bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2024–11–03
eightteen papers selected by
William Grey, University of York
  1. Development of iPSC-derived human bone marrow organoid for autonomous hematopoiesis and patient-derived HSPC engraftment.
  2. Modification of Lhx2 activity for ex vivo amplification of human iPSC-derived hematopoietic stem/progenitor cells.
  3. Understanding MDS stem cells: Advances and limitations.
  4. Met-Flow analyses of the metabolic heterogeneity associated with different stages of cord blood-derived hematopoietic cell differentiation.
  5. The E3 Ubiquitin Ligase Trip12 attenuates Wnt9a/Fzd9b signaling during hematopoietic stem cell development.
  6. The E3 ubiquitin ligase MARCH5 promotes mitochondrial fusion and cell cycle progression in acute myeloid leukemia.
  7. MLL oncoprotein levels influence leukemia lineage identities.
  8. NUP98 fusion proteins and KMT2A-MENIN antagonize PRC1.1 to drive gene expression in AML.
  9. Targeted hematopoietic stem cell depletion through SCF-blockade.
  10. GPRASP protein deficiency triggers lymphoproliferative disease by affecting B-cell differentiation.
  11. Characterization of ligand-receptor pair in acute myeloid leukemia: a scoring model for prognosis, therapeutic response, and T cell dysfunction.
  12. Ever-evolving insights into the cellular and molecular drivers of lymphoid cell development.
  13. Quantifying mitochondrial protein import by mePRODmt proteomics.
  14. The Functional Transcriptomic Landscape Informs Therapeutic Strategies in Multiple Myeloma.
  15. Macrophages as Potential Therapeutic Targets in Acute Myeloid Leukemia.
  16. RAS-mutant leukaemia stem cells drive clinical resistance to venetoclax.
  17. Comparative small molecule screening of primary human acute leukemias, engineered human leukemia and leukemia cell lines.
  18. Type I-conventional dendritic cells support the progression of multiple myeloma in the bone marrow.
  1. Blood Adv. 2024 Oct 29. pii: bloodadvances.2024013361. [Epub ahead of print]
    Development of iPSC-derived human bone marrow organoid for autonomous hematopoiesis and patient-derived HSPC engraftment.
    Kehan Ren, Ermin Li, Inci Aydemir, Yijie Liu, Xu Han, Honghao Bi, Pan Wang, Kara Tao, Amy Ji, Yi-Hua Chen, Jing Yang, Madina Sukhanova, Peng Ji.
      Current efforts in translational studies in hematology often rely on immunodeficient mouse models for engrafting patient-derived hematopoietic stem and progenitor cells (HSPCs), yet these models often face challenges in effectively engrafting cells from patients with various diseases, such as myelodysplastic syndromes (MDS). In this study, we developed an induced pluripotent stem cell (iPSC)-derived human bone marrow organoid model that closely replicates the bone marrow microenvironment, facilitating the engraftment of MDS patient-derived HSPCs, thereby mirroring the patients' distinct disease characteristics. Specifically, through advanced microscopy, we verified the development of a complex three-dimensional network of endothelial, stromal, and hematopoietic cells within the organoids, resembling the autonomous human marrow microenvironment. Furthermore, we showed that HSPCs derived from the donor bone marrow of normal individuals or patients with MDS can migrate to and proliferate within the organoid's vascular niche while maintaining self-renewal and original genetic profiles. Within the organoids, the differentiation patterns from MDS HSPCs were significantly distinct compared to the multilineage hematopoiesis from normal HSPCs, which can be correlated with the clinical manifestations of the disease. These findings underscore the significance of the organoid model in studying human hematopoiesis and the pathophysiology of hematologic diseases, offering new avenues for personalized medicine and therapeutic interventions.
    DOI:  https://doi.org/10.1182/bloodadvances.2024013361
  2. Front Cell Dev Biol. 2024 ;12 1482989
    Modification of Lhx2 activity for ex vivo amplification of human iPSC-derived hematopoietic stem/progenitor cells.
    Kenji Kitajima, Yuna Takahashi, Hikaru Ando, Minako Shingai, Mako Hamasaki, Miyu Tanikawa, Mai Kanokoda, Marino Nakajima, Yasumasa Nishito, Takahiko Hara.
      Hematopoietic stem cells (HSCs) obtained from patient-derived human induced pluripotent stem cells (iPSCs) are a promising tool for curing various hematological disorders. We previously demonstrated that enforced expression of the LIM-homeobox transcription factor Lhx2, which is essential for mouse embryonic hematopoiesis, leads to generation of engraftable and expandable hematopoietic stem cells (HSCs) from mouse iPSCs. However, it remained unknown whether Lhx2 can induce HSCs from human iPSCs. Here, we investigated the effect of Lhx2 overexpression on hematopoietic differentiation of human iPSCs. Unexpectedly, Lhx2 severely inhibited proliferation of human iPSC-derived hematopoietic cells. Thus, Lhx2 exhibited differential effects on mouse and human hematopoietic cells. Further studies implied that the inhibitory effect of Lhx2 on human iPSC-derived hematopoietic cells was due to insufficient transcriptional activation ability. Therefore, we modified Lhx2 to strengthen its activity as a transcriptional activator. This modified Lhx2 could induce ex vivo amplification of human iPSC-derived hematopoietic stem/progenitor cells (HSPCs). We believe that these findings will facilitate the development of a method to efficiently produce HSCs from human iPSCs.
    Keywords:  HSPCs; Lhx2; differentiation; ex vivo amplification; homeobox; iPSCs; organoid
    DOI:  https://doi.org/10.3389/fcell.2024.1482989
  3. Semin Hematol. 2024 Sep 28. pii: S0037-1963(24)00110-0. [Epub ahead of print]
    Understanding MDS stem cells: Advances and limitations.
    Sweta B Patel, Daniel R Moskop, Craig T Jordan, Eric M Pietras.
      In work spanning several decades, extensive studies have focused on the properties of malignant stem cells that drive the pathogenesis of acute myeloid leukemia (AML). However, relatively little attention has been devoted to several serious myeloid malignancies that occur prior to the onset of frank leukemia, including myelodysplastic syndrome (MDS). Like leukemia, MDS is hypothesized to arise from a pool of immature malignant stem and progenitor cells (MDS-SCs) that serve as a reservoir for disease evolution and progression1. While multiple studies have sought to identify and characterize the biology and vulnerabilities of MDS-SCs, yet translation of scientific concepts to therapeutically impactful regimens has been limited. Here, we evaluate the currently known properties of MDS-SCs as well as the post-transcriptional mechanisms that drive MDS pathogenesis at a stem and progenitor level. We highlight limits and gaps in our characterization and understanding of MDS-SCs and address the extent to which the properties of MDS-SC are (and can be) inferred from the characterization of LSCs.
    Keywords:  Leukemia stem cell; Myelodysplastic syndrome; Myelodysplastic syndrome stem cell
    DOI:  https://doi.org/10.1053/j.seminhematol.2024.09.007
  4. Front Immunol. 2024 ;15 1425585
    Met-Flow analyses of the metabolic heterogeneity associated with different stages of cord blood-derived hematopoietic cell differentiation.
    Sen Zhang, Xiaodong Kong, Ming Yao, Jinfeng Qi, Ying Li, Haoyue Liang, Yuan Zhou.
       Background: The differentiation of hematopoietic cells is significantly affected by cell metabolic activity. However, despite increasing interest in this field, there has been no comprehensive investigation of the metabolic functions of human hematopoietic cells during specific phases of differentiation. Thus, this study was conducted to develop a method for comparing hematopoietic cell lineage differentiation based on the metabolic functions of the cell. The metabolic activity of human umbilical cord-derived hematopoietic cells was examined during various phases of differentiation, specifically, hematopoietic stem cells (HSCs), hematopoietic progenitor cells, and differentiated blood cells. This approach was used to develop comprehensive metabolic maps corresponding to the different stages.
    Results: HSCs were found to have robust fatty acid (FA) synthesis, FA oxidation, pentose phosphate pathway (PPP) activity, and glucose uptake, shown by their significantly higher expression of ACAC, CPT1A, G6PD, and GLUT1 as compared to differentiated pluripotent progenitor cells, common myeloid progenitors, megakaryocyte erythroid progenitors, lympho-myeloid primed progenitors, and granulocyte-macrophage progenitor cell populations. In monocytic differentiation, higher levels of ACAC, ASS1, ATP5A, CPT1A, G6PD, GLUT1, IDH2, PRDX2, and HK1 protein expression were evident in classical and intermediate monocytes relative to non-classical monocytes, consistent with high anabolic and catabolic levels. Compared with myelocytes and mature cells, the meta-myelocyte and pro-myelocyte populations of granulocytes show significantly elevated levels of ACAC, ASS1, ATP5A, CPT1A, G6PD, IDH2, PRDX2, and HK. In contrast to naïve and regulatory B cells, pro-B cells had higher levels of oxidative phosphorylation, while regulatory B cells showed greater PPP activity, glucose uptake, and tricarboxylic acid cycle activity. The analyses of T cells also indicated significantly higher ACAC, ASS1, ATP5A, CPT1A, G6PD, GLUT1, IDH2, PRDX2, and HK1 expression levels in CD4+ populations compared with CD8+ populations.
    Conclusions: The results provide comprehensive analytical methods and reference values for future systematic studies into the metabolic functions of various cord blood-derived hematopoietic cell populations in different pathological or physiological conditions. These findings could also contribute to research on the connection between cellular metabolism and cancer or aging.
    Keywords:  Met-Flow; hematopoietic cells; lineage differentiation; metabolic chart; umbilical cord blood
    DOI:  https://doi.org/10.3389/fimmu.2024.1425585
  5. bioRxiv. 2024 Oct 25. pii: 2024.10.25.620301. [Epub ahead of print]
    The E3 Ubiquitin Ligase Trip12 attenuates Wnt9a/Fzd9b signaling during hematopoietic stem cell development.
    Jessica Ensing, Amber D Ide, Carla Gilliland, Visakuo Tsurho, Isabella Caza, Amber N Stratman, Nathan J Lanning, Stephanie Grainger.
      Wnt signaling is essential for both the development and homeostasis of diverse cellular lineages, including hematopoietic stem cells. Organism-wide, Wnt signals are tightly regulated, as overactivation of the pathway can lead to tumorigenesis. Although numerous Wnt ligands and Frizzled (Fzd) receptors exist, how particular Wnt/Fzd pairings are established and how their signals are regulated is poorly understood. We have previously identified the requirements of the cognate pairing of Wnt9a and Fzd9b for early hematopoietic stem cell proliferation. However, the specific signals governing activation, but equally important, the molecular mechanisms required to turn the signal 'off,' are unknown. Here, we show that the E3 ubiquitin ligase Trip12 (thyroid hormone receptor interactor 12) is specifically required to ubiquitinate the third intracellular loop of Fzd9b at K437, targeting it for lysosomal degradation. In contrast to other ubiquitin ligases described to regulate the cell surface availability of multiple Fzds broadly, our data indicate that Trip12 is selective for Fzd9b. We further demonstrate that this occurs through ubiquitination at K437 of Fzd9b in the third intracellular loop, ultimately leading to a decrease in Fzd9b receptor availability and in Wnt9a/Fzd9b signaling that impacts hematopoietic stem cell proliferation in zebrafish. Our results point to specific mechanisms driving the availability of different Fzd receptors. Determining how particular Fzd abundance is regulated at the membrane will be critical to developing specific therapies for human intervention.
    One sentence summary: Trip12 ubiquitinates Fzd9b.
    DOI:  https://doi.org/10.1101/2024.10.25.620301
  6. Blood Adv. 2024 Oct 29. pii: bloodadvances.2024013890. [Epub ahead of print]
    The E3 ubiquitin ligase MARCH5 promotes mitochondrial fusion and cell cycle progression in acute myeloid leukemia.
    Clement Larrue, Sarah Mouche, Jérôme Tamburini.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2024013890
  7. Nat Commun. 2024 Oct 29. 15(1): 9341
    MLL oncoprotein levels influence leukemia lineage identities.
    Derek H Janssens, Melodie Duran, Dominik J Otto, Weifang Wu, Yiling Xu, Danielle Kirkey, Charles G Mullighan, Joanna S Yi, Soheil Meshinchi, Jay F Sarthy, Kami Ahmad, Steven Henikoff.
      Chromosomal translocations involving the mixed-lineage leukemia (MLL) locus generate potent oncogenic fusion proteins (oncoproteins) that disrupt regulation of developmental gene expression. By profiling the oncoprotein-target sites of 36 broadly representative MLL-rearranged leukemia samples, including three samples that underwent a lymphoid-to-myeloid lineage-switching event in response to therapy, we find the genomic enrichment of the oncoprotein is highly variable between samples and subject to dynamic regulation. At high levels of expression, the oncoproteins preferentially activate either an acute lymphoblastic leukemia (ALL) program, enriched for pro-B-cell genes, or an acute myeloid leukemia (AML) program, enriched for hematopoietic-stem-cell genes. The fusion-partner-specific-binding patterns over these gene sets are highly correlated with the prevalence of each mutation in ALL versus AML. In lineage-switching samples the oncoprotein levels are reduced and the oncoproteins preferentially activate granulocyte-monocyte progenitor (GMP) genes. In a sample that lineage switched during treatment with the menin inhibitor revumenib, the oncoprotein and menin are reduced to undetectable levels, but ENL, a transcriptional cofactor of the oncoprotein, persists on numerous oncoprotein-target loci, including genes in the GMP-like lineage-switching program. We propose MLL oncoproteins promote lineage-switching events through dynamic chromatin binding at lineage-specific target genes, and may support resistance to menin inhibitors through similar changes in chromatin occupancy.
    DOI:  https://doi.org/10.1038/s41467-024-53399-8
  8. Cell Rep. 2024 Oct 29. pii: S2211-1247(24)01252-X. [Epub ahead of print]43(11): 114901
    NUP98 fusion proteins and KMT2A-MENIN antagonize PRC1.1 to drive gene expression in AML.
    Emily B Heikamp, Cynthia Martucci, Jill A Henrich, Dana S Neel, Sanisha Mahendra-Rajah, Hannah Rice, Daniela V Wenge, Florian Perner, Yanhe Wen, Charlie Hatton, Scott A Armstrong.
      Control of stem cell-associated genes by Trithorax group (TrxG) and Polycomb group (PcG) proteins is frequently misregulated in cancer. In leukemia, oncogenic fusion proteins hijack the TrxG homolog KMT2A and disrupt PcG activity to maintain pro-leukemogenic gene expression, though the mechanisms by which oncofusion proteins antagonize PcG proteins remain unclear. Here, we define the relationship between NUP98 oncofusion proteins and the non-canonical polycomb repressive complex 1.1 (PRC1.1) in leukemia using Menin-KMT2A inhibitors and targeted degradation of NUP98 fusion proteins. Eviction of the NUP98 fusion-Menin-KMT2A complex from chromatin is not sufficient to silence pro-leukemogenic genes. In the absence of PRC1.1, key oncogenes remain transcriptionally active. Transition to a repressed chromatin state requires the accumulation of PRC1.1 and repressive histone modifications. We show that PRC1.1 loss leads to resistance to small-molecule Menin-KMT2A inhibitors in vivo. Therefore, a critical function of oncofusion proteins that hijack Menin-KMT2A activity is antagonizing repressive chromatin complexes.
    Keywords:  CP: Cancer; CP: Molecular biology; acute myeloid leukemia; chromatin complex; lysine methyltransferase 2A; menin; nascent transcriptomics; non-canonical polycomb repressive complex 1.1; nucleoporin 98-rearrangement; oncogenic fusion protein
    DOI:  https://doi.org/10.1016/j.celrep.2024.114901
  9. Stem Cell Res Ther. 2024 Oct 29. 15(1): 387
    Targeted hematopoietic stem cell depletion through SCF-blockade.
    Yan Yi Chan, Pui Yan Ho, Carla Dib, Leah Swartzrock, Maire Rayburn, Hana Willner, Ethan Ko, Katie Ho, Julian D Down, Adam C Wilkinson, Hiro Nakauchi, Morgane Denis, Taylor Cool, Agnieszka Czechowicz.
       BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a curative treatment for many diverse blood and immune diseases. However, HSCT regimens currently commonly utilize genotoxic chemotherapy and/or total body irradiation (TBI) conditioning which causes significant morbidity and mortality through inducing broad tissue damage triggering infections, graft vs. host disease, infertility, and secondary cancers. We previously demonstrated that targeted monoclonal antibody (mAb)-based HSC depletion with anti(α)-CD117 mAbs could be an effective alternative conditioning approach for HSCT without toxicity in severe combined immunodeficiency (SCID) mouse models, which has prompted parallel clinical αCD117 mAbs to be developed and tested as conditioning agents in clinical trials starting with treatment of patients with SCID. Subsequent efforts have built upon this work to develop various combination approaches, though none are optimal and how any of these mAbs fully function is unknown.
    METHODS: To improve efficacy of mAb-based conditioning as a stand-alone conditioning approach for all HSCT settings, it is critical to understand the mechanistic action of αCD117 mAbs on HSCs. Here, we compare the antagonistic properties of αCD117 mAb clones including ACK2, 2B8, and 3C11 as well as ACK2 fragments in vitro and in vivo in both SCID and wildtype (WT) mouse models. Further, to augment efficacy, combination regimens were also explored.
    RESULTS: We confirm that only ACK2 inhibits SCF binding fully and prevents HSC proliferation in vitro. Further, we verify that this corresponds to HSC depletion in vivo and donor engraftment post HSCT in SCID mice. We also show that SCF-blocking αCD117 mAb fragment derivatives retain similar HSC depletion capacity with enhanced engraftment post HSCT in SCID settings, but only full αCD117 mAb ACK2 in combination with αCD47 mAb enables enhanced donor HSC engraftment in WT settings, highlighting that the Fc region is not required for single-agent efficacy in SCID settings but is required in immunocompetent settings. This combination was the only non-genotoxic conditioning approach that enabled robust donor engraftment post HSCT in WT mice.
    CONCLUSION: These findings shed new insights into the mechanism of αCD117 mAb-mediated HSC depletion. Further, they highlight multiple approaches for efficacy in SCID settings and optimal combinations for WT settings. This work is likely to aid in the development of clinical non-genotoxic HSCT conditioning approaches that could benefit millions of people world-wide.
    DOI:  https://doi.org/10.1186/s13287-024-03981-0
  10. Hemasphere. 2024 Nov;8(11): e70037
    GPRASP protein deficiency triggers lymphoproliferative disease by affecting B-cell differentiation.
    Antonio Morales-Hernández, Emilia Kooienga, Heather Sheppard, Gabriela Gheorghe, Claire Caprio, Ashley Chabot, Shannon McKinney-Freeman.
      Gprasp1 and Gprasp2 encode proteins that control the stability and cellular trafficking of CXCR4, a master regulator of hematopoiesis whose dynamic regulation is required for appropriate trafficking of B-cells in the germinal center (GC). Here, we report that Gprasp1 and Gprasp2-deficient B-cells accumulate in the GC and show transcriptional abnormalities, affecting the mechanisms controlling Aicda expression and exposing them to excessive somatic hypermutation. Consequently, about 30% of mice transplanted with Gprasp-deficient hematopoietic stem and progenitor cells developed a biologically aggressive and fatal B-cell hyperproliferative disease by 20-50 weeks posttransplant. Histological and molecular profiling reveal that Gprasp1- and Gprasp2-deficient neoplasms morphologically resemble human high-grade B-cell lymphomas of germinal center origin with shared morphologic features of both Burkitt Lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), and molecular features consistent with DLBCL, as well as elevated mutational burden and heterogenous transcriptional and mutational signature. Thus, reduced Gprasp1 and Gprasp2 gene expression perturbs B-cell maturation and increases the risk of B-cell neoplasms of germinal center origin. As this model recapitulates the essential features of the heterogenous group of human hematopoietic malignancies, it could be a powerful tool to interrogate the mechanisms of lymphomagenesis for these cancers.
    DOI:  https://doi.org/10.1002/hem3.70037
  11. Front Oncol. 2024 ;14 1473048
    Characterization of ligand-receptor pair in acute myeloid leukemia: a scoring model for prognosis, therapeutic response, and T cell dysfunction.
    Chunlan Fu, Di Qiu, Mei Zhou, Shaobo Ni, Xin Jin.
       Introduction: The significance of ligand-receptor (LR) pair interactions in the progression of acute myeloid leukemia (AML) has been the focus of numerous studies. However, the relationship between LR pairs and the prognosis of AML, as well as their impact on treatment outcomes, is not fully elucidated.
    Methods: Leveraging data from the TCGA-LAML cohort, we mapped out the LR pair interactions and distinguished specific molecular subtypes, with each displaying distinct biological characteristics. These subtypes exhibited varying mutation landscapes, pathway characteristics, and immune infiltration levels. Further insight into the immune microenvironment among these subtypes revealed disparities in immune cell abundance.
    Results: Notably, one subtype showed a higher prevalence of CD8 T cells and plasma cells, suggesting increased adaptive immune activities. Leveraging a multivariate Lasso regression, we formulated an LR pair-based scoring model, termed "LR.score," to classify patients based on prognostic risk. Our findings underscored the association between elevated LR scores and T-cell dysfunction in AML. This connection highlights the LR score's potential as both a prognostic marker and a guide for personalized therapeutic interventions. Moreover, our LR.score revealed substantial survival prediction capacities in an independent AML cohort. We highlighted CLEC11A, ICAM4, ITGA4, and AVP as notably AML-specific.
    Discussion: qRT-PCR analysis on AML versus normal bone marrow samples confirmed the significant downregulation of CLEC11A, ITGA4, ICAM4, and AVP in AML, suggesting their inverse biomarker potential in AML. In summary, this study illuminates the significance of the LR pair network in predicting AML prognosis, offering avenues for more precise treatment strategies tailored to individual patient profiles.
    Keywords:  Acute Myeloid Leukemia; Ligand-receptor; T cell; prognosis; therapeutic response
    DOI:  https://doi.org/10.3389/fonc.2024.1473048
  12. Exp Hematol. 2024 Oct 23. pii: S0301-472X(24)00532-0. [Epub ahead of print] 104667
    Ever-evolving insights into the cellular and molecular drivers of lymphoid cell development.
    Vu L Tran, Myriam L R Haltalli, Jingjing Li, Dawn S Lin, Masayuki Yamashita, Shalin H Naik, Ellen V Rothenberg.
      Lymphocytes play a critical role in adaptive immunity and defense mechanisms, but the molecular mechanisms by which hematopoietic stem and progenitor cells differentiate into T and B lymphocytes are not fully established. Pioneer studies identify several transcription factors essential for lymphoid lineage determination. Yet, many questions remain unanswered about how these transcription factors interact with each other and with chromatin at different developmental stages. This interaction regulates a network of genes and proteins, promoting lymphoid lineage differentiation while suppressing other lineages. Throughout this intricate biological process, any genetic or epigenetic interruptions can derail normal differentiation trajectories, potentially leading to various human pathological conditions. Here, we summarize recent advances in understanding lymphoid cell development, which was the focus of the Winter 2024 International Society for Experimental Hematology webinar.
    Keywords:  Notch signaling; early T cell commitment; lymphoid-primed progenitors; transcription factors
    DOI:  https://doi.org/10.1016/j.exphem.2024.104667
  13. Methods Enzymol. 2024 ;pii: S0076-6879(24)00347-1. [Epub ahead of print]706 449-474
    Quantifying mitochondrial protein import by mePRODmt proteomics.
    Süleyman Bozkurt, Bhavesh S Parmar, Christian Münch.
      Mitochondrial protein import is crucial for maintaining cellular health and homeostasis. Disruptions in this process have been linked to various diseases. Traditional methods for studying mitochondrial protein import predominantly focus on individual proteins and lack the dynamic resolution needed to fully appreciate the complexity of mitochondrial proteostasis and protein trafficking. To address these limitations, we developed a technique called mitochondria-specific multiplexed enhanced protein dynamics (mePRODmt). This method is a novel application of the mePROD methodology and utilizes pulsed stable isotope labeling with amino acids in cell culture (pSILAC)-based proteomics approach to study transient mitochondrial protein import. This chapter outlines the mePRODmt protocol, which includes the preparation of heavy SILAC-labeled peptides for boosting overall mitochondrial peptide signals (booster), SILAC labeling of cultured cells under experimental conditions, mitochondria isolation, sample preparation for multiplex proteomics using tandem mass tags (TMT) for isobaric labeling, recommended liquid chromatography-mass spectrometry (LC-MS) settings for reporter ion quantitation and a data analysis pipeline to analyze pSILAC-TMT data.
    Keywords:  Mass spectrometry; Mitochondria; Mitochondrial protein import; Proteomics; SILAC; TMT multiplex; Translation; mePROD; pSILAC
    DOI:  https://doi.org/10.1016/bs.mie.2024.07.017
  14. Cancer Res. 2024 Oct 30.
    The Functional Transcriptomic Landscape Informs Therapeutic Strategies in Multiple Myeloma.
    Praneeth Reddy Sudalagunta, Rafael R Canevarolo, Mark B Meads, Maria Silva, Xiaohong Zhao, Christopher L Cubitt, Samer S Sansil, Gabriel DeAvila, Raghunandan Reddy Alugubelli, Ryan T Bishop, Alexandre Tungesvik, Qi Zhang, Oliver Hampton, Jamie K Teer, Eric A Welsh, Sean J Yoder, Bijal D Shah, Lori Hazlehurst, Robert A Gatenby, Dane R Van Domelen, Yi Chai, Feng Wang, Andrew DeCastro, Amanda M Bloomer, Erin M Siegel, Conor C Lynch, Daniel M Sullivan, Melissa Alsina, Taiga Nishihori, Jason Brayer, John L Cleveland, William Dalton, Christopher J Walker, Yosef Landesman, Rachid Baz, Ariosto S Silva, Kenneth H Shain.
      Several therapeutic agents have been approved for treating multiple myeloma (MM), a cancer of bone marrow resident plasma cells. Predictive biomarkers for drug response could help guide clinical strategies to optimize outcomes. Here, we present an integrated functional genomic analysis of tumor samples from MM patients that were assessed for their ex vivo drug sensitivity to 37 drugs, clinical variables, cytogenetics, mutational profiles, and transcriptomes. This analysis revealed a MM transcriptomic topology that generates "footprints" in association with ex vivo drug sensitivity that have both predictive and mechanistic applications. Validation of the transcriptomic footprints for the anti-CD38 monoclonal antibody daratumumab and the nuclear export inhibitor selinexor demonstrated that these footprints can accurately classify clinical responses. The analysis further revealed that daratumumab and selinexor have anti-correlated mechanisms of resistance, and treatment with a selinexor-based regimen immediately after a daratumumab-containing regimen was associated with improved survival in three independent clinical trials, supporting an evolutionary-based strategy involving sequential therapy. These findings suggest that this unique repository and computational framework can be leveraged to inform underlying biology and to identify therapeutic strategies to improve treatment of MM.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-0886
  15. Biomedicines. 2024 Oct 11. pii: 2306. [Epub ahead of print]12(10):
    Macrophages as Potential Therapeutic Targets in Acute Myeloid Leukemia.
    Oana Mesaros, Madalina Onciul, Emilia Matei, Corina Joldes, Laura Jimbu, Alexandra Neaga, Oana Serban, Mihnea Zdrenghea, Ana Maria Nanut.
      Acute myeloid leukemia (AML) is a heterogenous malignant hemopathy, and although new drugs have emerged recently, current treatment options still show limited efficacy. Therapy resistance remains a major concern due to its contribution to treatment failure, disease relapse, and increased mortality among patients. The underlying mechanisms of resistance to therapy are not fully understood, and it is crucial to address this challenge to improve therapy. Macrophages are immune cells found within the bone marrow microenvironment (BMME), of critical importance for leukemia development and progression. One defining feature of macrophages is their plasticity, which allows them to adapt to the variations in the microenvironment. While this adaptability is advantageous during wound healing, it can also be exploited in cancer scenarios. Thus, clinical and preclinical investigations that target macrophages as a therapeutic strategy appear promising. Existing research indicates that targeting macrophages could enhance the effectiveness of current AML treatments. This review addresses the importance of macrophages as therapeutic targets including relevant drugs investigated in clinical trials such as pexidartinib, magrolimab or bexmarilimab, but also provides new insights into lesser-known therapies, like macrophage receptor with a collagenous structure (MACRO) inhibitors and Toll-like receptor (TLR) agonists.
    Keywords:  acute myeloid leukemia; leukemia-associated macrophages; therapeutic targets; tumor-associated macrophages
    DOI:  https://doi.org/10.3390/biomedicines12102306
  16. Nature. 2024 Oct 30.
    RAS-mutant leukaemia stem cells drive clinical resistance to venetoclax.
    Junya Sango, Saul Carcamo, Maria Sirenko, Abhishek Maiti, Hager Mansour, Gulay Ulukaya, Lewis E Tomalin, Nataly Cruz-Rodriguez, Tiansu Wang, Malgorzata Olszewska, Emmanuel Olivier, Manon Jaud, Bettina Nadorp, Benjamin Kroger, Feng Hu, Lewis Silverman, Stephen S Chung, Elvin Wagenblast, Ronan Chaligne, Ann-Kathrin Eisfeld, Deniz Demircioglu, Dan A Landau, Piro Lito, Elli Papaemmanuil, Courtney D DiNardo, Dan Hasson, Marina Konopleva, Eirini P Papapetrou.
      Cancer driver mutations often show distinct temporal acquisition patterns, but the biological basis for this, if any, remains unknown. RAS mutations occur invariably late in the course of acute myeloid leukaemia, upon progression or relapsed/refractory disease1-6. Here, by using human leukaemogenesis models, we first show that RAS mutations are obligatory late events that need to succeed earlier cooperating mutations. We provide the mechanistic explanation for this in a requirement for mutant RAS to specifically transform committed progenitors of the myelomonocytic lineage (granulocyte-monocyte progenitors) harbouring previously acquired driver mutations, showing that advanced leukaemic clones can originate from a different cell type in the haematopoietic hierarchy than ancestral clones. Furthermore, we demonstrate that RAS-mutant leukaemia stem cells (LSCs) give rise to monocytic disease, as observed frequently in patients with poor responses to treatment with the BCL2 inhibitor venetoclax. We show that this is because RAS-mutant LSCs, in contrast to RAS-wild-type LSCs, have altered BCL2 family gene expression and are resistant to venetoclax, driving clinical resistance and relapse with monocytic features. Our findings demonstrate that a specific genetic driver shapes the non-genetic cellular hierarchy of acute myeloid leukaemia by imposing a specific LSC target cell restriction and critically affects therapeutic outcomes in patients.
    DOI:  https://doi.org/10.1038/s41586-024-08137-x
  17. Leukemia. 2024 Oct 29.
    Comparative small molecule screening of primary human acute leukemias, engineered human leukemia and leukemia cell lines.
    Safia Safa-Tahar-Henni, Karla Páez Martinez, Verena Gress, Nayeli Esparza, Élodie Roques, Florence Bonnet-Magnaval, Mélanie Bilodeau, Valérie Gagné, Eva Bresson, Sophie Cardin, Nehme El-Hachem, Isabella Iasenza, Gabriel Alzial, Isabel Boivin, Naoto Nakamichi, Anne-Cécile Soufflet, Cristina Mirela Pascariu, Jean Duchaine, Simon Mathien, Éric Bonneil, Kolja Eppert, Anne Marinier, Guy Sauvageau, Geneviève Deblois, Pierre Thibault, Josée Hébert, Connie J Eaves, Sonia Cellot, Frédéric Barabé, Brian T Wilhelm.
      Targeted therapeutics for high-risk cancers remain an unmet medical need. Here we report the results of a large-scale screen of over 11,000 molecules for their ability to inhibit the survival and growth in vitro of human leukemic cells from multiple sources including patient samples, de novo generated human leukemia models, and established human leukemic cell lines. The responses of cells from de novo models were most similar to those of patient samples, both of which showed striking differences from the cell-line responses. Analysis of differences in subtype-specific therapeutic vulnerabilities made possible by the scale of this screen enabled the identification of new specific modulators of apoptosis, while also highlighting the complex polypharmacology of anti-leukemic small molecules such as shikonin. These findings introduce a new platform for uncovering new therapeutic options for high-risk human leukemia, in addition to reinforcing the importance of the test sample choice for effective drug discovery.
    DOI:  https://doi.org/10.1038/s41375-024-02400-w
  18. Front Immunol. 2024 ;15 1444821
    Type I-conventional dendritic cells support the progression of multiple myeloma in the bone marrow.
    Sayaka Suzuki, Kazuma Komiya, Shogo Tsuda, Miya Yoshino, Tsuneyasu Kaisho, P Leif Bergsagel, Koji Kawamura, Tetsuya Fukuda, Koji Tokoyoda.
       Purpose: Type I conventional dendritic cells (cDC1s) play a key role in priming anti-tumor cytotoxic T cells and inducing immune tolerance for self-antigens and tumor antigens. However, it remains unclear whether cDC1 has a protective or pathogenic role in multiple myeloma. We investigated a role of cDC1 in myeloma progression.
    Methods: A myeloma mouse model was performed by intravenous transplantation of Vk*MYC myeloma cells into XCR1-Diphtheria toxin receptor (DTR) knock-in or wild-type mice. Following injection with Diphtheria toxin (DT), monoclonal (M)-proteins and myeloma cells were analyzed by ELISA and flow cytometry.
    Results: Here we show that inducible depletion of cDC1 after myeloma transplantation markedly suppressed the progression of myeloma in the bone marrow and extramedullary sites, such as the spleen. cDC1 appeared in the bone marrow and spleen of myeloma-transplanted mice, which highly expressed CD103 and lowly produced interleukin (IL)-12. Consequently, the frequencies of exhausted CD8 T cells and regulatory T cells significantly decreased in the bone marrow of cDC1-depleted mice.
    Conclusions: cDC1 supports the progression of myeloma inducing exhausted CD8 T cells and regulatory T cells.
    Keywords:  CD103; bone marrow; conventional dendritic cell; multiple myeloma; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1444821
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