bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2024–06–30
28 papers selected by
William Grey, University of York
  1. IL-9 Secreted by Leukemia Stem Cells Induces Th1-Skewed CD4+ T-Cells, which Promote Their Expansion.
  2. Protocol to construct humanized mice with adult CD34+ hematopoietic stem and progenitor cells.
  3. BF170 hydrochloride enhances the emergence of hematopoietic stem and progenitor cells.
  4. Reprogramming of RNA m6A Modification Is Required for Acute Myeloid Leukemia Development.
  5. Chronic TNF in the aging microenvironment exacerbates Tet2-loss-of-function myeloid expansion.
  6. Serglycin controls megakaryocyte retention of platelet factor 4 and influences megakaryocyte fate in bone marrow.
  7. Imaging Flow Cytometry and Convolutional Neural Network-Based Classification Enable Discrimination of Hematopoietic and Leukemic Stem Cells in Acute Myeloid Leukemia.
  8. Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging.
  9. Utilizing Epigenetic Regulators to improve HSC-based lentiviral gene therapy.
  10. Leukemic Stem Cells and Hematological Malignancies.
  11. The landscape of RNA-chromatin interaction reveals small non-coding RNAs as essential mediators of leukemia maintenance.
  12. Slow-replicating leukemia cells represent a leukemia stem cell population with high cell-surface CD74 expression.
  13. G2 arrest primes hematopoietic stem cells for megakaryopoiesis.
  14. Lysosomal acid lipase A modulates leukemia stem cell response to venetoclax/tyrosine kinase inhibitor combination therapy in blast phase chronic myeloid leukemia.
  15. Revitalizing the Aging Immune System Through Selective Stem Cell Targeting.
  16. Identification of ubiquitination-related hub genes in chronic myeloid leukemia cell by bioinformatics analysis.
  17. Cancer stem cell mimicry for immune evasion and therapeutic resistance.
  18. TRIM26 deficiency enhancing liver regeneration through macrophage polarization and β-catenin pathway activation.
  19. Oncogene induced TIM-3 ligand expression dictates susceptibility to anti-TIM-3 therapy in mice.
  20. DDX41 haploinsufficiency causes inefficient hematopoiesis under stress and cooperates with p53 mutations to cause hematologic malignancy.
  21. CAR-T Cells in Acute Myeloid Leukemia: Where Do We Stand?
  22. Alkylamine-tethered molecules recruit FBXO22 for targeted protein degradation.
  23. Importance of PTM of FLT3 in acute myeloid leukemia.
  24. The proteogenomic landscape of multiple myeloma reveals insights into disease biology and therapeutic opportunities.
  25. The extracellular matrix integrates mitochondrial homeostasis.
  26. A newly identified gene Ahed plays essential roles in murine haematopoiesis.
  27. Intensive Induction Chemotherapy versus Hypomethylating Agents in Combination with Venetoclax in NPM1-mutant AML.
  28. Advancements in Hematopoietic Stem Cell Gene Therapy: A Journey of Progress for Viral Transduction.
  1. Blood. 2024 Jun 28. pii: blood.2024024000. [Epub ahead of print]
    IL-9 Secreted by Leukemia Stem Cells Induces Th1-Skewed CD4+ T-Cells, which Promote Their Expansion.
    Ramin Radpour, Cedric Simillion, Bofei Wang, Hussein A Abbas, Carsten Riether, Adrian Franz Ochsenbein.
      In acute myeloid leukemia (AML), leukemia stem and progenitor cells (LSCs and LPCs) interact with various cell types in the bone marrow (BM) microenvironment, regulating their expansion and differentiation. To study the interaction of CD4+ and CD8+ T-cells in the BM with LSCs and LPCs, we analyzed their transcriptome and predicted cell-cell interactions by unbiased high-throughput correlation network analysis. We found that CD4+ T-cells in the BM of AML patients were activated and skewed towards Th1-polarization whereas IL-9 producing (Th9) CD4+ T-cells were absent. In contrast to normal hematopoietic stem cells (HSCs), LSCs produced IL-9 and the correlation modelling predicted IL9 in LSCs as a main hub-gene that activates CD4+ T-cells in AML. Functional validation revealed that IL-9R signaling in CD4+ T-cells leads to activation of the JAK-STAT pathway that induces the upregulation of KMT2A, KMT2C genes resulting in methylation on histone H3 at lysine 4 (H3K4) to promote genome accessibility and transcriptional activation. This induced Th1-skewing, proliferation and effector cytokine secretion, including interferon (IFN)-ɣ and tumor necrosis factor (TNF)-α. IFN-ɣ and to a lesser extend TNF-α produced by activated CD4+ T-cells, induced the expansion of LSCs. In accordance with our findings, high IL9 expression in LSCs and high IL9R, TNF and IFNG expression in BM-infiltrating CD4+ T-cells correlated with worse overall survival in AML. Thus, IL-9 secreted by AML LSCs shapes a Th1-skewed immune environment that promotes their expansion by secreting IFN-ɣ and TNF-α.
    DOI:  https://doi.org/10.1182/blood.2024024000
  2. STAR Protoc. 2024 Jun 26. pii: S2666-1667(24)00320-4. [Epub ahead of print]5(3): 103155
    Protocol to construct humanized mice with adult CD34+ hematopoietic stem and progenitor cells.
    Chun I Yu, Rick Maser, Florentina Marches, Jacques Banchereau, Karolina Palucka.
      Humanized mice, defined as mice with human immune systems, have become an emerging model to study human hematopoiesis, infectious disease, and cancer. Here, we describe the techniques to generate humanized NSGF6 mice using adult human CD34+ hematopoietic stem and progenitor cells (HSPCs). We describe steps for constructing and monitoring the engraftment of humanized mice. We then detail procedures for tissue processing and immunophenotyping by flow cytometry to evaluate the multilineage hematopoietic differentiation. For complete details on the use and execution of this protocol, please refer to Yu et al.1.
    Keywords:  Flow Cytometry; Immunology; Model Organisms
    DOI:  https://doi.org/10.1016/j.xpro.2024.103155
  3. Development. 2024 Jul 01. pii: dev202476. [Epub ahead of print]151(13):
    BF170 hydrochloride enhances the emergence of hematopoietic stem and progenitor cells.
    WenYe Liu, YuYan Ding, Zheng Shen, Cong Xu, William Yi, Ding Wang, Yi Zhou, Leonard I Zon, Jing-Xia Liu.
      Generation of hematopoietic stem and progenitor cells (HSPCs) ex vivo and in vivo, especially the generation of safe therapeutic HSPCs, still remains inefficient. In this study, we have identified compound BF170 hydrochloride as a previously unreported pro-hematopoiesis molecule, using the differentiation assays of primary zebrafish blastomere cell culture and mouse embryoid bodies (EBs), and we demonstrate that BF170 hydrochloride promoted definitive hematopoiesis in vivo. During zebrafish definitive hematopoiesis, BF170 hydrochloride increases blood flow, expands hemogenic endothelium (HE) cells and promotes HSPC emergence. Mechanistically, the primary cilia-Ca2+-Notch/NO signaling pathway, which is downstream of the blood flow, mediated the effects of BF170 hydrochloride on HSPC induction in vivo. Our findings, for the first time, reveal that BF170 hydrochloride is a compound that enhances HSPC induction and may be applied to the ex vivo expansion of HSPCs.
    Keywords:  BF170 hydrochloride; Blood flow; Ca2+; HSPCs; Notch/NO; Primary cilia
    DOI:  https://doi.org/10.1242/dev.202476
  4. Genomics Proteomics Bioinformatics. 2024 Jun 24. pii: qzae049. [Epub ahead of print]
    Reprogramming of RNA m6A Modification Is Required for Acute Myeloid Leukemia Development.
    Weidong Liu, Yuhua Wang, Shuxin Yao, Guoqiang Han, Jin Hu, Rong Yin, Fuling Zhou, Ying Cheng, Haojian Zhang.
      Hematopoietic homeostasis is maintained by hematopoietic stem cells (HSCs), and it is tightly controlled at multiple levels to sustain the self-renewal capacity and differentiation potential of HSCs. Dysregulation of self-renewal and differentiation of HSCs leads to the development of hematologic diseases, including acute myeloid leukemia (AML). Thus, understanding the underlying mechanisms of HSC maintenance and the development of hematologic malignancies is one of the fundamental scientific endeavors in stem cell biology. N  6-methyladenosine (m6A) is a common modification in mammalian messenger RNAs (mRNAs) and plays important roles in various biological processes. In this study, we performed a comparative analysis of the dynamics of the RNA m6A methylome of hematopoietic stem and progenitor cells (HSPCs) and leukemia-initiating cells (LICs) in AML. We found that RNA m6A modification regulates the transformation of long-term HSCs into short-term HSCs and determines the lineage commitment of HSCs. Interestingly, m6A modification leads to reprogramming that promotes cellular transformation during AML development, and LIC-specific m6A targets are recognized by different m6A readers. Moreover, the very long chain fatty acid transporter ATP-binding cassette subfamily D member 2 (ABCD2) is a key factor that promotes AML development, and deletion of ABCD2 damages clonogenic ability, inhibits proliferation, and promotes apoptosis of human leukemia cells. This study provides a comprehensive understanding of the role of m6A in regulating cell state transition in normal hematopoiesis and leukemogenesis, and identifies ABCD2 as a key factor in AML development.
    Keywords:  ATP-binding cassette subfamily D member 2; Acute myeloid leukemia; Hematopoiesis; Leukemia initiating cells; RNA m6A modification
    DOI:  https://doi.org/10.1093/gpbjnl/qzae049
  5. Blood Adv. 2024 Jun 26. pii: bloodadvances.2023011833. [Epub ahead of print]
    Chronic TNF in the aging microenvironment exacerbates Tet2-loss-of-function myeloid expansion.
    Candice Quin, Erica N DeJong, Amy Jm McNaughton, Marco M Buttigieg, Salman Basrai, Sagi Abelson, Margaret Larche, Michael J Rauh, Dawn Me Bowdish.
      Somatic mutations in the TET2 gene occur more frequently with age, imparting an intrinsic hematopoietic stem cell (HSC) advantage and contributing to a phenomenon termed clonal hematopoiesis of indeterminate potential (CHIP). Individuals with TET2-mutant CHIP have a higher risk of developing myeloid neoplasms and other aging-related conditions. Despite its role in unhealthy aging, the extrinsic mechanisms driving TET2-mutant CHIP clonal expansion remain unclear. We previously showed an environment containing TNF favours TET2-mutant HSC expansion in vitro. We therefore postulated that age-related increases in TNF also provide an advantage to HSCs with TET2-mutations in vivo. To test this hypothesis, we generated mixed bone marrow chimeric mice of old wild-type (WT) and TNF-/- genotypes reconstituted with WT CD45.1+ and Tet2-/-CD45.2+ HSCs. We show that age-associated increases in TNF dramatically increased the expansion of Tet2-/-cells in old WT recipient mice, with strong skewing towards the myeloid lineage. This aberrant myelomonocytic advantage was mitigated in old TNF-/- recipient mice, suggesting that TNF signalling is essential for the expansion Tet2-mutant myeloid clones. Examination of human rheumatoid arthritis patients with clonal hematopoiesis revealed that hematopoietic cells carrying certain mutations, including in TET2, may be sensitive to reduced TNF bioactivity following blockade with adalimumab. This suggests that targeting TNF may reduce the burden of some forms of CHIP. To our knowledge, this is the first evidence to demonstrate that TNF has a causal role in driving TET2-mutant CHIP in vivo. These findings highlight TNF as a candidate therapeutic target to control TET2-mutant CHIP.
    DOI:  https://doi.org/10.1182/bloodadvances.2023011833
  6. Blood Adv. 2024 Jun 28. pii: bloodadvances.2024012995. [Epub ahead of print]
    Serglycin controls megakaryocyte retention of platelet factor 4 and influences megakaryocyte fate in bone marrow.
    Joshua T Lykins, Isabelle C Becker, Virginia Camacho, Hammodah R Alfar, JoonWoo Park, Joseph E Italiano, Sidney W Whiteheart.
      Megakaryocytes (MKs) produce platelets, and like other hematopoietic progenitors they are involved in homeostatic aspects of their bone marrow niche. MKs release and endocytose various factors, such as platelet factor 4 (PF4/CXCL4). Here we show that the intra-α-granular proteoglycan, serglycin (SRGN) plays a key role in this process by retaining PF4 and perhaps other factors during MK maturation. Immature, SRGN-/- MKs released ~80% of their PF4 and conditioned media from these cells negatively affected wild-type MK differentiation in vitro. This was replicated in wild-type MKs, by treatment with the polycation surfen, a known inhibitor of glycosaminoglycan/protein interactions. In vivo, SRGN-/- mice had an interstitial accumulation of PF4, TGFβ-1, IL-1β, and TNF-α in their bone marrow and increased numbers of immature MKs, consistent with their mild thrombocytopenia. SRGN-/- mice also had reduced numbers of hematopoietic stem cells and multipotent progenitors, reduced laminin, and increased collagen I deposition. These findings demonstrate that MKs depend on SRGN and its charged glycosaminoglycans to balance the distribution of PF4 and perhaps other factors between their α-granules and their adjacent extracellular spaces. Disrupting this balance negatively affects MK development and bone marrow microenvironment homeostasis.
    DOI:  https://doi.org/10.1182/bloodadvances.2024012995
  7. Int J Mol Sci. 2024 Jun 12. pii: 6465. [Epub ahead of print]25(12):
    Imaging Flow Cytometry and Convolutional Neural Network-Based Classification Enable Discrimination of Hematopoietic and Leukemic Stem Cells in Acute Myeloid Leukemia.
    Trine Engelbrecht Hybel, Sofie Hesselberg Jensen, Matthew A Rodrigues, Thomas Engelbrecht Hybel, Maya Nautrup Pedersen, Signe Håkansson Qvick, Marie Hairing Enemark, Marie Bill, Carina Agerbo Rosenberg, Maja Ludvigsen.
      Acute myeloid leukemia (AML) is a heterogenous blood cancer with a dismal prognosis. It emanates from leukemic stem cells (LSCs) arising from the genetic transformation of hematopoietic stem cells (HSCs). LSCs hold prognostic value, but their molecular and immunophenotypic heterogeneity poses challenges: there is no single marker for identifying all LSCs across AML samples. We hypothesized that imaging flow cytometry (IFC) paired with artificial intelligence-driven image analysis could visually distinguish LSCs from HSCs based solely on morphology. Initially, a seven-color IFC panel was employed to immunophenotypically identify LSCs and HSCs in bone marrow samples from five AML patients and ten healthy donors, respectively. Next, we developed convolutional neural network (CNN) models for HSC-LSC discrimination using brightfield (BF), side scatter (SSC), and DNA images. Classification using only BF images achieved 86.96% accuracy, indicating significant morphological differences. Accuracy increased to 93.42% when combining BF with DNA images, highlighting differences in nuclear morphology, although DNA images alone were inadequate for accurate HSC-LSC discrimination. Model development using SSC images revealed minor granularity differences. Performance metrics varied substantially between AML patients, indicating considerable morphologic variations among LSCs. Overall, we demonstrate proof-of-concept results for accurate CNN-based HSC-LSC differentiation, instigating the development of a novel technique within AML monitoring.
    Keywords:  acute myeloid leukemia; artificial intelligence; convolutional neural network; deep learning; hematopoietic stem cells; imaging flow cytometry; leukemic stem cells
    DOI:  https://doi.org/10.3390/ijms25126465
  8. Cell Stem Cell. 2024 Jun 19. pii: S1934-5909(24)00207-8. [Epub ahead of print]
    Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging.
    Niels Asger Jakobsen, Sven Turkalj, Andy G X Zeng, Bilyana Stoilova, Marlen Metzner, Susann Rahmig, Murtaza S Nagree, Sayyam Shah, Rachel Moore, Batchimeg Usukhbayar, Mirian Angulo Salazar, Grigore-Aristide Gafencu, Alison Kennedy, Simon Newman, Benjamin J L Kendrick, Adrian H Taylor, Rasheed Afinowi-Luitz, Roger Gundle, Bridget Watkins, Kim Wheway, Debra Beazley, Alex Murison, Alicia G Aguilar-Navarro, Eugenia Flores-Figueroa, Stephanie G Dakin, Andrew J Carr, Claus Nerlov, John E Dick, Stephanie Z Xie, Paresh Vyas.
      Clonal hematopoiesis (CH) arises when hematopoietic stem cells (HSCs) acquire mutations, most frequently in the DNMT3A and TET2 genes, conferring a competitive advantage through mechanisms that remain unclear. To gain insight into how CH mutations enable gradual clonal expansion, we used single-cell multi-omics with high-fidelity genotyping on human CH bone marrow (BM) samples. Most of the selective advantage of mutant cells occurs within HSCs. DNMT3A- and TET2-mutant clones expand further in early progenitors, while TET2 mutations accelerate myeloid maturation in a dose-dependent manner. Unexpectedly, both mutant and non-mutant HSCs from CH samples are enriched for inflammatory and aging transcriptomic signatures, compared with HSCs from non-CH samples, revealing a non-cell-autonomous effect. However, DNMT3A- and TET2-mutant HSCs have an attenuated inflammatory response relative to wild-type HSCs within the same sample. Our data support a model whereby CH clones are gradually selected because they are resistant to the deleterious impact of inflammation and aging.
    Keywords:  DNMT3A; TET2; aging; clonal competition; clonal hematopoiesis; hematopoietic stem cells; single-cell RNA-seq; single-cell genomics; somatic mosaicism
    DOI:  https://doi.org/10.1016/j.stem.2024.05.010
  9. Blood Adv. 2024 Jun 25. pii: bloodadvances.2024013047. [Epub ahead of print]
    Utilizing Epigenetic Regulators to improve HSC-based lentiviral gene therapy.
    Parisa Tajer, Emin Onur Karakaslar, Kirsten Canté-Barrett, Brigitta Naber, Sandra Vloemans, Marja van Eggermond, Marie-Louise van der Hoorn, Erik B van den Akker, Karin Pike-Overzet, Frank Jt Staal.
      Curative benefits of autologous and allogeneic transplantation of hematopoietic stem cells (HSCs) have been proven for various diseases. However, the low number of true HSCs that can be collected from patients and subsequently in vitro maintenance and expansion of true HSCs for genetic correction remain challenging. Addressing this issue, we here focused on optimizing culture conditions to improve the ex vivo expansion of true HSCs for gene therapy purposes. In particular, we explore the use of epigenetic regulators to enhance the effectiveness of HSC-based lentiviral (LV) gene therapy. The HDAC inhibitor Quisinostat and the bromodomain inhibitor CPI203 each promote ex vivo expansion of functional HSCs, as validated by xenotransplantation assays and single cell RNA-sequencing analysis. We confirmed the stealth effect of LV transduction on the loss of HSC numbers in commonly used culture protocols, while addition of Quisinostat or CPI203 improved expansion of HSCs in transduction protocols. Of note, we demonstrated that addition of Quisinostat improved LV transduction efficiency of HSCs and early progenitors. Our suggested culture conditions highlight the potential therapeutic effect of epigenetic regulators in hematopoietic stem cell biology and their clinical applications to advance HSC-based gene correction.
    DOI:  https://doi.org/10.1182/bloodadvances.2024013047
  10. Int J Mol Sci. 2024 Jun 17. pii: 6639. [Epub ahead of print]25(12):
    Leukemic Stem Cells and Hematological Malignancies.
    Hee-Seon Choi, Byoung Soo Kim, Sik Yoon, Sae-Ock Oh, Dongjun Lee.
      The association between leukemic stem cells (LSCs) and leukemia development has been widely established in the context of genetic alterations, epigenetic pathways, and signaling pathway regulation. Hematopoietic stem cells are at the top of the bone marrow hierarchy and can self-renew and progressively generate blood and immune cells. The microenvironment, niche cells, and complex signaling pathways that regulate them acquire genetic mutations and epigenetic alterations due to aging, a chronic inflammatory environment, stress, and cancer, resulting in hematopoietic stem cell dysregulation and the production of abnormal blood and immune cells, leading to hematological malignancies and blood cancer. Cells that acquire these mutations grow at a faster rate than other cells and induce clone expansion. Excessive growth leads to the development of blood cancers. Standard therapy targets blast cells, which proliferate rapidly; however, LSCs that can induce disease recurrence remain after treatment, leading to recurrence and poor prognosis. To overcome these limitations, researchers have focused on the characteristics and signaling systems of LSCs and therapies that target them to block LSCs. This review aims to provide a comprehensive understanding of the types of hematopoietic malignancies, the characteristics of leukemic stem cells that cause them, the mechanisms by which these cells acquire chemotherapy resistance, and the therapies targeting these mechanisms.
    Keywords:  hematological malignancy; hematopoietic stem cell; leukemia; leukemic stem cell
    DOI:  https://doi.org/10.3390/ijms25126639
  11. Leukemia. 2024 Jun 28.
    The landscape of RNA-chromatin interaction reveals small non-coding RNAs as essential mediators of leukemia maintenance.
    Haiyang Yun, Julian Zoller, Fengbiao Zhou, Christian Rohde, Yi Liu, Maximilian Felix Blank, Stefanie Göllner, Carsten Müller-Tidow.
      RNA constitutes a large fraction of chromatin. Spatial distribution and functional relevance of most of RNA-chromatin interactions remain unknown. We established a landscape analysis of RNA-chromatin interactions in human acute myeloid leukemia (AML). In total more than 50 million interactions were captured in an AML cell line. Protein-coding mRNAs and long non-coding RNAs exhibited a substantial number of interactions with chromatin in cis suggesting transcriptional activity. In contrast, small nucleolar RNAs (snoRNAs) and small nuclear RNAs (snRNAs) associated with chromatin predominantly in trans suggesting chromatin specific functions. Of note, snoRNA-chromatin interaction was associated with chromatin modifications and occurred independently of the classical snoRNA-RNP complex. Two C/D box snoRNAs, namely SNORD118 and SNORD3A, displayed high frequency of trans-association with chromatin. The transcription of SNORD118 and SNORD3A was increased upon leukemia transformation and enriched in leukemia stem cells, but decreased during myeloid differentiation. Suppression of SNORD118 and SNORD3A impaired leukemia cell proliferation and colony forming capacity in AML cell lines and primary patient samples. Notably, this effect was leukemia specific with less impact on healthy CD34+ hematopoietic stem and progenitor cells. These findings highlight the functional importance of chromatin-associated RNAs overall and in particular of SNORD118 and SNORD3A in maintaining leukemia propagation.
    DOI:  https://doi.org/10.1038/s41375-024-02322-7
  12. Mol Oncol. 2024 Jun 22.
    Slow-replicating leukemia cells represent a leukemia stem cell population with high cell-surface CD74 expression.
    Huan Li, Zhijie Cao, Yiming Liu, Zhenya Xue, Yishuang Li, Haiyan Xing, Yingxi Xu, Runxia Gu, Shaowei Qiu, Hui Wei, Min Wang, Qing Rao, Jianxiang Wang.
      Persistence of quiescent leukemia stem cells (LSCs) after treatment most likely contributes to chemotherapy resistance and poor prognosis of leukemia patients. Identification of this quiescent cell population would facilitate eradicating LSCs. Here, using a cell-tracing PKH26 (PKH) dye that can be equally distributed to daughter cells following cell division in vivo, we identify a label-retaining slow-cycling leukemia cell population from AML1-ETO9a (AE9a) leukemic mice. We find that, compared with cells not maintaining PKH-staining, a higher proportion of PKH-retaining cells are in G0 phase, and PKH-retaining cells exhibit increased colony formation ability and leukemia initiation potential. In addition, PKH-retaining cells possess high chemo-resistance and are more likely to be localized to the endosteal bone marrow region. Based on the transcriptional signature, HLA class II histocompatibility antigen gamma chain (Cd74) is highly expressed in PKH-retaining leukemia cells. Furthermore, cell surface CD74 was identified to be highly expressed in LSCs of AE9a mice and CD34+ human leukemia cells. Compared to Lin-CD74- leukemia cells, Lin-CD74+ leukemia cells of AE9a mice exhibit higher stemness properties. Collectively, our findings reveal that the identified slow-cycling leukemia cell population represents an LSC population, and CD74+ leukemia cells possess stemness properties, suggesting that CD74 is a candidate LSC surface marker.
    Keywords:  CD74; acute myeloid leukemia; chemotherapy resistance; leukemia stem cell; quiescence; self‐renewal
    DOI:  https://doi.org/10.1002/1878-0261.13690
  13. Cell Rep. 2024 Jun 26. pii: S2211-1247(24)00716-2. [Epub ahead of print]43(7): 114388
    G2 arrest primes hematopoietic stem cells for megakaryopoiesis.
    Corey M Garyn, Oriol Bover, John W Murray, Jing Ma, Karen Salas-Briceno, Susan R Ross, Hans-Willem Snoeck.
      In contrast to most hematopoietic lineages, megakaryocytes (MKs) can derive rapidly and directly from hematopoietic stem cells (HSCs). The underlying mechanism is unclear, however. Here, we show that DNA damage induces MK markers in HSCs and that G2 arrest, an integral part of the DNA damage response, suffices for MK priming followed by irreversible MK differentiation in HSCs, but not in progenitors. We also show that replication stress causes DNA damage in HSCs and is at least in part due to uracil misincorporation in vitro and in vivo. Consistent with this notion, thymidine attenuated DNA damage, improved HSC maintenance, and reduced the generation of CD41+ MK-committed HSCs. Replication stress and concomitant MK differentiation is therefore one of the barriers to HSC maintenance. DNA damage-induced MK priming may allow rapid generation of a lineage essential to immediate organismal survival, while also removing damaged cells from the HSC pool.
    Keywords:  CP: Molecular biology; CP: Stem cell research; DNA damage; G2-arrest; direct megakarypoiesis; hematopoietic stem cells; hyperploidy; megakaryocytes
    DOI:  https://doi.org/10.1016/j.celrep.2024.114388
  14. Haematologica. 2024 Jun 27.
    Lysosomal acid lipase A modulates leukemia stem cell response to venetoclax/tyrosine kinase inhibitor combination therapy in blast phase chronic myeloid leukemia.
    Mohd Minhajuddin, Amanda Winters, Haobin Ye, Shanshan Pei, Brett Stevens, Austin Gillen, Krysta Engel, Stephanie Gipson, Monica Ransom, Maria Amaya, Anagha Inguva, Maura Gasparetto, Mark J Althoff, Regan Miller, Ian Shelton, Hunter Tolison, Anna Krug, Rachel Culp-Hill, Angelo D'Alessandro, Daniel W Sherbenou, Daniel A Pollyea, Clayton Smith, Craig T Jordan.
      The treatment of blast phase chronic myeloid leukemia (bpCML) remains a challenge due at least in part to drug resistance of leukemia stem cells (LSCs). Recent clinical evidence suggests that the BCL-2 inhibitor venetoclax in combination with ABL-targeting tyrosine kinase inhibitors (TKIs) can eradicate bpCML LSCs. In this report, we employed preclinical models of bpCML to investigate the efficacy and underlying mechanism of LSC-targeting with venetoclax/TKI combinations. Transcriptional analysis of LSCs exposed to venetoclax and dasatinib revealed upregulation of genes involved in lysosomal biology, in particular lysosomal acid lipase A (LIPA), a regulator of free fatty acids. Metabolomic analysis confirmed increased levels of free fatty acids in response to venetoclax/dasatinib. Pre-treatment of leukemia cells with bafilomycin, a specific lysosome inhibitor, or genetic perturbation of LIPA, resulted in increased sensitivity of leukemia cells toward venetoclax/dasatinib, implicating LIPA in treatment resistance. Importantly, venetoclax/dasatinib treatment does not affect normal stem cell function, suggestive of a leukemia-specific response. These results demonstrate that venetoclax/dasatinib is an LSCselective regimen in bpCML and that disrupting LIPA and fatty acid transport enhances venetoclax/dasatinib response in targeting LSCs, providing a rationale for exploring lysosomal disruption as an adjunct therapeutic strategy to prolong disease remission.
    DOI:  https://doi.org/10.3324/haematol.2023.284716
  15. Cell Reprogram. 2024 Jun;26(3): 93-95
    Revitalizing the Aging Immune System Through Selective Stem Cell Targeting.
    Anna Konturek-Ciesla, David Bryder.
      The interplay between aging and immune system deterioration presents a formidable challenge to human health, especially in the context of a globally aging population. Aging is associated with a decline in the body's ability to combat infections and an increased risk of various diseases, underlining the importance of rejuvenating the immune system as a strategy for promoting healthier aging. In issue 628 of Nature (2024), Ross et al. present a compelling study that introduces a novel strategy for rejuvenating the aged immune system (Ross et al., 2024). By using antibodies to selectively eliminate "aberrant" hematopoietic stem cells (HSCs), this research opens new avenues for addressing age-related immune deterioration.
    DOI:  https://doi.org/10.1089/cell.2024.0029
  16. J Cancer. 2024 ;15(12): 3750-3759
    Identification of ubiquitination-related hub genes in chronic myeloid leukemia cell by bioinformatics analysis.
    Qian Zhou, Zhuoran Li, Li Meng, Ying Wang, Muhammad Sameer Ashaq, Yuan Li, Baobing Zhao.
      Purpose: Chronic myeloid leukemia stem cells (CML-LSCs) are posited as the primary instigators of resistance to tyrosine kinase inhibitors (TKIs) and recurrence of CML. Ubiquitination, a post-translational modification, has been implicated in the worsening process of CML. A more detailed understanding of their crosstalk needs further investigation. Our research aims to explore the potential ubiquitination-related genes in CML-LSC using bioinformatics analysis that might be the target for the eradication of LSCs. Methods: The ubiquitination modification-related differentially expressed genes (UUC-DEGs) between normal hematopoietic stem cells (HSCs) and LSCs were obtained from GSE47927 and iUUCD database. Subsequently, the hub UUC-DEGs were identified through protein-protein interaction (PPI) network analysis utilizing the STRING database and the MCODE plug-in within the Cytoscape platform. The upstream regulation network of the hub UUC-DEGs was studied by hTFtarget, PROMO, miRDB and miRWalk databases respectively. Then the correlation between the hub UUC-DEGs and the immune cells was analyzed by the CIBERSORT algorithm and "ggcorrplot" package. Finally, we validated the function of hub UUC-DEGs in CML animal models, CML cell lines and CD34+ cells of the GSE24739 dataset. Results: There is a strong association between the 4 hub UUC genes (AURKA, Fancd2, Cdc20 and Uhrf1) of LSCs and the infiltration of CD4+/CD8+ T cells, NK cells and monocytes. 8 TFs and 23 miRNAs potentially targeted these 4 hub genes were constructed. Among these hub genes, Fancd2, Cdc20 and Uhrf1 were found to be highly expressed in CML-LSC, which knocking down resulted in significant inhibition of CML cell proliferation. Conclusions: From the perspective of bioinformatics analysis, UHRF1 and CDC20 were identified as the novel key ubiquitination-related genes in CML-LSCs and the pathogenesis of CML.
    Keywords:  CDC20; Chronic myeloid leukemia stem cell; FANCD2; UHRF1; Ubiquitination
    DOI:  https://doi.org/10.7150/jca.96405
  17. Cell Stem Cell. 2024 Jun 16. pii: S1934-5909(24)00211-X. [Epub ahead of print]
    Cancer stem cell mimicry for immune evasion and therapeutic resistance.
    Phei Er Saw, Qiang Liu, Ping-Pui Wong, Erwei Song.
      Cancer stem cells (CSCs) are heterogeneous, possess self-renewal attributes, and orchestrate important crosstalk in tumors. We propose that the CSC state represents "mimicry" by cancer cells that leads to phenotypic plasticity. CSC mimicry is suggested as CSCs can impersonate immune cells, vasculo-endothelia, or lymphangiogenic cells to support cancer growth. CSCs facilitate both paracrine and juxtracrine signaling to prime tumor-associated immune and stromal cells to adopt pro-tumoral phenotypes, driving therapeutic resistance. Here, we outline the ingenuity of CSCs' mimicry in their quest to evade immune detection, which leads to immunotherapeutic resistance, and highlight CSC-mimicry-targeted therapeutic strategies for robust immunotherapy.
    Keywords:  cancer stem cells; immunotherapeutic resistance; immunotherapy; mimicry
    DOI:  https://doi.org/10.1016/j.stem.2024.06.003
  18. Cell Death Dis. 2024 Jun 26. 15(6): 453
    TRIM26 deficiency enhancing liver regeneration through macrophage polarization and β-catenin pathway activation.
    Tingting Li, Wei Zhong, Mengqi Li, Zile Shao, Gongye Zhang, Weiwei Wang, Zhixing Gao, Xuemei Tan, Ziyi Xu, Fanghong Luo, Gang Song.
      Liver regeneration is a complex process involving the crosstalk between parenchymal and non-parenchymal cells, especially macrophages. However, the underlying mechanisms remain incompletely understood. Here, we identify the E3 ubiquitin ligase TRIM26 as a crucial regulator of liver regeneration. Following partial hepatectomy or acute liver injury induced by carbon tetrachloride, Trim26 knockout mice exhibit enhanced hepatocyte proliferation compared to wild-type controls, while adeno-associated virus (AAV)-mediated overexpression of Trim26 reverses the promotional effects. Mechanistically, Trim26 deficiency promotes the recruitment of macrophages to the liver and their polarization towards pro-inflammatory M1 phenotype. These M1 macrophages secrete Wnts, including Wnt2, which subsequently stimulate hepatocyte proliferation through the activation of Wnt/β-catenin signaling. In hepatocytes, Trim26 knockdown reduces the ubiquitination and degradation of β-catenin, thereby further enhancing Wnt/β-catenin signaling. Pharmacological inhibition of Wnt/β-catenin pathway by ICG-001 or depletion of macrophages by clodronate liposomes diminishes the pro-regenerative effects of Trim26 deficiency. Moreover, bone marrow transplantation experiments provide evidence that Trim26 knockout in myeloid cells alone can also promote liver regeneration, highlighting the critical role of macrophage Trim26 in this process. Taken together, our study uncovers TRIM26 as a negative regulator of liver regeneration by modulating macrophage polarization and Wnt/β-catenin signaling in hepatocytes, providing a potential therapeutic target for promoting liver regeneration in clinical settings.
    DOI:  https://doi.org/10.1038/s41419-024-06798-0
  19. J Clin Invest. 2024 Jun 25. pii: e177460. [Epub ahead of print]
    Oncogene induced TIM-3 ligand expression dictates susceptibility to anti-TIM-3 therapy in mice.
    Nana Talvard-Balland, Lukas M Braun, Karen O Dixon, Melissa Zwick, Helena Engel, Alina Hartmann, Sandra Duquesne, Livius Penter, Geoffroy Andrieux, Lukas Simon Rindlisbacher, Andrea Acerbis, Jule Ehmann, Christoph Köllerer, Michela Ansuinelli, Andres Rettig, Kevin Moschallski, Petya Apostolova, Tilman Brummer, Anna L Illert, Markus A Schramm, Yurong Cheng, Anna Köttgen, Justus Duyster, Hans D Menssen, Jerome Ritz, Bruce R Blazar, Melanie Boerries, Annette Schmitt Graeff, Nurefsan Sariipek, Peter van Galen, Joerg M Buescher, Nina Cabezas-Wallscheid, Heike L Pahl, Erika L Pearce, Robert J Soiffer, Catherine J Wu, Luca Vago, Burkhard Becher, Natalie Köhler, Tobias Wertheimer, Vijay K Kuchroo, Robert Zeiser.
      Leukemia relapse is a major cause of death after allogeneic hematopoietic cell transplantation (allo-HCT). We tested the potential of targeting TIM-3 for improving graft-versus-leukemia (GVL) effects. We observed differential expression of TIM-3 ligands when hematopoietic stem cells overexpressed certain oncogenic-driver mutations. Anti-TIM-3 Ab-treatment improved survival of mice bearing leukemia with oncogene-induced TIM-3 ligand expression. Conversely, leukemia cells with low ligand expression were anti-TIM-3 treatment-resistant. In vitro, TIM-3 blockade or genetic deletion in CD8+ T cells (Tc) enhanced Tc activation, proliferation and IFN-γ production while enhancing GVL effects, preventing Tc exhaustion and improving Tc cytotoxicity and glycolysis in vivo. Conversely, TIM-3 deletion in myeloid cells did not affect allogeneic Tc proliferation and activation in vitro, suggesting that anti-TIM-3-treatment-mediated GVL effects are Tc-induced. In contrast to anti-PD-1 and anti-CTLA-4-treatment, anti-TIM-3-treatment did not enhance acute graft-versus-host-disease (aGVHD). TIM-3 and its ligands were frequently expressed in acute myeloid leukemia (AML) cells of patients with post-allo-HCT relapse. We deciphered the connection between oncogenic mutations found in AML and TIM-3 ligands expression and identify anti-TIM-3-treatment as a strategy to enhance GVL effects via metabolic and transcriptional Tc-reprogramming, without exacerbation of aGVHD. Our findings support clinical testing of anti-TIM-3 Abs in patients with AML relapse post-allo-HCT.
    Keywords:  Bone marrow transplantation; Transplantation
    DOI:  https://doi.org/10.1172/JCI177460
  20. Leukemia. 2024 Jun 27.
    DDX41 haploinsufficiency causes inefficient hematopoiesis under stress and cooperates with p53 mutations to cause hematologic malignancy.
    Emily Stepanchick, Andrew Wilson, Analise M Sulentic, Kwangmin Choi, Kathleen Hueneman, Daniel T Starczynowski, Timothy M Chlon.
      Germline heterozygous mutations in DDX41 predispose individuals to hematologic malignancies in adulthood. Most of these DDX41 mutations result in a truncated protein, leading to loss of protein function. To investigate the impact of these mutations on hematopoiesis, we generated mice with hematopoietic-specific knockout of one Ddx41 allele. Under normal steady-state conditions, there was minimal effect on lifelong hematopoiesis, resulting in a mild yet persistent reduction in red blood cell counts. However, stress induced by transplantation of the Ddx41+/- BM resulted in hematopoietic stem/progenitor cell (HSPC) defects and onset of hematopoietic failure upon aging. Transcriptomic analysis of HSPC subsets from the transplanted BM revealed activation of cellular stress responses, including upregulation of p53 target genes in erythroid progenitors. To understand how the loss of p53 affects the phenotype of Ddx41+/- HSPCs, we generated mice with combined Ddx41 and Trp53 heterozygous deletions. The reduction in p53 expression rescued the fitness defects in HSPC caused by Ddx41 heterozygosity. However, the combined Ddx41 and Trp53 mutant mice were prone to developing hematologic malignancies that resemble human myelodysplastic syndrome and acute myeloid leukemia. In conclusion, DDX41 heterozygosity causes dysregulation of the response to hematopoietic stress, which increases the risk of transformation with a p53 mutation.
    DOI:  https://doi.org/10.1038/s41375-024-02304-9
  21. Biomedicines. 2024 May 28. pii: 1194. [Epub ahead of print]12(6):
    CAR-T Cells in Acute Myeloid Leukemia: Where Do We Stand?
    Daniela Damiani, Mario Tiribelli.
      Despite recent advances, the prognosis of acute myeloid leukemia (AML) remains unsatisfactory due to disease recurrence and the development of resistance to both conventional and novel therapies. Engineered T cells expressing chimeric antigen receptors (CARs) on their cellular surface represent one of the most promising anticancer agents. CAR-T cells are increasingly used in patients with B cell malignancies, with remarkable clinical results despite some immune-related toxicities. However, at present, the role of CAR-T cells in myeloid neoplasms, including AML, is extremely limited, as specific molecular targets for immune cells are generally lacking on AML blasts. Besides the paucity of dispensable targets, as myeloid antigens are often co-expressed on normal hematopoietic stem and progenitor cells with potentially intolerable myeloablation, the AML microenvironment is hostile to T cell proliferation due to inhibitory soluble factors. In addition, the rapidly progressive nature of the disease further complicates the use of CAR-T in AML. This review discusses the current state of CAR-T cell therapy in AML, including the still scanty clinical evidence and the potential approaches to overcome its limitations, including genetic modifications and combinatorial strategies, to make CAR-T cell therapy an effective option for AML patients.
    Keywords:  CAR-T cells; acute myeloid leukemia; cell targets; immunotherapy; prognosis
    DOI:  https://doi.org/10.3390/biomedicines12061194
  22. Nat Commun. 2024 Jun 26. 15(1): 5409
    Alkylamine-tethered molecules recruit FBXO22 for targeted protein degradation.
    Chrysanthi Kagiou, Jose A Cisneros, Jakob Farnung, Joanna Liwocha, Fabian Offensperger, Kevin Dong, Ka Yang, Gary Tin, Christina S Horstmann, Matthias Hinterndorfer, Joao A Paulo, Natalie S Scholes, Juan Sanchez Avila, Michaela Fellner, Florian Andersch, J Thomas Hannich, Johannes Zuber, Stefan Kubicek, Steven P Gygi, Brenda A Schulman, Georg E Winter.
      Targeted protein degradation (TPD) relies on small molecules to recruit proteins to E3 ligases to induce their ubiquitylation and degradation by the proteasome. Only a few of the approximately 600 human E3 ligases are currently amenable to this strategy. This limits the actionable target space and clinical opportunities and thus establishes the necessity to expand to additional ligases. Here we identify and characterize SP3N, a specific degrader of the prolyl isomerase FKBP12. SP3N features a minimal design, where a known FKBP12 ligand is appended with a flexible alkylamine tail that conveys degradation properties. We found that SP3N is a precursor and that the alkylamine is metabolized to an active aldehyde species that recruits the SCFFBXO22 ligase for FKBP12 degradation. Target engagement occurs via covalent adduction of Cys326 in the FBXO22 C-terminal domain, which is critical for ternary complex formation, ubiquitylation and degradation. This mechanism is conserved for two recently reported alkylamine-based degraders of NSD2 and XIAP, thus establishing alkylamine tethering and covalent hijacking of FBXO22 as a generalizable TPD strategy.
    DOI:  https://doi.org/10.1038/s41467-024-49739-3
  23. Acta Biochim Biophys Sin (Shanghai). 2024 Jun 24.
    Importance of PTM of FLT3 in acute myeloid leukemia.
    Jianwei Liu, Jianguo Gu.
      FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase expressed in hematopoietic cells. Internal-tandem duplication domain (ITD) mutation and tyrosine kinase domain (TKD) mutation are the two most common mutations in acute myeloid leukemia (AML). Post-translational modifications (PTMs) of FLT3, such as glycosylation and ubiquitination, have been shown to impact various aspects of the protein in both wild-type (WT) and mutant forms of FLT3. In this review, we describe how the glycosylation status of FLT3 affects its subcellular localization, which significantly impacts the activation of downstream signaling, and the impact of specific ubiquitination on FLT3 function and stability, which may be associated with disease progression. Moreover, potential novel therapeutic strategies involving a combination of FLT3 tyrosine kinase inhibitors and drugs targeting glycosylation or ubiquitination are discussed.
    Keywords:  AML; FLT3; cellular signaling; glycosylation; ubiquitination
    DOI:  https://doi.org/10.3724/abbs.2024112
  24. Nat Cancer. 2024 Jun 28.
    The proteogenomic landscape of multiple myeloma reveals insights into disease biology and therapeutic opportunities.
    Evelyn Ramberger, Valeriia Sapozhnikova, Yuen Lam Dora Ng, Anna Dolnik, Matthias Ziehm, Oliver Popp, Eric Sträng, Miriam Kull, Florian Grünschläger, Josefine Krüger, Manuela Benary, Sina Müller, Xiang Gao, Arunima Murgai, Mohamed Haji, Annika Schmidt, Raphael Lutz, Axel Nogai, Jan Braune, Dominik Laue, Christian Langer, Cyrus Khandanpour, Florian Bassermann, Hartmut Döhner, Monika Engelhardt, Christian Straka, Michael Hundemer, Dieter Beule, Simon Haas, Ulrich Keller, Hermann Einsele, Lars Bullinger, Stefan Knop, Philipp Mertins, Jan Krönke.
      Multiple myeloma (MM) is a plasma cell malignancy of the bone marrow. Despite therapeutic advances, MM remains incurable, and better risk stratification as well as new therapies are therefore highly needed. The proteome of MM has not been systematically assessed before and holds the potential to uncover insight into disease biology and improved prognostication in addition to genetic and transcriptomic studies. Here we provide a comprehensive multiomics analysis including deep tandem mass tag-based quantitative global (phospho)proteomics, RNA sequencing, and nanopore DNA sequencing of 138 primary patient-derived plasma cell malignancies encompassing treatment-naive MM, plasma cell leukemia and the premalignancy monoclonal gammopathy of undetermined significance, as well as healthy controls. We found that the (phospho)proteome of malignant plasma cells are highly deregulated as compared with healthy plasma cells and is both defined by chromosomal alterations as well as posttranscriptional regulation. A prognostic protein signature was identified that is associated with aggressive disease independent of established risk factors in MM. Integration with functional genetics and single-cell RNA sequencing revealed general and genetic subtype-specific deregulated proteins and pathways in plasma cell malignancies that include potential targets for (immuno)therapies. Our study demonstrates the potential of proteogenomics in cancer and provides an easily accessible resource for investigating protein regulation and new therapeutic approaches in MM.
    DOI:  https://doi.org/10.1038/s43018-024-00784-3
  25. Cell. 2024 Jun 24. pii: S0092-8674(24)00638-X. [Epub ahead of print]
    The extracellular matrix integrates mitochondrial homeostasis.
    Hanlin Zhang, C Kimberly Tsui, Gilberto Garcia, Larry K Joe, Haolun Wu, Ayane Maruichi, Wudi Fan, Sentibel Pandovski, Peter H Yoon, Brant M Webster, Jenni Durieux, Phillip A Frankino, Ryo Higuchi-Sanabria, Andrew Dillin.
      Cellular homeostasis is intricately influenced by stimuli from the microenvironment, including signaling molecules, metabolites, and pathogens. Functioning as a signaling hub within the cell, mitochondria integrate information from various intracellular compartments to regulate cellular signaling and metabolism. Multiple studies have shown that mitochondria may respond to various extracellular signaling events. However, it is less clear how changes in the extracellular matrix (ECM) can impact mitochondrial homeostasis to regulate animal physiology. We find that ECM remodeling alters mitochondrial homeostasis in an evolutionarily conserved manner. Mechanistically, ECM remodeling triggers a TGF-β response to induce mitochondrial fission and the unfolded protein response of the mitochondria (UPRMT). At the organismal level, ECM remodeling promotes defense of animals against pathogens through enhanced mitochondrial stress responses. We postulate that this ECM-mitochondria crosstalk represents an ancient immune pathway, which detects infection- or mechanical-stress-induced ECM damage, thereby initiating adaptive mitochondria-based immune and metabolic responses.
    Keywords:  TGF-β; TMEM2; extracellular matrix; hyaluronan; immunity; mitochondria
    DOI:  https://doi.org/10.1016/j.cell.2024.05.057
  26. Nat Commun. 2024 Jun 25. 15(1): 5090
    A newly identified gene Ahed plays essential roles in murine haematopoiesis.
    Ritsuko Nakai, Takafumi Yokota, Masahiro Tokunaga, Mikiro Takaishi, Tomomasa Yokomizo, Takao Sudo, Henyun Shi, Yoshiaki Yasumizu, Daisuke Okuzaki, Chikara Kokubu, Sachiyo Tanaka, Katsuyoshi Takaoka, Ayako Yamanishi, Junko Yoshida, Hitomi Watanabe, Gen Kondoh, Kyoji Horie, Naoki Hosen, Shigetoshi Sano, Junji Takeda.
      The development of haematopoiesis involves the coordinated action of numerous genes, some of which are implicated in haematological malignancies. However, the biological function of many genes remains elusive and unknown functional genes are likely to remain to be uncovered. Here, we report a previously uncharacterised gene in haematopoiesis, identified by screening mutant embryonic stem cells. The gene, 'attenuated haematopoietic development (Ahed)', encodes a nuclear protein. Conditional knockout (cKO) of Ahed results in anaemia from embryonic day 14.5 onward, leading to prenatal demise. Transplantation experiments demonstrate the incapacity of Ahed-deficient haematopoietic cells to reconstitute haematopoiesis in vivo. Employing a tamoxifen-inducible cKO model, we further reveal that Ahed deletion impairs the intrinsic capacity of haematopoietic cells in adult mice. Ahed deletion affects various pathways, and published databases present cancer patients with somatic mutations in Ahed. Collectively, our findings underscore the fundamental roles of Ahed in lifelong haematopoiesis, implicating its association with malignancies.
    DOI:  https://doi.org/10.1038/s41467-024-49252-7
  27. Blood Adv. 2024 Jun 28. pii: bloodadvances.2024012858. [Epub ahead of print]
    Intensive Induction Chemotherapy versus Hypomethylating Agents in Combination with Venetoclax in NPM1-mutant AML.
    Jan Philipp Bewersdorf, Shai Shimony, Rory M Shallis, Yiwen Liu, Guillaume Berton, Eva Johanna Schaefer, Amer M Zeidan, Aaron D Goldberg, Eytan M Stein, Guido Marcucci, Rebecca Bystrom, R Coleman Lindsley, Evan C Chen, Jorge Miguel Ramos Perez, Anthony S Stein, Vinod A Pullarkat, Ibrahim Aldoss, Daniel J DeAngelo, Donna S Neuberg, Richard M Stone, Sylvain Garciaz, Brian J Ball, Maximilian Stahl.
      While intensive induction chemotherapy (IC) remains the standard of care for younger patients with acute myeloid leukemia (AML), data from older patients shows that hypomethylating agents + venetoclax (HMA/VEN) can lead to durable remissions among patients with NPM1 mutations. Whether IC or HMA/VEN is superior in patients ≥60 years-old with NPM1-mutant AML is unknown. To compare IC and HMA/VEN, we performed an international, multicenter retrospective cohort study of patients with newly diagnosed, NPM1-mutant AML.We included 221 patients (147 IC, 74 HMA/VEN) with previously untreated NPM1-mutant AML. Composite complete remission (cCR; defined as CR + CR with incomplete count recovery [CRi]) rate was similar for IC and HMA/VEN (cCR: 85% vs. 74%; p=0.067). While OS was favorable with IC in unselected patients compared to HMA/VEN (24-month OS 59% [95% CI: 52-69%] vs. 38% [95% CI 27-55%]; p=0.013), it was not statistically different among patients 60-75 years-old (60% [95% CI 52-70%] vs. 44% [95% CI 29-66%]; p=0.069) and patients who received an allogeneic stem cell transplant (70% [95% CI: 58-85%] vs. 66% [95% CI: 44-100%]; p=0.56). Subgroup analyses suggested that patients with normal cytogenetics (24-month OS with IC 65% [95% 56-74%] vs. 40% [95% CI: 26-60%] with HMA/VEN; p=0.009) and without FLT3-ITD mutations might benefit from IC compared with HMA/VEN (24-month OS: 68% [95% CI: 59-79%] vs. 43% [95% CI: 29-63%]; p=0.008). In multivariable analysis, OS was not statistically different for patients treated with IC and HMA/VEN (hazard ratio for death HMA/VEN vs. IC: 0.71; 95% CI: 0.40-1.27; p=0.25).
    DOI:  https://doi.org/10.1182/bloodadvances.2024012858
  28. Cells. 2024 Jun 15. pii: 1039. [Epub ahead of print]13(12):
    Advancements in Hematopoietic Stem Cell Gene Therapy: A Journey of Progress for Viral Transduction.
    Aurora Giommetti, Eleni Papanikolaou.
      Hematopoietic stem cell (HSC) transduction has undergone remarkable advancements in recent years, revolutionizing the landscape of gene therapy specifically for inherited hematologic disorders. The evolution of viral vector-based transduction technologies, including retroviral and lentiviral vectors, has significantly enhanced the efficiency and specificity of gene delivery to HSCs. Additionally, the emergence of small molecules acting as transduction enhancers has addressed critical barriers in HSC transduction, unlocking new possibilities for therapeutic intervention. Furthermore, the advent of gene editing technologies, notably CRISPR-Cas9, has empowered precise genome modification in HSCs, paving the way for targeted gene correction. These striking progresses have led to the clinical approval of medicinal products based on engineered HSCs with impressive therapeutic benefits for patients. This review provides a comprehensive overview of the collective progress in HSC transduction via viral vectors for gene therapy with a specific focus on transduction enhancers, highlighting the latest key developments, challenges, and future directions towards personalized and curative treatments.
    Keywords:  gene therapy; hematopoietic stem cells (HSC); rare diseases; transduction; transduction enhancers; viral vectors
    DOI:  https://doi.org/10.3390/cells13121039
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