bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2026–07–05
seventeen papers selected by
William Grey, University of York
  1. Phosphorylated DEK sustains leukemia stem cells by enabling PBX3-driven transcriptional reprogramming.
  2. Metabolism of Young and Aged Hematopoietic and Acute Myeloid Leukemia Stem Cells: Insights for Rejuvenation and Therapy.
  3. Inhibition of inflammation and senescence with azole compound C7 enables expansion of hematopoietic stem and progenitor cells.
  4. Single-cell architecture of purinergic signaling in human cord blood hematopoietic stem and progenitor cells.
  5. Psychological stress drives aging-like hematopoietic stem cell dysfunction through a brain-gut-bone marrow axis.
  6. Selective targeting of RSK signaling with PMD-026 suppresses FLT3-activated acute myeloid leukemia while sparing normal hematopoiesis.
  7. Hierarchical lineage tracing reveals diverse pathways of cytarabine resistance.
  8. Clonal Analyses Reveal the Impact of Hematopoietic Stem and Progenitor Cell Aging on T Cell Development.
  9. Beyond apoptosis: LSC state dictates metabolic and anti-apoptotic vulnerabilities.
  10. Therapeutic inhibition of telomeric DNA damage response rescues hematopoietic dysfunction driven by telomere shortening and aging.
  11. When mitochondria lose their fold: matrix proteostasis and stress signaling.
  12. Menin-MLL inhibitors enhance JUND activity in MLLr leukemic cells contributing to tumorigenesis and therapy resistance.
  13. NSD2 Degradation Remediates the Oncogenic Cistrome in t(4;14) Multiple Myeloma.
  14. Identification of long non-coding RNAs involved in leukemogenesis and venetoclax response in acute myeloid leukemia through functional CRISPR-dCas9 interference screens.
  15. FATP2-mediated lipid metabolism enhances chimeric antigen receptor T-cell therapy resistance in B-cell acute lymphoblastic leukemia.
  16. Democratized single-cell proteomics resolves cell state heterogeneity in skin tumors.
  17. Branching architecture of tryptophan metabolism determines therapeutic vulnerability in acute myeloid leukemia.
  1. Blood. 2026 Jun 30. pii: blood.2025032710. [Epub ahead of print]
    Phosphorylated DEK sustains leukemia stem cells by enabling PBX3-driven transcriptional reprogramming.
    Yufei Lei, Yanru Lai, Yan Li, Yuxia Wang, Haiqi Fan, Qiang Gong, Feng Wu, Qinrong Yan, Hanqing Zeng, Jianchuan Deng, Yu Hou, Zhe Chen.
      Leukemia stem cells (LSCs) drive acute myeloid leukemia (AML) initiation, relapse, and chemoresistance, yet the core post-translational events sustaining LSC maintenance remain poorly defined. Here, through phosphoproteomic profiling of normal hematopoietic stem and progenitor cells (HSPCs) versus LSC-enriched populations, we identify DEK phosphorylation as a critical modification during leukemogenesis. Functional studies in MLL-AF9- and HOXA9/MEIS1-driven AML mouse models, as well as patient-derived xenografts (PDXs), demonstrate that DEK deficiency impairs LSC maintenance and AML progression. Moreover, DEK deletion enhances LSC chemosensitivity to the standard-of-care combination of azacitidine and venetoclax (Aza/Ven), whereas DEK overexpression confers robust chemoresistance. Mechanistically, DEK recruits the transcription factor GABPA to upregulate the transcriptional cofactor PBX3, a key oncogenic driver in AML, thereby sustaining the leukemogenic transcriptional program. This DEK-GABPA interaction strictly depends on DEK phosphorylation at Ser301/303/306/307 (the 4S sites), which stabilizes the conformation of the DEK-GABPA complex. We identify casein kinase 2 (CK2) as the upstream kinase that directly phosphorylates DEK-4S sites. Importantly, blockade of DEK phosphorylation via 4S site mutagenesis or treatment with the clinical-stage CK2 inhibitor CX-4945 selectively depletes LSCs while sparing normal HSPCs. Furthermore, combining CX-4945 with venetoclax promotes LSC apoptosis and represses the PBX3-driven leukemogenic transcriptional program, exhibiting synergistic anti-AML effects both in vitro and in vivo. Collectively, our findings uncover a previously unrecognized phosphorylation event (DEK-4S phosphorylation) that sustains LSCs and establish the CK2-DEK axis as a promising LSC-specific therapeutic strategy for AML.
    DOI:  https://doi.org/10.1182/blood.2025032710
  2. Aging Dis. 2026 Jun 27.
    Metabolism of Young and Aged Hematopoietic and Acute Myeloid Leukemia Stem Cells: Insights for Rejuvenation and Therapy.
    Alhomidi Almotiri.
      Hematopoietic stem cells (HSCs) reside in the adult bone marrow and sustain the lifelong production of blood and immune cells. The processes of HSC quiescence, activation, and aging are complex and are orchestrated by a combination of intrinsic and extrinsic stimuli. Similarly, leukemic stem cells (LSCs) are responsible for the initiation of leukemia and drug resistance. Metabolic adaptations are critical for these processes, and research in this area is rapidly evolving. In this review, the metabolic programs, including glycolysis, mitochondrial metabolism, and amino acid and lipid metabolism, of young HSCs, aged HSCs, leukemia blasts, and LSCs are comparatively presented, with a greater focus on aged HSCs and LSCs, as aging and leukemia represent substantial health challenges. The clinical implications of metabolic vulnerabilities, either for rejuvenating aged HSCs or selectively killing LSCs, are also discussed.
    DOI:  https://doi.org/10.14336/AD.2026.0302
  3. Stem Cells Transl Med. 2026 Jun 27. pii: szag037. [Epub ahead of print]15(7):
    Inhibition of inflammation and senescence with azole compound C7 enables expansion of hematopoietic stem and progenitor cells.
    Ze Hui Kok, Lin Ming Lee, Kelvin Y H Liu, John Ouyang, Vikneswari Rajasegaran, Samantha P S Lim, Jui Wan Loh, Jing Yi Lee, Abner H Lim, Cedric Chuan Young Ng, Jason Yongsheng Chan, Sudipto Bari, William Ying Khee Hwang.
      Human hematopoietic stem and progenitor cells (HSPCs) derived from umbilical cord blood (UCB) are often insufficient in quantity for transplantation, necessitating efforts for ex vivo expansion. We previously developed a novel azole-based small molecule, C7, as a structural analog of the p38 mitogen-activated protein kinase inhibitor SB203580. C7 mediated robust ex vivo expansion of UCB HSPCs from unselected mononuclear cells, compared to its structural analogs and other published compounds. However, the molecular underpinnings of C7's potency remained unclear. In this work, we demonstrate that C7 preferentially enhances the proliferation and viability of early HSPC subsets upon direct culture with pre-isolated HSPCs, while limiting mitochondrially-derived reactive oxygen species production linked to oxidative stress. C7 treatment enhances hematopoietic stem cell self-renewal and in vivo multilineage reconstitution without T- or myeloid lineage bias. Unlike existing p38 inhibitors, C7 targets multiple kinases and pathways to achieve superior HSPC expansion through suppression of NFκB and IL-10 inflammatory signaling and attenuation of stress/senescence‑associated markers (eg, SERPINB2 and CDKN1A/p21). This mechanism of action of C7 is distinct from those of other existing compounds used for ex vivo HSPC expansion and has implications for application in other ex vivo culture platforms and clinical settings.
    Keywords:  cellular proliferation; cellular senescence; cord blood; hematopoietic stem cell transplantation; inflammation
    DOI:  https://doi.org/10.1093/stcltm/szag037
  4. Leukemia. 2026 Jul 01.
    Single-cell architecture of purinergic signaling in human cord blood hematopoietic stem and progenitor cells.
    M Molenda, J Jarczak, P Kieszek, M Z Ratajczak, M Kucia.
      Purinergic signaling has emerged as a key regulator of hematopoietic stem and progenitor cell (HSPC) trafficking, metabolism, and innate immune responsiveness. Our previous studies demonstrated that extracellular ATP promotes HSPC mobilization, homing, and engraftment by activating P2X purinergic receptors and engaging the Nlrp3 inflammasome downstream, whereas enzymatic conversion of ATP to extracellular adenosine exerts opposite, anti-inflammatory effects. Subsequently, we postulated that purinergic signaling is an evolutionarily ancient regulatory system that remains intrinsically embedded within the hematopoietic stem cell program. However, its transcriptional organization across distinct human HSPC subsets remains unknown. We applied single-cell RNA sequencing to human umbilical cord blood-derived CD133⁺Lin⁻CD45⁺ and CD34⁺Lin⁻CD45⁺ cells enriched for HSPCs. We identified transcriptionally distinct clusters representing primitive progenitors and lineage-primed intermediates, and we demonstrated a hierarchical organization of purinergic receptors and nucleotide-metabolizing enzymes across these populations. Primitive HSPCs exhibited a restricted purinergic repertoire coupled with intracellular nucleotide recycling machinery, consistent with a tightly regulated metabolic-immune state. Lineage-biased clusters showed selective enrichment of receptors and ectonucleotidases associated with inflammatory activation, migration, and fate commitment. Together, these findings establish purinergic signaling as a fundamental, cell-intrinsic regulator of early hematopoiesis and highlight how this ancient signaling pathway shapes human stem cell fate decisions.
    DOI:  https://doi.org/10.1038/s41375-026-03031-z
  5. Cell Stem Cell. 2026 Jul 02. pii: S1934-5909(26)00204-3. [Epub ahead of print]33(7): 1205-1222.e11
    Psychological stress drives aging-like hematopoietic stem cell dysfunction through a brain-gut-bone marrow axis.
    Xiaobin Tian, Binghuo Wu, Keyue Yang, Ying Wang, Yishan Li, Jingjing Guan, Kaitao Wang, Yijun Zhao, Kexin Sun, Yanjun Ling, Jiayin Zheng, Mengyun Xie, Weiming Liu, Xiaojing Ye, Changzheng Li, Linjia Jiang, Meng Zhao.
      Chronic stress influences hematopoietic stem cells (HSCs). However, how psychological stress regulates HSC function remains incompletely understood. Here, we show that psychological stress impairs HSC self-renewal and lymphoid differentiation, inducing aging-like phenotypes. Stress suppresses neuronal activity in the medial prefrontal cortex (mPFC) and periaqueductal gray (PAG), leading to HSC dysfunction, whereas chemogenetic activation of these regions restores HSC function. Psychological stress or chemogenetic inhibition of the mPFC and PAG reduces the abundance of L. reuteri in the gut microbiota and lowers spermidine levels. Mechanistically, spermidine depletion suppresses mitochondrial autophagy, promotes mitochondrial peroxidative stress, and increases ferroptotic stress in HSCs. We further demonstrate that mPFC and PAG activity regulate the intestinal environment through a sympathetic pathway, reducing intestinal mucin levels, L. reuteri abundance, and spermidine levels. These findings identify a brain-gut-bone marrow axis linking psychological stress to aging-like HSC dysfunction through sympathetic regulation of intestinal microbiota and spermidine metabolism.
    Keywords:  aging; autophagy; hematopoietic stem cell; intestinal environment; lymphoid differentiation; metabolism; microbiota; psychological stress; spermidine; sympathetic pathway
    DOI:  https://doi.org/10.1016/j.stem.2026.05.012
  6. Leukemia. 2026 Jun 30.
    Selective targeting of RSK signaling with PMD-026 suppresses FLT3-activated acute myeloid leukemia while sparing normal hematopoiesis.
    Gavin M Traber, Kailen Mark, Aarthi Jayanthan, Hee-Don Chae, Minyoung Youn, Jenny Youm, Nick J Sharp, Sandra E Dunn, Kathleen M Sakamoto.
      
    DOI:  https://doi.org/10.1038/s41375-026-03034-w
  7. Nat Commun. 2026 Jun 30.
    Hierarchical lineage tracing reveals diverse pathways of cytarabine resistance.
    Rachel Saxe, Hannah Stuart, Abigail C Marshall, Fahiima Abdullahi, Zoë Chen, Francesco Emiliani, Aaron McKenna.
      Cancer cells adapt to treatment, leading to the emergence of clones that are more aggressive and resistant to anti-cancer therapies. We have a limited understanding of resistance mechanisms as we lack technologies to map cancer evolution under the selective pressure of treatment. To address this, we present a hierarchical, dynamic lineage-tracing method, FLARE (Following Lineage Adaptation and Resistance Evolution). We use FLARE to track the progression of acute myeloid leukemia (AML) cell lines treated with Cytarabine (AraC), a front-line treatment in AML, both in vitro and in vivo. We map distinct cellular lineages in both murine and human AML cell lines that are predisposed to AraC resistance. Using FLARE, we identify treatment-naïve populations responsible for seeding resistance that are characterized by upregulation of stemness markers and a cell adhesion-associated AraC-resistant lineage signature. We find that expression of this signature in pediatric AML is associated with the expansion of HSC-like malignant cells at relapse and significantly shorter overall survival. These findings underscore the role of pre-existing lineage states in driving relapse and establish FLARE as a platform for uncovering the evolving, heritable transcriptional programs that underlie tumor evolution.
    DOI:  https://doi.org/10.1038/s41467-026-74989-8
  8. Aging Cell. 2026 Jul;25(7): e70615
    Clonal Analyses Reveal the Impact of Hematopoietic Stem and Progenitor Cell Aging on T Cell Development.
    Julia Gensheimer, Jessica LaGosh, Emma R Moulton, Victoria Sun, Stephanie C de Barros, Encarnacion Montecino-Rodriguez, Gloria Yiu, Xuegang Yuan, Kenneth Dorshkind, Gay M Crooks.
      T cell output from the thymus falls throughout life and is associated with profound remodeling of the thymic stroma. To what extent the decline in T cell output is caused by aging of the hematopoietic stem and progenitor cells (HSPCs) has been difficult to define because of HSPC heterogeneity, the multi-stage process of HSPC migration, and the cross-talk between hematopoietic and stromal elements of the thymus. To address the contribution of HSPC aging on T cell development, we interrogated T cell differentiation of phenotypically defined HSPCs from young and aged bone marrow using the Artificial Thymic Organoid (ATO) system, an in vitro model which allows quantification of T cell differentiation from single HSPCs within a controlled microenvironment. Phenotypically, most HSCs from young bone marrow were CD150lo lymphoid-biased (Ly-HSC), whereas aged HSCs were predominantly CD150hi myeloid-biased (My-HSC). Clonal analysis showed Ly-HSCs had greater T cell potential than My-HSCs, but aging had little if any impact on T cell output from the same immunophenotypic HSC. Further, clonal studies of early thymic progenitors (ETPs) demonstrated comparable T cell potential in young and aged cells. We conclude that the hematopoietic contribution to thymic insufficiency during aging is likely due to a relative shift in the aged bone marrow to myeloid-biased HSCs, rather than a per cell loss of T cell potential across HSPC in general. The profound changes that occur in the thymic microenvironment during aging likely also provide a major contribution to defects in thymopoiesis.
    Keywords:  T‐lymphocytes; aging; bone marrow; hematopoiesis; hematopoietic stem cells; thymus gland
    DOI:  https://doi.org/10.1111/acel.70615
  9. Cell Stem Cell. 2026 Jul 02. pii: S1934-5909(26)00206-7. [Epub ahead of print]33(7): 1054-1056
    Beyond apoptosis: LSC state dictates metabolic and anti-apoptotic vulnerabilities.
    Juan L Coelho-Silva, João A Machado-Neto.
      Two studies1,2 published in the last issue of Cell Stem Cell reveal that leukemic stem cell (LSC) identity in acute myeloid leukemia (AML) encodes both anti-apoptotic dependencies and metabolic survival programs. They reframe LSC-directed therapy: eradication may require combinatorial targeting of BCL-2 family proteins and ferroptosis-suppressive ketogenesis in a cell-state-specific manner.
    DOI:  https://doi.org/10.1016/j.stem.2026.05.014
  10. Nat Aging. 2026 Jun 30.
    Therapeutic inhibition of telomeric DNA damage response rescues hematopoietic dysfunction driven by telomere shortening and aging.
    Alessia Oppezzo, Sara Sepe, Giada Cicio, Valeria Cancila, Emanuele Sasso, Anastasia Conti, Eugenia Marinelli, Matteo Cabrini, Rani Pallavi, Nicola Iacomino, Matilde Simoni, Dmitrii Malyshev, Sara Boggio, Alessia di Lillo, Ilaria Rosso, Sara Tavella, Lucrezia A Trastus, Francesca Rossiello, Giulia Roscia, Paolo Cantaloni, Alessandro Manenti, Paola Cavalcante, Pier Giuseppe Pelicci, Raffaella Di Micco, Alfredo Nicosia, Claudio Tripodo, Fabrizio d'Adda di Fagagna.
      Telomeres progressively shorten and accumulate damage with aging, and this contributes to cellular senescence and hematopoietic dysfunction. We previously showed that telomere dysfunction induces synthesis of telomeric noncoding RNAs required for activation of the telomeric DNA damage response (tDDR), a driver of senescence and inflammation. However, whether the tDDR causally impairs hematopoiesis remained unclear. Here we show in telomerase-deficient Terc-/- mice, which recapitulate telomere-driven hematopoietic dysfunction and aging, that targeting telomeric noncoding RNAs with telomeric antisense oligonucleotides (tASO) suppresses tDDR in hematopoietic organs, reduces senescence and inflammation, alleviates hematopoietic dysfunction, and enhances hematopoietic stem cell fitness and repopulating potential in vivo. Similar observations were recapitulated in aged wild-type mice, and ex vivo treatment with tASO improved the function of human hematopoietic stem cells from aged donors. Taken together, our results identify tDDR as a pathogenic driver of hematopoietic decline and support tASO-mediated tDDR inhibition as a potential therapeutic strategy for telomere biology disorders and age-associated hematopoietic aging.
    DOI:  https://doi.org/10.1038/s43587-026-01136-9
  11. Front Physiol. 2026 ;17 1873221
    When mitochondria lose their fold: matrix proteostasis and stress signaling.
    Nils Bertram, Dejana Mokranjac.
      A dedicated network of chaperones and proteases is present in the mitochondrial matrix that orchestrates import, folding, disaggregation and eventually degradation of proteins. When this network is overwhelmed, unfolded or misfolded proteins accumulate in different types of aggregates which may either support recovery of functional proteins, initiate spatial sequestration or drive toxic aggregation. Here, we discuss mitochondrial protein aggregation and how mitochondrial proteostasis stress is communicated to the rest of the cell.
    Keywords:  Hsp70; mitochondria; mitochondria-nuclear signaling; protein aggregation; proteostasis
    DOI:  https://doi.org/10.3389/fphys.2026.1873221
  12. Blood. 2026 Jun 29. pii: blood.2025032363. [Epub ahead of print]
    Menin-MLL inhibitors enhance JUND activity in MLLr leukemic cells contributing to tumorigenesis and therapy resistance.
    Ezgi Ozyerli-Goknar, Sheikh Nizamuddin, Viktor Fetsch, Martin L Biniossek, Alina Hartmann, Florian Perner, Gerard M McGeehan, Scott A Armstrong, Robert Zeiser, H T Marc Timmers.
      MLL-rearranged (MLLr) acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) involve reciprocal translocations of the KMT2A (MLL1) gene with various translocation partner genes, which yields oncogenic chimeric MLL1 fusion proteins (MLL-FPs). Menin, the protein product of the MEN1 gene, is essential for the leukemogenic activity of MLL-FPs. Revumenib is a small-molecule inhibitor that selectively disrupts the menin-MLL interaction, and it is now in clinical use for treatment of MLLr and NPM1-mutated (NPM1c) acute leukemia. Notably, menin also interacts with the JUND member of the AP-1 transcription factor family through a conserved protein sequence in the MLL1/2 binding pocket of menin. Despite this structural similarity, the impact of menin-MLL inhibitors on JUND function has remained unexplored. Here, we investigated the influence of menin-MLL inhibitors on JUND activity. Quantitative mass spectrometry analysis of MLLr leukemic cells demonstrated that menin-MLL inhibitors also disrupt menin-JUND interactions. Furthermore, CRISPR-mediated inactivation of JUND or pharmacological inhibition using JNK inhibitors synergistically enhanced the anti-leukemic effects of menin-MLL inhibitors leading to reduced cell proliferation, cell cycle arrest and apoptosis. RNA sequencing and chromatin binding assays revealed that menin-MLL inhibitor treatment increased JUND chromatin occupancy leading to upregulation of target genes and contributing to resistance against menin-MLL inhibitors. Immunocompromised mice engrafted with JUND-deficient leukemia cells exhibited reduced tumor burden compared to control mice engrafted with wild type leukemic cells. These findings reveal a role for JUND in MLLr AML and suggest that targeting JUND transcription factor activity enhances the efficacy of menin-MLL inhibitors towards MLLr leukemic cells.
    DOI:  https://doi.org/10.1182/blood.2025032363
  13. Blood. 2026 Jun 29. pii: blood.2025031998. [Epub ahead of print]
    NSD2 Degradation Remediates the Oncogenic Cistrome in t(4;14) Multiple Myeloma.
    Bo Hu, Jacob Edwards, Hardik Modi, Jim Gamez, Oscar Enrique Echeagaray, Kyle Hess, Yue Ren, Diana Anderson, Marta Larrayoz, Jinyi Zhu, Scott Arne Johnson, Gauri Deb, Diana Jankeel, Preethi Janardhanan, Jim Leisten, Sophie Peng, Andy Christoforou, Nicholas Stong, Celia Fontanillo, Chad C Bjorklund, Patrick Ryan Hagner, Anita Krithivas Gandhi, Jose A Martínez-Climent, Rama Krishna Narla, Antonia Lopez-Girona, Mark Rolfe, Neil Bence, Deborah S Mortensen, Lynda Groocock.
      The t(4;14) chromosomal translocation drives overexpression of the histone methyltransferase NSD2 and defines a high-risk segment of multiple myeloma (MM) patients. Herein, we report the discovery of NSD2-LDD, a cereblon-recruiting and PWWP1-mediated ligand directed degrader (LDD) that selectively and potently eliminates full length and PWWP1 domain containing NSD2 protein isoforms. NSD2-LDD treatment induces global loss of H3K36me2 leading to promoter-proximal spreading of H3K27me3 and re-wiring of cis-regulatory interactions that reverse t(4;14) transcriptional programs. These effects suppress MM disease-associated phenotypes including stromal adhesion, three-dimensional colony growth and paracrine signaling. By integrating patient single cell profiles with model 3D epigenomic and spatial transcriptomics, we delineate t(4;14) disease state together with the tumor-intrinsic reprogramming and resultant remodeling of the bone marrow microenvironment upon NSD2 degradation. In cell line derived xenografts and genetically engineered mouse models of t(4;14), NSD2-LDD extends median survival accompanied by tumoral H3K36me2 loss and niche re-modelling. Although the NSD2-LDD response is restricted to PWWP1-containining models, collectively this work validates NSD2 as a tractable dependency and supports clinical development of NSD2 degradation as a novel, targeted therapeutic strategy in high-risk MM.
    DOI:  https://doi.org/10.1182/blood.2025031998
  14. Noncoding RNA Res. 2026 Oct;20 29-43
    Identification of long non-coding RNAs involved in leukemogenesis and venetoclax response in acute myeloid leukemia through functional CRISPR-dCas9 interference screens.
    Elisabetta Cozzi, Anne Neddermeyer, Sophia Miliara, Xiangfu Zhong, Tyler Weirick, Nona Struyf, Tom Erkers, Chung Chau Hon, Andreas Lennartsson, Sören Lehmann.
      Acute myeloid leukemia (AML) is a malignant hematologic disease with poor prognosis, and improved understanding of its biology is critical for patient outcomes. While protein-coding genes in AML are well characterized, the role of long non-coding RNAs (lncRNAs) remains largely unexplored. Here, we investigated how lncRNAs contribute to AML biology and treatment resistance. Three high-throughput lncRNA-CRISPR-interference (CRISPRi) screens were performed in the AML cell line MOLM-13, targeting 7996 lncRNAs expressed in hematopoietic cells, with knockdowns directed to transcription start sites defined through cap analysis of gene expression (CAGE) sequencing. Effects on proliferation, differentiation, and response to the Bcl-2 inhibitor venetoclax were assessed. In total, 58, 4, and 23 lncRNAs were found to affect proliferation, differentiation, and venetoclax sensitivity, respectively. Three proliferation-associated lncRNAs (MIR17HG, CATG00000106133.1, and CATG00000056792.1) and one venetoclax-associated lncRNA (AC009299.3) were further investigated. CATG00000106133.1 was enriched in de novo and cytogenetically normal AML and correlated with NPM1 and IDH2 mutations. Gene Ontology and Reactome analyses of RNA-seq from CATG00000106133.1 knockout cells revealed roles in cytokine signaling and immune pathways. AC009299.3, linked to venetoclax response, was associated with poor outcome, adverse risk, and increased age in AML patients. Collectively, this study identifies four lncRNAs implicated in key leukemogenic processes, highlighting their potential for understanding AML biology, prognosis, and therapeutic response.
    Keywords:  Acute myeloid leukemia (AML); CRISPR interference screens; Differentiation; Long non-coding RNAs (lncRNAs); Proliferation; Venetoclax
    DOI:  https://doi.org/10.1016/j.ncrna.2026.05.002
  15. Leukemia. 2026 Jun 30.
    FATP2-mediated lipid metabolism enhances chimeric antigen receptor T-cell therapy resistance in B-cell acute lymphoblastic leukemia.
    Clarissa Garcia, Kaylyn U Lyons, Julian Grandvallet Contreras, Tian Liu, Alexis J Donnelly, Amanda J Novak, Amy Argabright, Colin Anderson, Abby Grier, Sabrina Smith, Joshua Michlin, Jesutomisin Olusoji, Railey G Mikeska, Xin Zhou, Huimin Geng, Jeremy T Rahkola, Hiten N Patel, Jeffrey G Jacot, Markus Müschen, Angelo D'Alessandro, John E Dick, Ilaria Iacobucci, Charles G Mullighan, Julie A Reisz, Tzu Phang, M Eric Kohler, Matthew T Witkowski.
      Relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) remains a leading cause of cancer-related death in children and young adults. While CD19-directed chimeric antigen receptor T cell (CAR-T) therapy offers promise, high rates of long-term failure underscore the need to understand resistance mechanisms. Our studies found p53 inactivation promotes CAR-T resistance in human pre-B-ALL cell lines. Through genome-wide CRISPR/Cas9 screening of CAR-sensitive TP53-wildtype and CAR-resistant TP53-mutated CD19 + B-ALL cell lines, we found the Fatty Acid Transport Protein 2 (FATP2, encoded by SLC27A2) is a leukemia-intrinsic mechanism of CAR-T resistance in TP53-mutant B-ALL. High SLC27A2 expression in pediatric B-ALL patients correlate with worse survival outcomes following conventional chemotherapy. Using B-ALL cell lines and patient-derived xenografts, we show that FATP2-expressing TP53-mutant B-ALL resistance to CAR-T is dependent on exogenous lipid uptake to fuel fatty acid oxidation (FAO) and cell survival, which can be pharmacologically targeted through inhibition of neutral lipolysis and CPT1. These findings identify FATP2-mediated fatty acid uptake and downstream FAO as a potential target to improve existing CAR-T efficacy in human B-ALL.
    DOI:  https://doi.org/10.1038/s41375-026-03030-0
  16. Life Sci Alliance. 2026 Sep;pii: e202603759. [Epub ahead of print]9(9):
    Democratized single-cell proteomics resolves cell state heterogeneity in skin tumors.
    Joseph Inns, Andrew Michael Frey, Weng Wi Ng, Matthias Trost, Neil Rajan.
      Single-cell proteomics (SCP) reveals cellular heterogeneity and biological insights inaccessible to bulk analysis. Existing limitations are cost, sample loss during processing, and accessibility to state-of-the-art instrumentation. We describe a label-free SCP methodology in human tissue, combining FACS, oil-immersion cell handling, mass spectrometry, and neural-network-derived spectral libraries, which address these issues. We tested this methodology in a skin tumor syndrome, CYLD cutaneous syndrome (CCS), assessing tumor heterogeneity. Using a Bruker timsTOF HT platform, we quantified >4,000 proteins, averaging ∼700 per cell, through a cost-effective pipeline without specialised liquid handling infrastructure. By using preexisting bioinformatic tools from the scRNA-seq field, we implemented a robust analysis methodology, discriminating between macrophages, dendritic cells, and tumor keratinocytes, in an unbiased analysis of 419 CCS tumor cells. We validated the biological accuracy of cell annotations by cross referencing with each cell's FACS markers. Furthermore, we identified a novel CCS tumor-associated macrophage population, which carried a tumor microenvironment remodelling signature. Our findings demonstrate an accessible SCP technology capable of yielding novel biological discoveries in clinical tissue.
    DOI:  https://doi.org/10.26508/lsa.202603759
  17. Cell Death Dis. 2026 Jun 30.
    Branching architecture of tryptophan metabolism determines therapeutic vulnerability in acute myeloid leukemia.
    Tomasz Pienkowski, Marianna Ciwun, Anna Tankiewicz-Kwedlo, Aleksandra Golonko, Lukasz Bolkun, Jaroslaw Piszcz, Waldemar Priebe, Dariusz Pawlak.
      Acute myeloid leukemia (AML) exhibits metabolic reprogramming that supports immune evasion and treatment resistance. The kynurenine pathway (KP) is a key regulator of tumor-immune interactions, yet its downstream organization and clinical relevance in AML remain unclear. Here, we combined in vitro models with patient serum profiling to determine whether KP branching patterns are associated with treatment response. Extracellular KP metabolites were quantified in AML cell lines (HL-60 and MOLM-14) following induction regimens, and quantified circulating KP metabolites in patient serum samples collected from AML patients before and after induction therapy. Treatment was associated with normalization of tryptophan depletion and kynurenine accumulation in responders, indicating partial restoration of systemic KP homeostasis. Notably, baseline (pre-treatment) samples from patients who were later classified as non-responders exhibited a distinct metabolic phenotype characterized by persistent kynurenine elevation, increased anthranilic and kynurenic acid levels, and enrichment of 3-hydroxykynurenine flux, suggesting preferential engagement of oxidative and immunomodulatory KP branches. Among evaluated metabolic indices, the 3-hydroxykynurenine-to-kynurenine ratio demonstrated the strongest discriminatory capacity for distinguishing response to induction therapy (DA: daunorubicin + cytarabine; DAC: daunorubicin + cytarabine + cladribine), outperforming individual metabolite measurements and highlighting functional pathway flux rather than absolute metabolite abundance as a determinant of clinical outcome.
    DOI:  https://doi.org/10.1038/s41419-026-09050-z
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