bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2025–01–05
seventeen papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. AOH1996 targets mitochondrial dynamics and metabolism in leukemic stem cells via mitochondrial PCNA inhibition.
  2. Clonal hematopoiesis JAKs up plaque formation.
  3. Validation and improvement of the molecular international prognostic scoring system in Chinese patients with myelodysplastic syndromes.
  4. Post-Relapse Outcomes of Older Patients With NPM1-Mutated AML Are Favorable With Allo Transplant in Second Remission.
  5. Treatment patterns and outcomes in secondary acute myeloid leukemia arising after hypomethylating agents: PETHEMA registry study.
  6. Hematopoietic cell transplantation soon after first relapse in acute myeloid leukemia - the CONS.
  7. Molecular, clinical, and prognostic implications of RAS pathway alterations in adult acute myeloid leukemia.
  8. Deciphering the effect of UM171 on human hematopoietic progenitor cell fate through clonal analysis.
  9. Hematopoietic cell transplantation soon after first relapse in acute myeloid leukemia - the PROS.
  10. Somatic mtDNA mutation burden shapes metabolic plasticity in leukemogenesis.
  11. Bone Marrow Endothelial Progenitor Cells remodelling facilitates normal hematopoiesis during Acute Myeloid Leukemia Complete Remission.
  12. A Review of Clonal Relationships in Myeloproliferative Neoplasms With Co-Mutations of JAK2, CALR or MPL and BCR::ABL1.
  13. An inflammatory state defines a high-risk T-lineage acute lymphoblastic leukemia subgroup.
  14. Decoding cost-effectiveness of PNH therapies.
  15. Constitutive activation of the Src-family kinases Fgr and Hck enhances the tumor burden of acute myeloid leukemia cells in immunocompromised mice.
  16. Parallel single-cell metabolic analysis and extracellular vesicle profiling reveal vulnerabilities with prognostic significance in acute myeloid leukemia.
  17. Bone marrow niches orchestrate stem-cell hierarchy and immune tolerance.
  1. Exp Hematol Oncol. 2024 Dec 28. 13(1): 123
    AOH1996 targets mitochondrial dynamics and metabolism in leukemic stem cells via mitochondrial PCNA inhibition.
    HyunJun Kang, Melissa Valerio, Jia Feng, Long Gu, Dinh Hoa Hoang, Amanda Blackmon, Shawn Sharkas, Khyatiben Pathak, Jennifer Jossart, Zhuo Li, Hongyu Zhang, Bin Zhang, Patrick Pirrotte, J Jefferson P Perry, Robert J Hickey, Linda Malkas, Guido Marcucci, Le Xuan Truong Nguyen.
      Cytoplasmic proliferating cell nuclear antigen (PCNA) is highly expressed in acute myeloid leukemia (AML) cells, supporting oxidative metabolism and leukemia stem cell (LSC) growth. We report on AOH1996 (AOH), an oral compound targeting cancer-associated PCNA, which shows significant antileukemic activity. AOH inhibited growth in AML cell lines and primary CD34 + CD38 - blasts (LSC-enriched) in vitro while sparing normal hematopoietic stem cells (HSCs). In vivo, AOH-treated mice demonstrated prolonged survival compared to controls (50 vs. 35 days; p < 0.0001) with reduced LSC burden, as shown in secondary transplants (42 vs. 30 days, p < 0.0001). Mechanistically, AOH disrupted mitochondrial PCNA's binding to the OPA1 protein, enhancing OPA1's interaction with its E3 ligase, MARCH5, which led to OPA1 degradation. This process reduced mitochondrial length, fatty acid oxidation (FAO), and oxidative phosphorylation (OXPHOS), thereby inhibiting LSC expansion. The addition of venetoclax (VEN), an FDA-approved Bcl-2 inhibitor, further enhanced AOH's effects, reducing mitochondrial length, FAO, and OXPHOS while improving survival in AML models. While VEN is approved for AML, AOH is under clinical investigation for solid tumors, and our findings support its broader therapeutic potential.
    Keywords:  AML; AOH1996; Leukemic stem cells; Mitochondrial metabolism; PCNA inhibitor
    DOI:  https://doi.org/10.1186/s40164-024-00586-4
  2. J Clin Invest. 2025 Jan 02. pii: e187529. [Epub ahead of print]135(1):
    Clonal hematopoiesis JAKs up plaque formation.
    Koral Campbell, Qing Li.
      Clonal hematopoiesis (CH) is a condition in which hematopoietic stem cells (HSCs) acquire mutations seen in leukemia. While individuals with CH generally do not show signs of hematologic disease, the condition becomes more common with age and correlates with age-related diseases, especially cardiovascular disease (CVD). JAK2 mutations in HSCs can lead to CH and correlate with atherosclerosis, but the condition has been difficult to study because of challenges modeling the mutant cells at very low frequency. In this issue of the JCI, Liu et al. developed a low-allele-burden (LAB) mouse model in which a small number of bone marrow cells carrying the Jak2VF mutation were transplanted into mice predisposed to hyperlipidemia. Along with recapitulating features of plaque development, the authors identified the phagocytic receptors MERTK and TREM2 in WT cells as downstream of the inflammatory cytokine IL-1. These findings provide potential targets for preventing or treating patients at risk for CH-associated CVD.
    DOI:  https://doi.org/10.1172/JCI187529
  3. Ann Hematol. 2024 Dec 30.
    Validation and improvement of the molecular international prognostic scoring system in Chinese patients with myelodysplastic syndromes.
    Nanfang Huang, Yang Song, Lingyun Wu, Qi He, Zheng Zhang, Juan Guo, Feng Xu, Chunkang Chang, Xiao Li.
      Various prognostic models have been proposed to improve the accuracy of prognostic assessment for Myelodysplastic syndromes (MDS). Recently, the Molecular International Prognostic Scoring System (IPSS-M) has been developed. Here, we validated the accuracy of IPSS-M in Chinese MDS patients, and proposed a prognostic model more suitable for Chinese patients. We analyzed the clinical, molecular and cytogenetic data of 798 primary MDS patients, and compared the accuracy of IPSS-R and IPSS-M in predicting overall survival (OS) and acute myeloid leukemia (AML) transformation. Using Cox proportional hazards model, we screened out 14 genes that had significant impacts on OS and AML progression. In our study, 44.86% of individuals were reclassified from IPSS-R to IPSS-M, of whom 64.80% were upstaged and 35.2% were downstaged. IPSS-M showed better performance than IPSS-R in predicting AML transformation (C-index: 0.84 vs. 0.81), but it was similar to IPSS-R in OS (C-index: 0.77 vs. 0.76). By combining age, mutational data and IPSS-R, we developed a new prognostic model more suitable for the Chinese patients (c-index was 0.81 for OS and 0.89 for AML transformation, respectively).
    Keywords:  IPSS-M; Mutation; Myelodysplastic syndromes; Prognostic model
    DOI:  https://doi.org/10.1007/s00277-024-06162-4
  4. Eur J Haematol. 2024 Dec 30.
    Post-Relapse Outcomes of Older Patients With NPM1-Mutated AML Are Favorable With Allo Transplant in Second Remission.
    Avraham Frisch, Chezi Ganzel, Yishai Ofran, Baher Krayem, Arnon Haran, Vladimir Vainstein, Shlomzion Aumann, Noa Gross Even-Zohar, Boaz Nachmias.
      Molecular assessment of measurable residual disease (MRD) in NPM1-mutated AML patients is a powerful prognostic tool to identify the risk of relapse. There is limited data regarding MRD-guided decisions against alloSCT in elderly patients and FLT3-ITD co-mutation. We describe the outcome of NPM1-mutated AML patients in whom alloSCT was deferred based on ELN 2017 risk and MRD response. We report a relapse rate of 53% in this group, with a much higher incidence for older than 60 years patients than for younger patients (73% vs. 37%). When comparing outcomes of alloSCT in CR1 to intensive chemotherapy consolidation within each age group, patients over 60 years and patients with FLT3-ITD co-mutation had significantly lower RFS with intensive consolidation. Yet, in all subgroups, the lower RFS did not translate into OS difference, suggesting that relapsed NPM1 patients can often be salvaged and consequently achieve long-term remission. Our study supports the use of MRD response along with FLT3-ITD status in the decision to use post-remission therapy. We demonstrate that older patients and patients with FLT3-ITD-mutated AML have a high relapse rate but can be salvaged, leading to long-term survival.
    Keywords:  Acute myeloid leukemia; Measurable residual disease; NPM1; relapse
    DOI:  https://doi.org/10.1111/ejh.14375
  5. Cancer. 2025 Jan 01. 131(1): e35696
    Treatment patterns and outcomes in secondary acute myeloid leukemia arising after hypomethylating agents: PETHEMA registry study.
    Pilar Lloret-Madrid, Blanca Boluda, Joaquín Martínez-López, Juan Bergua, Eduardo Rodriguez Arboli, Jorge Labrador, Claudia Sossa, Cristina Gil, Lorenzo Algarra, Esperanza Lavilla-Rubira, Josefina Serrano, Beatriz de Rueda, Francisco Ibañez, Bernardo J González González, María Luz Amigo, Daniel García Belmonte, Carlos Rodríguez-Medina, María I Gómez-Roncero, Mercedes Colorado, José L López Lorenzo, Mar Tormo, Olga Arce Fernández, Isabel Cano-Ferri, Antonio Solana-Altabella, Maria-Angeles Foncillas, Ana Alfonso Pierola, Susana Vives, Marta Valero Núñez, Hernán López-Vidal, Esther Pérez-Santaolalla, Lourdes Hermosín Ramos, Raimundo García Boyero, Laura Llorente González, Alicia Roldán, Soledad Casado Calderón, Joana Brioso Infante, Teresa Olave, Julio García-Suárez, Almudena de Laiglesia, Rebeca Rodríguez-Veiga, Fernanda Trigo, David Martínez-Cuadrón, Pau Montesinos.
       BACKGROUND: Patients with secondary acute myeloid leukemia who previously received hypomethylating agents for prior myeloid neoplasms (HMA-sAML) face a dismal prognosis.
    METHODS: The authors analyze the characteristics, therapeutic approaches, and outcomes of patients with HMA-sAML from the Programa Español para el Tratamiento de Hemopatías Malignas (PETHEMA) registry.
    RESULTS: A total of 479 patients were included, mostly from prior myelodysplastic syndrome (84%). Frontline therapy consisted of intensive chemotherapy (IC) in 31%, low-dose cytarabine-based in 19%, supportive care and clinical trial 17% each, and HMA-based therapy in 12% and 4% in venetoclax-based regimen. Complete remission was achieved in 95 patients (27%), with higher rate among IC and venetoclax-based groups (44% and 41%, respectively). The median overall survival (OS) was 4.93 months, with 7.68 months for IC patients, 7.82 months after HMA monotherapy, and 4.66 months after venetoclax-based regimens. Patients who underwent allogeneic hematopoietic stem cell transplantation in first remission (n = 33, 9%) had a better survival outcome (median OS not reached). Multivariate analyses identified age (≥65 years), Eastern Cooperative Oncology Group >2, higher white blood cell count, and adverse risk cytogenetic as adverse prognostic factors, whereas NPM1 mutation was a favorable factor.
    CONCLUSIONS: Patients with HMA-sAML have a poor prognosis and suboptimal outcomes with conventional treatments, including BCL2 inhibitors, highlighting the need for clinical trials targeting this population.
    Keywords:  acute myeloid leukemia; hypomethylating agents; myelodysplastic syndrome; outcomes; secondary AML
    DOI:  https://doi.org/10.1002/cncr.35696
  6. Haematologica. 2025 Jan 01. 110(1): 7-10
    Hematopoietic cell transplantation soon after first relapse in acute myeloid leukemia - the CONS.
    Yishai Ofran, Jacob M Rowe.
      
    DOI:  https://doi.org/10.3324/haematol.2024.286780
  7. Leuk Lymphoma. 2025 Jan 02. 1-11
    Molecular, clinical, and prognostic implications of RAS pathway alterations in adult acute myeloid leukemia.
    Fenghong Zhang, Yizi Liu, Yiyan Zhu, Qingyuan Wang, Xiangyu Zhao, Qian Wang, Yu Chen, Suning Chen.
      Alterations in the RAS pathway underscore the pathogenic complexity of acute myeloid leukemia (AML), yet the full spectrum, including CBL, NF1, PTPN11, KRAS, and NRAS, remains to be fully elucidated. In this retrospective study of 735 adult AML patients, the incidence of RAS pathway alterations was 32.4%, each with distinct clinical characteristics. Venetoclax combined with hypomethylating agents (VEN + HMA) did not significantly improve response rates compared to intensive chemotherapy (IC) group. In the IC group, PTPN11 mutations in the N-SH2 domain showed a trend toward poorer prognosis, though not statistically significant in multivariate analysis, while NRAS mutations correlated with improved outcomes. In the VEN + HMA group, PTPN11 mutations in the N-SH2 domain emerged as an independent adverse prognostic marker. NRAS or KRAS mutations showed no survival advantage compared to wild-type, aligning with their intermediate-risk classification in the 2024 ELN guidelines. These findings emphasize the need for treatment-specific risk stratification for RAS pathway mutations in AML.
    Keywords:  AML; RAS pathway alterations; prognosis; therapy; venetoclax
    DOI:  https://doi.org/10.1080/10428194.2024.2441855
  8. Nat Commun. 2025 Jan 02. 16(1): 195
    Deciphering the effect of UM171 on human hematopoietic progenitor cell fate through clonal analysis.
    Patrick Coulombe, Elisa Tomellini, Jalila Chagraoui, Nadine Mayotte, Guy Sauvageau.
      Ex vivo expansion of hematopoietic stem cells (HSC) requires the maintenance of a stemness state while cells are proliferating. This can be achieved via exposure to UM171 which leads to the degradation of chromatin modifiers and prevents the loss of key epigenetic marks. However, the chromatin landscape varies across populations within the hematopoietic system and the effect of UM171 on self-renewal and differentiation potential of different hematopoietic progenitor cells is less characterized. To address this, we use the CellTag barcoding approach to track the fate of individual stem and progenitor cells during in vitro expansion. We show that, in addition to its HSC self-renewing property, UM171 specifically modulates cell fate of a precursor common to erythroid, megakaryocytic, and mast cells in favor of self-renewal and a mast-bias differentiation trajectory. This differentiation bias can be driven by pro-inflammatory signaling pathways that are activated downstream of UM171 and results in an abundant mast cell population that can be transplanted as part of the graft to populate mice tissues in xenotransplantation studies.
    DOI:  https://doi.org/10.1038/s41467-024-55225-7
  9. Haematologica. 2025 Jan 01. 110(1): 4-6
    Hematopoietic cell transplantation soon after first relapse in acute myeloid leukemia - the PROS.
    Edward Copelan, Robert P Gale.
      
    DOI:  https://doi.org/10.3324/haematol.2024.285784
  10. Sci Adv. 2025 Jan 03. 11(1): eads8489
    Somatic mtDNA mutation burden shapes metabolic plasticity in leukemogenesis.
    Xiujie Li-Harms, Jingjun Lu, Yu Fukuda, John Lynch, Aditya Sheth, Gautam Pareek, Marcin M Kaminski, Hailey S Ross, Christopher W Wright, Amber L Smith, Huiyun Wu, Yong-Dong Wang, Marc Valentine, Geoffrey Neale, Peter Vogel, Stanley Pounds, John D Schuetz, Min Ni, Mondira Kundu.
      The role of somatic mitochondrial DNA (mtDNA) mutations in leukemogenesis remains poorly characterized. To determine the impact of somatic mtDNA mutations on this process, we assessed the leukemogenic potential of hematopoietic progenitor cells (HPCs) from mtDNA mutator mice (Polg D257A) with or without NMyc overexpression. We observed a higher incidence of spontaneous leukemogenesis in recipients transplanted with heterozygous Polg HPCs and a lower incidence of NMyc-driven leukemia in those with homozygous Polg HPCs compared to controls. Although mtDNA mutations in heterozygous and homozygous HPCs caused similar baseline impairments in mitochondrial function, only heterozygous HPCs responded to and supported altered metabolic demands associated with NMyc overexpression. Homozygous HPCs showed altered glucose utilization with pyruvate dehydrogenase inhibition due to increased phosphorylation, exacerbated by NMyc overexpression. The impaired growth of NMyc-expressing homozygous HPCs was partially rescued by inhibiting pyruvate dehydrogenase kinase, highlighting a relationship between mtDNA mutation burden and metabolic plasticity in leukemogenesis.
    DOI:  https://doi.org/10.1126/sciadv.ads8489
  11. Nat Commun. 2024 Dec 30. 15(1): 10832
    Bone Marrow Endothelial Progenitor Cells remodelling facilitates normal hematopoiesis during Acute Myeloid Leukemia Complete Remission.
    Tong Xing, Li-Juan Hu, Hong-Yan Zhao, Chen-Yuan Li, Zhen-Kun Wang, Meng-Zhu Shen, Zhong-Shi Lyu, Jing Wang, Yu Wang, Hao Jiang, Qian Jiang, Ying-Jun Chang, Xiao-Hui Zhang, Yuan Kong, Xiao-Jun Huang.
      Although acute myeloid leukemia (AML) affects hematopoietic stem cell (HSC)-supportive microenvironment, it is largely unknown whether leukemia-modified bone marrow (BM) microenvironment can be remodeled to support normal hematopoiesis after complete remission (CR). As a key element of BM microenvironment, endothelial progenitor cells (EPCs) provide a feasible way to investigate BM microenvironment remodeling. Here, we find reduced and dysfunctional BM EPCs in AML patients, characterized by impaired angiogenesis and high ROS levels, could be partially remodeled after CR and improved by N-acetyl-L-cysteine (NAC). Importantly, HSC-supporting ability of BM EPCs is partially recovered, whereas leukemia-supporting ability is decreased in CR patients. Mechanistically, the transcriptome characteristics of leukemia-modified BM EPCs return to near-normal after CR. In a classic AML mouse and chemotherapy model, BM vasculature and normal hematopoiesis are reversed after CR. In summary, we provide further insights into how leukemia-modified BM microenvironment can be remodeled to support normal hematopoiesis after CR, which can be further improved by NAC.
    DOI:  https://doi.org/10.1038/s41467-024-55051-x
  12. Clin Lymphoma Myeloma Leuk. 2024 Dec 05. pii: S2152-2650(24)02418-2. [Epub ahead of print]
    A Review of Clonal Relationships in Myeloproliferative Neoplasms With Co-Mutations of JAK2, CALR or MPL and BCR::ABL1.
    Mohammadamin Noorafrooz, Sanaz Ghods, Robert Peter Gale, Ramin Noorafrooz.
      BCR::ABL1-negative myelo-proliferative neoplasms (MPNs) are characterized by mutations in JAK2, CALR, or MPL. Usually these mutations are co-exclusive of each other and of BCR::ABL1. We reviewed clonal interactions in 177 subjects with mutations in JAK2, CALR, or MPL and BCR::ABL1 including JAK2/BCR::ABL1 (N = 142), CALR/BCR::ABL1 (N = 31), MPL/BCR::ABL1 (N = 3). Co-mutations can arise in the same clone or in different sub-clones. In this review we used clonality data, mutation sequencing and therapy response evaluation to address this question. We found that in subjects with JAK2/BCR::ABL1 co-mutations there is a complex, branched clonal evolution. In contrast, in subjects with CALR/BCR::ABL1, co-mutations are in different sub-clones. There are too few data in subjects with MPL/BCR::ABL1 to critically analyze. However, indirect methods for assessing clonality limit our conclusions. Understanding clonal architecture of MPNs with co-mutations is needed to understand the underlying biology and give appropriate therapy.
    Keywords:  Branching evolution; CML; Clonal interactions; MPNs; Tyrosine kinase inhibitors
    DOI:  https://doi.org/10.1016/j.clml.2024.11.007
  13. Sci Transl Med. 2025 Jan;17(779): eadr2012
    An inflammatory state defines a high-risk T-lineage acute lymphoblastic leukemia subgroup.
    Mark Gower, Ximing Li, Alicia G Aguilar-Navarro, Brian Lin, Minerva Fernandez, Gibran Edun, Mursal Nader, Vincent Rondeau, Andrea Arruda, Anne Tierens, Anna Eames Seffernick, Petri Pölönen, Juliette Durocher, Elvin Wagenblast, Lin Yang, Ho Seok Lee, Charles G Mullighan, David Teachey, Marissa Rashkovan, Cedric S Tremblay, Daniel Herranz, Tomer Itkin, Sanam Loghavi, John E Dick, Gregory Schwartz, Maria Agustina Perusini, Hassan Sibai, Johann Hitzler, Tanja A Gruber, Mark Minden, Courtney L Jones, Igor Dolgalev, Soheil Jahangiri, Anastasia N Tikhonova.
      T-lineage acute lymphoblastic leukemia (ALL) is an aggressive cancer comprising diverse subtypes that are challenging to stratify using conventional immunophenotyping. To gain insights into subset-specific therapeutic vulnerabilities, we performed an integrative multiomics analysis of bone marrow samples from newly diagnosed T cell ALL, early T cell precursor ALL, and T/myeloid mixed phenotype acute leukemia. Leveraging cellular indexing of transcriptomes and epitopes in conjunction with T cell receptor sequencing, we identified a subset of patient samples characterized by activation of inflammatory and stem gene programs. These inflammatory T-lineage samples exhibited distinct biological features compared with other T-lineage ALL samples, including the production of proinflammatory cytokines, prevalence of mutations affecting cytokine signaling and chromatin remodeling, an altered immune microenvironment, and poor treatment responses. Moreover, we found that, although inflammatory T-lineage ALL samples were less sensitive to dexamethasone, they exhibited unique sensitivity to a BCL-2 inhibitor, venetoclax. To facilitate classification of patients with T-lineage ALL, we developed a computational inflammatory gene signature scoring system, which stratified patients and was associated with disease prognosis in three additional patient cohorts. By identifying a high-risk T-lineage ALL subtype on the basis of an inflammatory score, our study provides a framework for targeted therapeutic approaches for these challenging-to-treat cancers.
    DOI:  https://doi.org/10.1126/scitranslmed.adr2012
  14. Blood. 2025 Jan 02. 145(1): 8-10
    Decoding cost-effectiveness of PNH therapies.
    Amar H Kelkar, Gregory A Abel.
      
    DOI:  https://doi.org/10.1182/blood.2024027053
  15. Sci Rep. 2025 Jan 02. 15(1): 174
    Constitutive activation of the Src-family kinases Fgr and Hck enhances the tumor burden of acute myeloid leukemia cells in immunocompromised mice.
    Sherry T Shu, Li Chen, Giancarlo Gonzalez-Areizaga, Thomas E Smithgall.
      Overexpression of the myeloid Src-family kinases Fgr and Hck has been linked to the development of acute myeloid leukemia (AML). Here we characterized the contribution of active forms of these kinases to AML cell cytokine dependence, inhibitor sensitivity, and AML cell engraftment in vivo. The human TF-1 erythroleukemia cell line was used as a model system as it does not express endogenous Hck or Fgr. To induce constitutive kinase activity, Hck and Fgr were fused to the coiled-coil (CC) oligomerization domain of the breakpoint cluster region protein associated with the Bcr-Abl tyrosine kinase in chronic myeloid leukemia. Expression of CC-Hck or CC-Fgr transformed TF-1 cells to a granulocyte-macrophage colony-stimulating factor (GM-CSF)-independent phenotype that correlated with enhanced phosphorylation of the kinase domain activation loop. Both CC-Hck and CC-Fgr cell populations became sensitized to growth arrest by Src-family kinase inhibitors previously shown to suppress the growth of bone marrow cells from AML patients in vitro and decrease AML cell engraftment in immunocompromised mice. Methionine substitution of the 'gatekeeper' residue (Thr338) also stimulated Hck and Fgr kinase activity and transformed TF-1 cells to GM-CSF independence without CC fusion. TF-1 cells expressing either active form of Hck or Fgr engrafted immunocompromised mice faster and developed more extensive tumors compared to mice engrafted with the parent cell line, resulting in shorter survival. Expression of wild-type Hck also significantly enhanced bone marrow engraftment without an activating mutation. Reverse phase protein array analysis linked active Hck and Fgr to the mammalian target of rapamycin complex-1/p70 S6 ribosomal protein (mTORC-1/S6) kinase and focal adhesion kinase (Fak) signaling pathways. Combining Hck and Fgr inhibitors with existing mTORC-1/S6 kinase or Fak inhibitors may improve clinical responses and reduce the potential for acquired resistance.
    DOI:  https://doi.org/10.1038/s41598-024-83740-6
  16. Nat Commun. 2024 Dec 30. 15(1): 10878
    Parallel single-cell metabolic analysis and extracellular vesicle profiling reveal vulnerabilities with prognostic significance in acute myeloid leukemia.
    Dorian Forte, Roberto Maria Pellegrino, Paolo Falvo, Paulina Garcia-Gonzalez, Husam B R Alabed, Filippo Maltoni, Davide Lombardi, Samantha Bruno, Martina Barone, Federico Pasini, Francesco Fabbri, Ivan Vannini, Benedetta Donati, Gianluca Cristiano, Chiara Sartor, Simona Ronzoni, Alessia Ciarrocchi, Sandra Buratta, Lorena Urbanelli, Carla Emiliani, Simona Soverini, Lucia Catani, Francesco Bertolini, Rafael José Argüello, Michele Cavo, Antonio Curti.
      Acute myeloid leukemia (AML) is an aggressive disease with a high relapse rate. In this study, we map the metabolic profile of CD34+(CD38low/-) AML cells and the extracellular vesicle signatures in circulation from AML patients at diagnosis. CD34+ AML cells display high antioxidant glutathione levels and enhanced mitochondrial functionality, both associated with poor clinical outcomes. Although CD34+ AML cells are highly dependent on glucose oxidation and glycolysis for energy, those from intermediate- and adverse-risk patients reveal increased mitochondrial dependence. Extracellular vesicles from AML are mainly enriched in stem cell markers and express antioxidant GPX3, with their profiles showing potential prognostic value. Extracellular vesicles enhance mitochondrial functionality and dependence on CD34+ AML cells via the glutathione/GPX4 axis. Notably, extracellular vesicles from adverse-risk patients enhance leukemia cell engraftment in vivo. Here, we show a potential noninvasive approach based on liquid 'cell-extracellular vesicle' biopsy toward a redefined metabolic stratification in AML.
    DOI:  https://doi.org/10.1038/s41467-024-55231-9
  17. Nature. 2025 Jan 01.
    Bone marrow niches orchestrate stem-cell hierarchy and immune tolerance.
    Kazuhiro Furuhashi, Miwako Kakiuchi, Ryosuke Ueda, Hiroko Oda, Simone Ummarino, Alexander K Ebralidze, Mahmoud A Bassal, Chen Meng, Tatsuyuki Sato, Jing Lyu, Min-Guk Han, Shoichi Maruyama, Yu Watanabe, Yuriko Sawa, Daisuke Kato, Hiroaki Wake, Boris Reizis, John A Frangos, David M Owens, Daniel G Tenen, Ionita C Ghiran, Simon C Robson, Joji Fujisaki.
      Stem cells reside in specialized microenvironments, termed niches, at several different locations in tissues1-3. The differential functions of heterogeneous stem cells and niches are important given the increasing clinical applications of stem-cell transplantation and immunotherapy. Whether hierarchical structures among stem cells at distinct niches exist and further control aspects of immune tolerance is unknown. Here we describe previously unknown new hierarchical arrangements in haematopoietic stem cells (HSCs) and bone marrow niches that dictate both regenerative potential and immune privilege. High-level nitric oxide-generating (NOhi) HSCs are refractory to immune attack and exhibit delayed albeit robust long-term reconstitution. Such highly immune-privileged, primitive NOhi HSCs co-localize with distinctive capillaries characterized by primary ciliated endothelium and high levels of the immune-checkpoint molecule CD200. These capillaries regulate the regenerative functions of NOhi HSCs through the ciliary protein IFT20 together with CD200, endothelial nitric oxide synthase and autophagy signals, which further mediate immunoprotection. Notably, previously described niche constituents, sinusoidal cells and type-H vessels2-10 co-localize with less immune-privileged and less potent NOlow HSCs. Together, we identify highly immune-privileged, late-rising primitive HSCs and characterize their immunoprotective niches comprising specialized vascular domains. Our results indicate that the niche orchestrates hierarchy in stem cells and immune tolerance, and highlight future immunotherapeutic targets.
    DOI:  https://doi.org/10.1038/s41586-024-08352-6
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