1 (FoxO1) is implicated in the development of HSCs, lentiviral vectors expressing knockdown (KD) or overexpression (OE) of FoxO1 were utilized in fetal liver-derived hematopoietic stem and progenitor cells (FL-HSPCs). The impacts on the proliferation and hematopoietic differentiation of FL-HSPCs were subsequently evaluated via flow cytometry (FCM). Furthermore, the effect of FoxO1-OE on the self-renewal of cord blood-derived hematopoietic stem and progenitor cells (CB-HSPCs) was investigated. Additionally, the transplantation ability of hematopoietic stem cells derived from these CB-HSPCs in mice after secondary transplantation was also assessed by FCM.
    RESULT: After knocking down FoxO1 in FL-HSPCs, the apoptosis rate was significantly increased, and the expression of hCD45 was significantly decreased. Conversely, overexpression of FoxO1 reversed this phenomenon, effectively promoting the expansion and differentiation of FL-HSPCs in vitro. Similarly, it was found that FoxO1-OE could effectively enhance the expansion of CB-HSPCs. Furthermore, upon transplantation of CB-HSPCs overexpressing FoxO1 into NSG mice, multilineage human hematopoietic reconstruction was promoted. Notably, the results of secondary transplantation revealed that only the FoxO1-OE group exhibited multilineage reconstitution.
    CONCLUSION: In conclusion, our study confirmed that FoxO1-OE could enhance the self-renewal and engraftment of CB-HSPCs.
    Keywords:  Differentiation; Engraftment; FoxO1; Hematological malignant diseases; Self-renewal
    DOI:  https://doi.org/10.1007/s11033-024-10140-4
  5. Blood Cancer J. 2024 Nov 26. 14(1): 207
    RSK1 dependency in FLT3-ITD acute myeloid leukemia.
    Tim Kong, Angelo B A Laranjeira, Christopher T Letson, LaYow Yu, Fan He, Aarthi Jayanthan, Gerrit Los, Sandra E Dunn, Grant A Challen, Stephen T Oh.
      Internal tandem duplications (ITD) in fms-like tyrosine kinase 3 (FLT3) represent the most common genetic alteration in de novo acute myeloid leukemia (AML). Here, we identify ribosomal protein s6 kinase a1 (RSK1) as a core dependency in FLT3-ITD AML and unveil the existence of crucial bi-directional regulation. RSK1 perturbation resulted in marked apoptosis and abrogated phosphorylation of FLT3 and associated downstream signaling cascades in FLT3-ITD AML cell lines. Using cycloheximide, MG-132, and ubiquitination assays, we further demonstrate mechanistically that RSK1 regulates FLT3-ITD activity, and protein stability through deubiqutinase USP1, which we identify as a second dependency. Importantly, multivariate analysis revealed heightened expression of RPS6KA1 and USP1 to be associated with poor patient prognosis, and these effectors may serve as biomarkers predictive of patient survival and therapeutic response to FLT3-ITD inhibitors. Lastly, RSK1 inhibition utilizing a first-in-class RSK inhibitor, PMD-026, that is currently undergoing Phase 2 development for breast cancer, diminished leukemic disease burden in MV4-11 xenograft and syngeneic Flt3ITDTet2KO leukemia models. These findings illustrate an unconventional and promising therapeutic strategy targeting FLT3-ITD leukemia.
    DOI:  https://doi.org/10.1038/s41408-024-01187-4
  6. Nat Genet. 2024 Nov 25.
    Single-cell multiomics analysis reveals dynamic clonal evolution and targetable phenotypes in acute myeloid leukemia with complex karyotype.
    Aino-Maija Leppä, Karen Grimes, Hyobin Jeong, Frank Y Huang, Alvaro Andrades, Alexander Waclawiczek, Tobias Boch, Anna Jauch, Simon Renders, Patrick Stelmach, Carsten Müller-Tidow, Darja Karpova, Markus Sohn, Florian Grünschläger, Patrick Hasenfeld, Eva Benito Garagorri, Vera Thiel, Anna Dolnik, Bernardo Rodriguez-Martin, Lars Bullinger, Krzysztof Mrózek, Ann-Kathrin Eisfeld, Alwin Krämer, Ashley D Sanders, Jan O Korbel, Andreas Trumpp.
      Chromosomal instability is a major driver of intratumoral heterogeneity (ITH), promoting tumor progression. In the present study, we combined structural variant discovery and nucleosome occupancy profiling with transcriptomic and immunophenotypic changes in single cells to study ITH in complex karyotype acute myeloid leukemia (CK-AML). We observed complex structural variant landscapes within individual cells of patients with CK-AML characterized by linear and circular breakage-fusion-bridge cycles and chromothripsis. We identified three clonal evolution patterns in diagnosis or salvage CK-AML (monoclonal, linear and branched polyclonal), with 75% harboring multiple subclones that frequently displayed ongoing karyotype remodeling. Using patient-derived xenografts, we demonstrated varied clonal evolution of leukemic stem cells (LSCs) and further dissected subclone-specific drug-response profiles to identify LSC-targeting therapies, including BCL-xL inhibition. In paired longitudinal patient samples, we further revealed genetic evolution and cell-type plasticity as mechanisms of disease progression. By dissecting dynamic genomic, phenotypic and functional complexity of CK-AML, our findings offer clinically relevant avenues for characterizing and targeting disease-driving LSCs.
    DOI:  https://doi.org/10.1038/s41588-024-01999-x
  7. bioRxiv. 2024 Nov 12. pii: 2024.11.11.623033. [Epub ahead of print]
    Genotype-immunophenotype relationships in NPM1 -mutant AML clonal evolution uncovered by single cell multiomic analysis.
    Morgan Drucker, Darren Lee, Xuan Zhang, Bailee Kain, Michael Bowman, Deedra Nicolet, Zhe Wang, Richard M Stone, Krzysztof Mrózek, Andrew J Carroll, Daniel T Starczynowski, Ross L Levine, John C Byrd, Ann-Kathrin Eisfeld, Nathan Salomonis, H Leighton Grimes, Robert L Bowman, Linde A Miles.
      Acute myeloid leukemia (AML) is a multi-clonal disease, existing as a milieu of clones with unique but related genotypes as initiating clones acquire subsequent mutations. However, bulk sequencing cannot fully capture AML clonal architecture or the clonal evolution that occurs as patients undergo therapy. To interrogate clonal evolution, we performed simultaneous single cell molecular profiling and immunophenotyping on 43 samples from 32 NPM1 -mutant AML patients at different stages of disease. Here we show that diagnosis and relapsed AML samples display similar clonal architecture patterns, but signaling mutations can drive increased clonal diversity specifically at relapse. We uncovered unique genotype-immunophenotype relationships regardless of disease state, suggesting leukemic lineage trajectories can be hard-wired by the mutations present. Analysis of longitudinal samples from patients on therapy identified dynamic clonal, transcriptomic, and immunophenotypic changes. Our studies provide resolved understanding of leukemic clonal evolution and the relationships between genotype and cell state in leukemia biology.
    DOI:  https://doi.org/10.1101/2024.11.11.623033
  8. Exp Hematol. 2024 Nov 27. pii: S0301-472X(24)00551-4. [Epub ahead of print] 104686
    Novel techniques to quantitatively assess age-dependent alterations in biophysical properties of HSPCs and bone marrow niche.
    Ho Anthony D, Tanaka Motomu.
      The present knowledge on hematopoietic stem and progenitor cell (HSPC) biology and aging is based largely on studies in mouse models. While mouse models are invaluable, they are not without limitations for defining how physical properties of HSPCs and their niche change with age. The bone marrow (BM) niche is a complex, interactive environment with multiple cell types. The structure and organization of the BM niche, especially the extracellular matrix (ECM), change with age. Provided with recent advances in quantitative analytical techniques and in vitro niche models, we have developed novel tools to quantitatively assess the impact of specific biochemical and physical cues on homing, adhesion and migration of HSPCs. Recent developments in in vitro niche models have also provided new insights into the interactions between HSPCs and their niche, particularly the role of matrix stiffness. Further research is needed to integrate physical biomarkers into comprehensive mathematical models of age-dependent HSPC-niche interactions. The key is to use mouse models in conjunction with direct analyses in in vitro niche models to achieve a more comprehensive understanding of age-dependent alterations in niche function and regulation.
    DOI:  https://doi.org/10.1016/j.exphem.2024.104686
  9. Cell Biol Toxicol. 2024 Nov 28. 40(1): 105
    RNF38 promotes gilteritinib resistance in acute myeloid leukemia via inducing autophagy by regulating ubiquitination of LMX1A.
    Yiyun Pan, Wen Zeng, Ting Liang, Xiaoming Nie, Kang Liu, Hailong Chen, Nengping Luo, Xiaodan Zhu, Keqiang Tian, Yijian Chen.
       BACKGROUND: Gilteritinib is a commonly used targeted drug for acute myeloid leukemia (AML), but the emergence of gilteritinib resistance greatly reduces the therapeutic effect. RING finger protein 38 (RNF38), a protein with RING Finger domain and E3 ubiquitin ligase activity, has been implicated in tumorigenesis and drug resistance. However, the role and mechanism of RNF38 in the gilteritinib resistance of AML remains unclear.
    METHODS: Normal AML cells were treated with gilteritinib to construct gilteritinib-resistant cells (MV4-11/Gilteritinib and MOLM-13/Gilteritinib). CCK8 assay, TUNEL staining and EdU assay were used to assess gilteritinib resistance, cell apoptosis and proliferation. The protein levels of autophagy-related markers, RNF38 and LIM homeobox transcription factor 1 alpha (LMX1A) were determined by western blot. Also, RNF38 and LMX1A mRNA levels were tested using qRT-PCR. Autophagic flux was assessed using mRFP-GFP-LC3 labeling, and autophagosome numbers was counted under transmission electron microscopy. Co-IP assay was employed to analyze interaction between RNF38 and LMX1A. The effects of LMX1A and RNF38 on AML tumorigenesis were analyzed by in vivo experiments.
    RESULTS: In gilteritinib-resistant AML cells, autophagy-related markers, mRFP-GFP-LC3 signals and autophagosome numbers were significantly enhanced. Autophagy inhibitor 3-MA could suppress gilteritinib resistance in AML cells. RNF38 knockdown inhibited gilteritinib resistance and autophagy in AML cells. Mechanistically, RNF38 reduced LMX1A expression by inducing its ubiquitination. RNF38 overexpression reversed the inhibitory effect of LMX1A on gilteritinib resistance and autophagy in AML cells, as well as AML tumor growth in vivo, while these effects could be abolished by proteasome inhibitor MG132.
    CONCLUSIONS: RNF38 induced autophagy to promote gilteritinib resistance in AML by increasing the ubiquitination of LMX1A.
    Keywords:  Acute myeloid leukemia; Autophagy; Gilteritinib; LMX1A; RNF38
    DOI:  https://doi.org/10.1007/s10565-024-09936-8
  10. Mol Cell Biochem. 2024 Nov 30.
    Human umbilical cord mesenchymal stem cells improve bone marrow hematopoiesis through regulation of bone marrow adipose tissue.
    Jingyi Feng, Miao Zhang, Huanying Ren, Yan Ren, Zhuanghui Hao, Sicheng Bian, Jiangxia Cui, Shuo Li, Jing Xu, Muteb Muyey Daniel, Fanggang Ren, Zhifang Xu, Yanhong Tan, Xiuhua Chen, Yaofang Zhang, Jianmei Chang, Hongwei Wang.
      Bone marrow adipose tissue (BMAT) exhibits a multitude of biological functionalities and influences hematopoiesis. The adiposity status of the bone marrow may play a role in the decline of hematopoietic function. Mesenchymal stem cells (MSCs) constitute crucial regulators within the bone marrow microenvironment; however, their precise role in modulating BMAT and the subsequent implications for hematopoiesis remain poorly understood. We conducted in vivo studies to observe the effects of human umbilical cord mesenchymal stem cells (hucMSCs) on BMAT accumulation and restoration of hematopoietic function in mice with drug-induced hematopoietic impairment. Concurrently, in vitro co-culture experiments were used to investigate the impact of hucMSCs on preadipocytes and mature adipocytes, and the potential subsequent consequences for hematopoietic cells. Moreover, we explored the potential mechanisms underlying these interactions. Our findings reveal that hucMSCs concomitantly mitigate BMAT accumulation and facilitate the recovery of hematopoietic function in mouse models with drug-induced hematopoietic impairment. In vitro, hucMSCs potentially impede adipogenic differentiation of 3T3-L1 preadipocytes through interference with the JAK2/STAT3 signaling pathway and affect the functionality of mature adipocytes, thus mitigating the detrimental effects of adipocytes on hematopoietic stem cells (HSCs). Furthermore, we demonstrate that hucMSCs may protect hematopoietic cells from adipocyte-induced damage by protecting antioxidative mechanisms. These results suggest that hucMSCs exhibit an inhibitory effect on the excessive expansion of adipose tissue and modulate adipose tissue function, which may potentially contribute to the regulation of the bone marrow microenvironment and favorably influence hematopoietic function improvement.
    Keywords:  Adipose; Bone marrow; Chemotherapy; Hematopoiesis; Mesenchymal stem cells (MSCs)
    DOI:  https://doi.org/10.1007/s11010-024-05156-0
  11. Cell Death Dis. 2024 Nov 27. 15(11): 861
    Oncogenic RTKs sensitize cancer cells to ferroptosis via c-Myc mediated upregulation of ACSL4.
    Na Sun, Jiawa Wang, Jianhua Qin, Shuang Ma, Jing Luan, Guoyuan Hou, Wei Zhang, Minghui Gao.
      Alteration or abnormal activation of RTKs have been recurrently observed and recognized as an important driving factor in the progression of many human cancers. Ferroptosis, an iron-dependent form of regulated necrosis triggered by the accumulation of lethal lipid peroxides on cell membranes, has been implicated in various tumor types. Here we reported that oncogenic RTKs/RAS/RAF/c-Myc axis promotes cancer cells to ferroptosis. Mechanistically, c-Myc binds to the promoter region of ACSL4 and promotes the expression of ACSL4, thereby sensitizes cells to ferroptosis. We further showed that RTKs/RAS/RAF promote ferroptosis by upregulating c-Myc mediated expression of ACSL4 in cancer cells. Notably, overexpression of RTKs enhances the vulnerability of melanoma to the ferroptosis inducer in mouse xenograft model. These findings may provide an attractive intervention strategy to target cancers with oncogenic activation of RTKs via a ferroptosis-inducing approach.
    DOI:  https://doi.org/10.1038/s41419-024-07254-9
  12. Science. 2024 Nov 29. 386(6725): eadj7615
    PIEZO-dependent mechanosensing is essential for intestinal stem cell fate decision and maintenance.
    Meryem B Baghdadi, Ronja M Houtekamer, Louisiane Perrin, Abilasha Rao-Bhatia, Myles Whelen, Linda Decker, Martin Bergert, Carlos Pérez-Gonzàlez, Réda Bouras, Giacomo Gropplero, Adrian K H Loe, Amin Afkhami-Poostchi, Xin Chen, Xi Huang, Stephanie Descroix, Jeffrey L Wrana, Alba Diz-Muñoz, Martijn Gloerich, Arshad Ayyaz, Danijela Matic Vignjevic, Tae-Hee Kim.
      Stem cells perceive and respond to biochemical and physical signals to maintain homeostasis. Yet, it remains unclear how stem cells sense mechanical signals from their niche in vivo. In this work, we investigated the roles of PIEZO mechanosensitive channels in the intestinal stem cell (ISC) niche. We used mouse genetics and single-cell RNA sequencing analysis to assess the requirement for PIEZO channels in ISC maintenance. In vivo measurement of basement membrane stiffness showed that ISCs reside in a more rigid microenvironment at the bottom of the crypt. Three-dimensional and two-dimensional organoid systems combined with bioengineered substrates and a stretching device revealed that PIEZO channels sense extracellular mechanical stimuli to modulate ISC function. This study delineates the mechanistic cascade of PIEZO activation that coordinates ISC fate decision and maintenance.
    DOI:  https://doi.org/10.1126/science.adj7615
  13. bioRxiv. 2024 Nov 12. pii: 2024.11.11.619147. [Epub ahead of print]
    Master regulators governing protein abundance across ten human cancer types.
    Zishan Wang, Megan Wojciechowicz, Jordan Rosen, Abdulkadir Elmas, Won-Min Song, Yansheng Liu, Kuan-Lin Huang.
      Protein abundance correlates only moderately with mRNA levels, and are modulated post-transcriptionally by a network of regulators including ribosomes, RNA-binding proteins (RBPs), and the proteasome. Here, we identified Ma ster P rotein abundance R egulators (MaPRs) across ten cancer types by devising a new computational pipeline that jointly analyzed transcriptomes and proteomes from 1,305 tumor samples. We identified 232 to 1,394 MaPRs per cancer type, mediating up to 79% of post- transcriptional regulatory networks. MaPRs exhibit high network connectivity, strong genetic dependency in cancer cells, and significant enrichment for RBPs. Combining tumor up-regulation, druggability, and target network analyses identified cancer-specific vulnerabilities. MaPRs predict tumor proteomic subtypes more accurately than other proteins. Finally, significant portions of RBP MaPR-target relationships were validated by experimental evidence from eCLIP binding and knockdown assays. Our findings uncover central MaPRs that govern post-transcriptional networks, highlighting diverse processes underlying human proteome regulation and identifying key regulators in cancer biology.
    DOI:  https://doi.org/10.1101/2024.11.11.619147
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