bims-scepro 2026-05-03 papers

bims-scepro

Biomed News

on Stem cell proteostasis

Issue of 2026–05–03
fourteen papers selected by
William Grey, University of York

Age-dependent regulation of hematopoiesis by megakaryocytes.
A single JAK2-V617F hematopoietic stem cell can initiate myeloproliferative neoplasm when transplanted into non-conditioned recipient mice.
Dynamic PEGDA-GelMA-HAMA microcarriers for efficient ex vivo expansion of human hematopoietic stem/progenitor cells.
The ATF4/PSAT1/JNK Signaling Axis Suppresses Ferroptosis to Drive Venetoclax Resistance in AML.
Lineage-specific CK2α deletion reshapes the transcriptome of hematopoietic stem cells toward an immune-primed state.
SIRT3 deSUMOylation sustains hematopoietic stem cell activities under stressful conditions via the DHX58-IRF7 axis.
ENO1 promotes acute myeloid leukemia progression through SCD1-mediated lipid metabolism reprogramming.
Combinatorial base editing couples disease correction with lineage amplification in hematopoietic stem and progenitor cells.
Evolution in single-cell proteomics drives new frontiers in cancer biology and precision medicine.
Proteotoxic stress response is governed by ER-associated sorting of proteasome transcriptional activators.
Multi-omics analysis of pediatric minimally differentiated acute myeloid leukemia reveals RUNX1-driven stemness and chemoresistance.
Simultaneous In-Depth Single-Cell Proteomic and Metabolomic Analysis.
Metabolomic Signatures of Relapse and Survival in AML Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation.
Multimodal immunopharmacologic screens identify drugs rewiring the cancer-immune interface.

Curr Opin Hematol. 2026 Apr 07.

Age-dependent regulation of hematopoiesis by megakaryocytes.

Sen Zhang, Sandra Pinho.

   PURPOSE OF REVIEW: Recent studies have expanded the concept of the bone marrow niche beyond stromal cells to include differentiated hematopoietic progeny as direct regulators of hematopoietic stem cells (HSCs). Among these, megakaryocytes have emerged as key niche regulators of HSC function across homeostasis, stress responses, aging, and disease. This review summarizes recent advances defining how aging alters megakaryocyte-mediated regulation of hematopoiesis.
RECENT FINDINGS: Megakaryocytes regulate HSC quiescence, lineage output, and stress responsiveness through spatial organization within the bone marrow microenvironment and the production of niche-derived factors. Recent studies revealed that aging is associated with changes in megakaryocyte abundance, maturation state, and transcriptional and secretory programs, resulting in altered niche functions and hematopoiesis. These findings establish megakaryocytes as dynamic niche components whose regulatory roles evolve across the lifespan.
SUMMARY: Age-dependent remodeling of the megakaryocytic niche provides a conceptual framework for understanding how hematopoietic regulation is reprogrammed with aging. Targeting megakaryocyte-derived niche signals may offer new opportunities to rejuvenate hematopoiesis and improve outcomes in age-associated hematopoietic disorders.

Keywords:  aging; bone marrow niche; hematopoietic stem cells; megakaryocytes

DOI:  https://doi.org/10.1097/MOH.0000000000000924
Hemasphere. 2026 May;10(5): e70359

A single JAK2-V617F hematopoietic stem cell can initiate myeloproliferative neoplasm when transplanted into non-conditioned recipient mice.

Quentin Kimmerlin, Morgane Hilpert, Nils Hansen, Alexandre Guy, Marc Usart, Jan Stetka, Patryk Sobieralski, Tiago Almeida Fonseca, Hui Hao-Shen, Radek C Skoda.

Myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells (HSCs) that are most frequently caused by acquired somatic mutations in JAK2. A number of conditional mouse models of JAK2-V617F-driven MPN have been generated that rely on Cre-LoxP-mediated activation, resulting in polyclonal disease. To more closely mimic the monoclonal origin of human MPN, transplantations of single purified JAK2-mutant HSCs or bone marrow (BM) at limiting dilutions into lethally irradiated recipient mice have been previously performed. However, irradiation is known to alter the BM microenvironment and also to induce transient aplasia accompanied by elevated cytokine levels that promote the expansion of the mutant clone. To overcome these limitations, we examined whether JAK2-V617F-mutant HSCs are able to engraft and initiate MPN in non-conditioned recipients. We found that BM from two different MPN models, one expressing the human JAK2-V617F, and another expressing the mouse Jak2-V617F, efficiently engrafted and initiated MPN in non-irradiated immunocompromised Rag2 -/- recipients. MPN evolved even in transplantations at limiting dilutions, showing the high competitiveness of single JAK2-mutant HSCs. In contrast, BM from mice expressing the human JAK2-V617F failed to engraft in non-conditioned immunocompetent C57BL/6 mice, while BM from mice expressing the mouse Jak2-V617F engrafted and initiated MPN, suggesting that mouse JAK2-V617F protein, which differs from the endogenous JAK2 in only one amino acid, was tolerated. Our results show that JAK2-V617F mutant HSCs can outcompete resident non-mutated HSCs even in the absence of elevated cytokine levels and without the need of emptying stem cell niches by irradiation.

DOI: https://doi.org/10.1002/hem3.70359
Colloids Surf B Biointerfaces. 2026 Apr 25. pii: S0927-7765(26)00335-8. [Epub ahead of print]265 115747

Dynamic PEGDA-GelMA-HAMA microcarriers for efficient ex vivo expansion of human hematopoietic stem/progenitor cells.

Yiming Liu, Meishan Guo, Lulu Shi, Ling Yu, Jingzhi Shen, Jianan Li, Yang Lv, Tiantian Cui, Lingping Zhao, Haiyang Wang, Junnian Zhou, Wen Yue, Zhitang Lyu, Mingyi Qu, Jiafei Xi.

  The clinical demand for hematopoietic stem cells (HSCs) far exceeds that of the available sources, driving the need for efficient ex vivo expansion technologies. A central challenge is the design of culture systems that promote HSCs proliferation while inhibiting differentiation, a balance that is poorly maintained in conventional static cultures. In this study, we engineered a novel biomimetic microcarrier (denoted as P7G3H2) by synthesizing a composite hydrogel from poly(ethylene glycol) diacrylate (PEGDA), gelatin methacryloyl (GelMA), and hyaluronic acid methacryloyl (HAMA). This material combination was designed to mimic the key aspects of the bone marrow niche, providing mechanical tunability (PEGDA), cell-adhesive motifs (GelMA), and bioactive signaling engagement (HAMA). We established a P7G3H2 microcarrier-based dynamic culture system to expand human umbilical cord blood-derived hematopoietic stem/progenitor cells (HSPCs). The new system yielded 3.76 times more total CD34+CD38- cells than the control group and enhanced the proportion of primitive cells by approximately 74% compared to controls after 7 days of expansion. The expanded cells preserved intrinsic multipotency and multi-lineage differentiation potential, while demonstrating a marked propensity for spontaneous erythroid differentiation during prolonged culture. This study demonstrates that a rationally designed biomaterial platform within a dynamic culture environment can significantly improve the efficiency and quality of HSPCs expansion, offering a promising strategy for scalable HSCs production.

Keywords:  Biomimetic Materials; Ex Vivo Expansion; Hematopoietic Stem Cells; Microcarriers

DOI:  https://doi.org/10.1016/j.colsurfb.2026.115747
Exp Cell Res. 2026 Apr 25. pii: S0014-4827(26)00162-X. [Epub ahead of print] 115045

The ATF4/PSAT1/JNK Signaling Axis Suppresses Ferroptosis to Drive Venetoclax Resistance in AML.

XunXun Zhu, WenHui Huang, MingYan Zhang, YanLing Tao, Hao Zhang.

  Metabolic reprogramming has emerged as a key driver of therapy resistance in acute myeloid leukemia (AML). Here, we identify phosphoserine aminotransferase 1 (PSAT1) as a critical metabolic determinant of venetoclax (VEN) resistance through the suppression of ferroptosis. PSAT1 was consistently upregulated in VEN-resistant cell lines and relapsed patient samples. Mechanistically, the transcription factor ATF4 directly bound the PSAT1 promoter, enhancing its expression and subsequently promoting glutathione synthesis, depleting the labile iron pool, and attenuating lipid peroxidation. Concurrently, PSAT1 functioned to restrain JNK/c-Jun signaling. Knockdown of PSAT1 restored VEN sensitivity by triggering ferroptosis and modulating the expression of BCL-2 and GPX4. Clinically, elevated PSAT1 expression predicted poor patient survival. Our findings unveil the ATF4/PSAT1/JNK axis as a master regulator of ferroptosis in AML, revealing a druggable pathway to overcome VEN resistance.

Keywords:  ATF4; Acute myeloid leukemia; JNK/c-Jun signaling; PSAT1; ferroptosis; venetoclax resistance

DOI:  https://doi.org/10.1016/j.yexcr.2026.115045
bioRxiv. 2026 Apr 15. pii: 2026.04.10.717787. [Epub ahead of print]

Lineage-specific CK2α deletion reshapes the transcriptome of hematopoietic stem cells toward an immune-primed state.

Hannah Valensi, Rajesh Rajaiah, Marudhu Shanmugam, Daniyal Muhammad, Upendar Golla, Katherine Mercer, Anush Karampuri, Sinisa Dovat, Chandrika Behura, Yasin Uzun.

Casein Kinase 2 (CK2) is a constitutively active kinase regulating proliferation and immune signaling and is frequently dysregulated in cancer, including acute myeloid leukemia (AML), making it a therapeutic target. CK2 comprises two catalytic subunits, CK2α or CK2α', with two regulatory β subunits. The role of CK2α, the predominant catalytic subunit and principal mediator of CK2 kinase activity in hematopoietic cells, in steady-state hematopoiesis remains undefined. To define how CK2α shapes hematopoietic cells, we used bone marrow and spleen tissue samples of wild type control and conditional knock out (KO) of CK2α ( Csnk2a1 ) in the hematopoietic compartment of transgenic mice. Using single-cell RNA sequencing, we profiled the transcriptomic changes associated with CK2α loss. Although HSC abundance was comparable between the control and CK2α-deficient samples, HSCs experienced the largest transcriptional response to CK2α loss among all cell types. CK2α-deficient HSCs displayed transcriptional remodeling for inflammatory and immune-associated programs, interferon signaling, and antigen presentation. Expression of inflammatory genes such as S100a8 and S100a9 , changed in opposite directions in bone marrow and spleen HSCs, demonstrating the transcriptional consequences of CK2α loss shaped by tissue context. Using a network-based approach, we identified immune-associated transcription factors Nfkb1, Rfx5, Hes1 , and AP-1 family members as regulatory hubs driving these inflammatory transcriptional states in CK2α-deficient HSCs. Cell-cell communication profiling revealed multiple gains and losses in ligand-receptor communication between the HSCs and their immune microenvironment in KO. Our findings identify CK2α as a regulator of immune transcriptional programs in HSCs and suggest that disruption of CK2 signaling influences stem cell behavior and immune activation in contexts relevant to hematologic malignancies and CK2-targeted cancer therapies.
Statement of significance: This study reveals that inhibiting the protein CK2α forces blood stem cells into a stressed, immune-primed state. These tissue-specific findings highlight potential side effects for cancer therapies targeting this essential regulatory kinase.

DOI: https://doi.org/10.64898/2026.04.10.717787
Haematologica. 2026 Apr 30.

SIRT3 deSUMOylation sustains hematopoietic stem cell activities under stressful conditions via the DHX58-IRF7 axis.

Xiaoxiao He, Jing Yu, Yilu Xu, Tianshi Wang, Yang Lu, Jiaxin Wu, Sijia Dan, Yiqiu Xia, Xingmei Mu, Li Xie, Chiqi Chen, Zhuo Yu, Jing Ye, Eric Gilson, Yaping Zhang, Jinke Cheng, Junke Zheng.

Hematopoietic stem cells (HSCs) sustain physiological hematopoiesis by generating all hematopoietic cells. However, the connection between HSC stemness/activities and organismal lifespan, especially under stress, remains incompletely understood. We previously revealed a unique mutation at the SUMOylation site of SIRT3 (lysine 223 to arginine, K223R) that could enhance its deacetylase activity. Here, using Sirt3-K223R transgenic mice, we demonstrate that SIRT3 deSUMOylation promotes HSC self-renewal, inhibits myeloid differentiation, and delays HSC senescence under multiple stress conditions. Notably, these effects are associated with extended lifespan in mice, though the underlying link between preserved HSC function and lifespan extension needs further investigation. Mechanistically, SIRT3 regulates mitochondrial metabolic activity and promotes the deacetylation of H3K9 and H3K27. This epigenetic modification attenuates the RIG-I signaling pathway by downregulating DHX58 and IRF7, sustaining HSC activities. Our study uncovers a unique SIRT3-DHX58-IRF7 axis that sustains HSC activities to delay organismal aging under stress, providing insights into potential anti-aging strategies targeting hematopoietic homeostasis.

DOI: https://doi.org/10.3324/haematol.2025.300025
Blood Adv. 2026 Apr 28. pii: bloodadvances.2025017973. [Epub ahead of print]

ENO1 promotes acute myeloid leukemia progression through SCD1-mediated lipid metabolism reprogramming.

Yijun Wu, Li Gao, Fang Fang, Zhiheng Li, Yixin Hu, Yongping Zhang, Chenwei Yang, Zhongling Wei, Xin Liu, Ying Yang, Fenli Zhang, Weiliang Zhang, Kaixuan Sun, Yizhen Li, Chun Yang, Jian Pan, Shaoyan Hu.

Alpha-enolase (ENO1) is a potential therapeutic target in acute myeloid leukemia (AML) owning to its elevated expression in AML cells. In this study, we investigated the association between high ENO1 expression, accelerated tumor progression and poor AML prognosis. Transcriptomic and metabolomic analyses indicated that ENO1 directly modulates lipid metabolism via regulating Stearoyl-CoA Desaturase 1 (SCD1) expression. We further demonstrated that ENO1 functions as a DNA-binding protein, interacting with the SCD1 promoter region to enhance SCD1 transcription. This results in increased synthesis of monounsaturated fatty acids, leading to increased resistance to lipid peroxidation and ferroptosis. Based on these results, we found that SSI-4, an SCD1 inhibitor, could enhance chemosensitivity of daunorubicin (DNR), which can induce ferroptosis in tumor cells, effectively reduced the resistance to ferroptosis in AML cells exhibiting high ENO1 expression. Overall, our study elucidates the mechanism of ENO1 promotes SCD1 transcription, driving lipid reprogramming and ferroptosis resistance within AML. Additionally, it highlights the therapeutic potential of combining SCD1 inhibition with DNR for AML patients with elevated ENO1 expression levels.

DOI: https://doi.org/10.1182/bloodadvances.2025017973
bioRxiv. 2026 Apr 14. pii: 2026.04.13.718029. [Epub ahead of print]

Combinatorial base editing couples disease correction with lineage amplification in hematopoietic stem and progenitor cells.

Kun Jia, Eric Soupene, Roshani Sinha, Benjamin J Lesch, Michael A Pendergast, Rachel Choi, Xinyi Zhang, Elisabetta M Foppiani, Zachary Kostamo, Simon N Chu, Devesh Sharma, Xinjie Yu, Marco Cordero, Mark C Walters, Tippi C MacKenzie, Vivien A Sheehan, M Kyle Cromer.

First-generation genome editing therapies have largely focused on correcting or compensating for pathogenic variants. However, as these approaches enter the clinic, emerging biological constraints limit maximal therapeutic impact. Because globin genes are activated late during erythroid differentiation, genome-corrected hematopoietic stem and progenitor cells (HSPCs) gain little selective advantage in the bone marrow. Here, we establish a strategy that links therapeutic genome edits to an erythroid fitness-enhancing allele to amplify the output of clinically relevant cells. We develop a multiplex base editing strategy that couples fetal hemoglobin (HbF) reactivation with erythroid lineage expansion. Introduction of a naturally occurring erythropoietin receptor truncation ( tEPOR ) associated with benign erythrocytosis increased erythroid cell production without impairing viability or differentiation. Combinatorial editing of tEPOR together with the BCL11A erythroid enhancer and HBG1/2 promoters in healthy donor, sickle cell disease, and β-thalassemia HSPCs synergistically increased erythroid proliferation and HbF expression beyond single base-edited or Casgevy-treated controls. Multiplex base-edited HSPCs retained long-term lineage repopulation and engraftment capacity in vivo , establishing a modular strategy that pairs disease correction with lineage amplification to improve therapeutic potency.

DOI: https://doi.org/10.64898/2026.04.13.718029
Cancer Biol Med. 2026 Apr 24. pii: j.issn.2095-3941.2025.0464. [Epub ahead of print]

Evolution in single-cell proteomics drives new frontiers in cancer biology and precision medicine.

Yi Liu, Yingdong Du, Ran Su, Ruibing Chen.

  The inherent heterogeneity of cancer leads to varied responses to treatment and underscores the need for the development of precision medicine. Single-cell proteomics is crucial for deciphering intra- and inter-tumor heterogeneity. Mass cytometry and other antibody-based technologies, which enable simultaneous quantification of >100 proteins per cell, have been widely applied in cancer studies. Concurrently, liquid chromatography-tandem mass spectrometry-based single-cell proteomics has dramatically improved protein coverage from approximately 1,000 to >6,500 proteins per cell, driven by enhanced sample preparation, instrumentation, and throughput. These high-throughput capabilities now empower large-scale, protein-level analyses, which have uncovered detailed maps of tumor heterogeneity. The resulting insights deepen our understanding of tumor biology and provide new opportunities for guiding precision cancer medicine.

Keywords:  Mass spectrometry; precision medicine; single-cell protein analysis; single-cell proteomics; tumor heterogeneity

DOI:  https://doi.org/10.20892/j.issn.2095-3941.2025.0464
Mol Cell. 2026 Apr 30. pii: S1097-2765(26)00238-8. [Epub ahead of print]

Proteotoxic stress response is governed by ER-associated sorting of proteasome transcriptional activators.

Gautier Langin, Margot Raffeiner, David Biermann, Mirita Franz, Daniela Spinti, Frederik Börnke, Boris Macek, Suayib Üstün.

  Proteotoxic stress, characterized by the accumulation of damaged proteins, poses a significant challenge to cellular homeostasis. To mitigate proteotoxicity, eukaryotes rely on the proteasome, which is regulated by proteasome transcriptional activators. As proteotoxicity can originate in different compartments, cells must integrate signals from multiple locations, yet the mechanisms coordinating this response remain unclear. Here, we show that the proteasome autoregulatory feedback loop functions as a gatekeeper enabling the communication between the nucleus and chloroplast. At the endoplasmic reticulum (ER), the plant proteasome transcriptional activators NAC53 and NAC78 undergo either ER-associated degradation (ERAD) or are released for nuclear translocation. We define this dual mechanism as ER-associated sorting (ERAS). While NAC53/78 activate proteasome gene expression, they repress photosynthesis-associated nuclear genes during proteotoxicity through a conserved cis-element. Together, our findings reveal a trade-off between proteasome activity and energy metabolism and establish a framework in which the proteasome feedback loop coordinates subcellular proteostasis and growth-defense balance.

Keywords:  pathogen; photosynthesis; proteasome; proteotoxicity; ubiquitination

DOI:  https://doi.org/10.1016/j.molcel.2026.04.004
Leukemia. 2026 Apr 29.

Multi-omics analysis of pediatric minimally differentiated acute myeloid leukemia reveals RUNX1-driven stemness and chemoresistance.

Tatsuya Kamitori, Satoshi Saida, Kazuki Mitani, Shinichi Tsujimoto, Hiroaki Goto, Hirofumi Shibata, Ryo Akazawa, Kiyotaka Isobe, Hiroo Ueno, Nobuyuki Kakiuchi, Akiko M Saito, Mitsuteru Hiwatari, Ko Kudo, Shinsuke Hirabayashi, Kohei Fukuoka, Katsuyoshi Koh, Takashi Taga, Hirohito Kubota, Itaru Kato, Katsutsugu Umeda, Souichi Adachi, Tomoko Kawai, Daisuke Tomizawa, Junji Ikeda, Norio Shiba, Yasuhide Hayashi, Seishi Ogawa, Junko Takita.

Minimally differentiated acute myeloid leukemia (AML-M0) is a rare and therapeutically challenging subgroup of AML characterized by immature hematopoietic stem cell-like features. To uncover the molecular basis, we conducted a comprehensive multi-omics analysis of 23 pediatric AML-M0 cases and compared them with 1483 leukemia samples. AML-M0 formed a characteristic group that exhibited global DNA hypermethylation and transcriptional suppression, particularly downregulation of genes related to oxidative phosphorylation and ribosome assembly compared to non-M0 AML. Genomic profiling revealed frequent loss-of-function alterations in RUNX1 (26%) and ETV6 (22%), along with activating mutations in signaling pathways (83%), such as RAS, FLT3, and JAK. Notably, RUNX1 alterations were significantly associated with a poor prognosis. Functional analyses using a CRISPR/Cas9-mediated RUNX1 knockout in a pediatric AML-M0 cell line showed stem cell-like transcriptional features and reduced expression of genes related to oxidative phosphorylation and ribosomal pathways. RUNX1 disruption was also associated with reduced in vitro sensitivity to multiple drugs, including cytarabine and anthracyclines. Our study provides the most comprehensive molecular characterization of pediatric AML-M0 to date and identifies RUNX1 alterations as important biological and clinical determinants. These insights highlight the potential strategies for precision therapy, including hypomethylating agents, signaling inhibitors, and metabolic targeting, to improve outcomes.

DOI: https://doi.org/10.1038/s41375-026-02967-6
Anal Chem. 2026 Apr 27.

Simultaneous In-Depth Single-Cell Proteomic and Metabolomic Analysis.

Jie Wu, Fang-Hua Lu, Li-Ye Tao, Ya-Li Wang, Yi Huang, Yu Wang, Yi Yang, Jian-Zhang Pan, Xiao Liang, Qun Fang.

Simultaneous characterization of proteomic and metabolomic profiles at the single-cell level is crucial for deciphering cellular heterogeneity and elucidating disease mechanisms. However, it is still a great challenge to achieve high-depth dual-omics analysis in the same single cell. Here, we propose a unified strategy called one-shot hybrid-mode single-cell proteome and metabolome analysis (hybrid-scPMA), in which the mass spectrometry (MS) detection mode of data-independent acquisition (DIA) is utilized for the analysis of peptides from protein digestion, and the data-dependent acquisition (DDA) mode is used for metabolite analysis in a single liquid chromatography-mass spectrometry (LC-MS) analysis run, enabling deep analysis of the proteome and metabolome in single-cell samples. Building upon the strategy, we established an improved single-cell multiomics analysis workflow that integrated automated single-cell capture, simplified sample pretreatment, LC injection and separation, and DIA-DDA hybrid-mode MS detection. With this approach, we achieved an average identification of 3510 protein groups and 255 metabolites from single HepG2 cells, representing a substantial increase in identification depth over previous approaches. We also performed time-resolved proteomic and metabolomic profiling of HepG2 single cells undergoing sorafenib drug intervention, resolving drug response characteristics at the single-cell level and providing multiomics insights into drug mechanisms from a proteo-metabolomic perspective.

DOI: https://doi.org/10.1021/acs.analchem.5c08090
Hematol Rep. 2026 Apr 07. pii: 27. [Epub ahead of print]18(2):

Metabolomic Signatures of Relapse and Survival in AML Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation.

Igor Novitzky-Basso, Changjiang Xu, Caden Chiarello, Julie A Reisz, Angelo D'Alessandro, Gary D Bader, Jonas Mattsson, Courtney Jones.

  Objectives: Allogeneic stem cell transplantation (HSCT) is curative in acute myeloid leukemia (AML) but is limited by relapse and non-relapse mortality (NRM). Metabolomic prognostic value is unclear. We assessed whether plasma metabolite profiles at diagnosis, pre-transplant, and post-transplant are associated with overall survival (OS) and cause-specific mortality. Methods: We retrospectively analyzed plasma metabolites from 63 AML patients undergoing HSCT (263 samples). Results: Higher levels of valine (hazard ratio [HR] 24.454), citrulline (HR 20.478), 5-oxoproline (HR 11.766), and glutamine (HR 8.701) associated with higher NRM, while inosine diphosphate (HR 0.091) and pyridoxamine-5'-phosphate (HR 0.313) associated with lower NRM. For relapse-related mortality (RRM), higher levels of phenylalanine (HR 26.585), leucine/isoleucine (HR 10.755), indolepyruvate (HR 7.676), and creatinine (HR 13.874) were associated with higher RRM, while trans-4-hydroxy-L-proline (HR 0.101) was associated with lower RRM. Higher post-transplant ornithine (HR 0.063), 3-sulfocatechol (HR 0.590), and indole-3-acetate (HR 0.359) were associated with improved OS. Mixed-effects modelling identified lower dehydroascorbate and citrate in relapsed patients, with dehydroascorbate remaining significant after false discovery rate adjustment. Conclusions: Metabolomic profiling nominated candidate metabolites for validation in larger prospective studies and elucidated mechanistic pathways, potentially informing novel interventions or risk-adapted monitoring strategies in HSCT.

Keywords:  acute myeloid leukemia; allogeneic stem cell transplant; metabolomics

DOI:  https://doi.org/10.3390/hematolrep18020027
bioRxiv. 2026 Apr 17. pii: 2026.04.13.717771. [Epub ahead of print]

Multimodal immunopharmacologic screens identify drugs rewiring the cancer-immune interface.

iCAN Flagship

Natural killer (NK) cell-based therapies are a promising approach in cancer, but their efficacy is limited by impaired effector function and tumor-intrinsic resistance. To systematically identify therapeutic strategies that target both sides of the cancer-immune interface, we designed a multimodal immunopharmacologic screening platform comprising high-throughput co-culture drug screens, cytokine secretome profiling, single-cell perturbation screens, and genome-scale CRISPR screening, followed by validation in biobanked patient-derived models. Applying the platform across five blood cancer types, we identified protein kinase C (PKC) activation to simultaneously increase effector cytotoxicity and cytokine secretion through transcriptomic rewiring, and tumor susceptibility to NK cell killing through tumor-intrinsic PKC-δ. In patient samples, PKC activation sensitized NK-resistant leukemic progenitors to NK cell killing. In addition, NEDD8 inhibition enhanced NK function and shifted tumor TNF signaling towards pro-apoptotic pathways. Our platform provides a systematic approach to identify drugs rewiring both sides of the cancer-immune interface to circumvent tumor immune resistance.

DOI: https://doi.org/10.64898/2026.04.13.717771