bims-scepro 2025-12-21 papers

bims-scepro

Biomed News

on Stem cell proteostasis

Issue of 2025–12–21
fifteen papers selected by
William Grey, University of York

Targeting IL-1/IRAK1/4 signaling in acute myeloid leukemia stem cells following treatment and relapse.
Transient SP140 inhibition unlocks hematopoietic stem cell fate from human pluripotent stem cells.
RPL5 deficiency-induced ribosomal stress targets a select subset of proteins and inhibits the PI3K-Akt-mTOR signaling pathway to eradicate leukemia stem cells.
Ribosomal protein control of hematopoietic stem cell transformation through regulation of metabolism.
Thrombopoietin increases susceptibility for EVI1 + KMT2A-MLLT3-driven AML expressing stem cell genes linked to poor outcome.
IL-27 limits HSPC differentiation during infection and protects from stem cell exhaustion.
Pharmacological Inhibition of miR-126 Enhances Venetoclax Activity in Acute Myeloid Leukemia.
Dynamics of clonal hematopoiesis and cellular responses to stress-induced toxicity in autologous stem cell transplantation.
The glycosaminoglycan oncofetal chondroitin sulfate represents a novel target for antibody drug-conjugate therapy for AML.
Leukemia-expanded splenic CD81+ erythroblasts potentiate disease progression in mice by reshaping leukemic cell metabolism.
Afg3l2 couples mitochondrial vitamin B12 trafficking to amino acid metabolism to safeguard hematopoietic stem cell homeostasis.
The pathogenesis of therapy-related myeloid neoplasms from TP53-mutant clonal hematopoiesis.
BET inhibitor-based combinations targeting novel dependencies in MECOM-rearranged (r) AML.
Nucleophosmin supports WNT-driven hyperproliferation and tumor initiation.
Compression-induced NF-κB activation sustains tumor cell survival in confinement by detoxifying aldehydes and promotes metastasis.

Leukemia. 2025 Dec 19.

Targeting IL-1/IRAK1/4 signaling in acute myeloid leukemia stem cells following treatment and relapse.

Tzu-Chieh Ho, Mark W LaMere, Hiroki Kawano, Daniel K Byun, Elizabeth A LaMere, Yu-Chiao Chiu, Chunmo Chen, Li-Ju Wang, Jian Wang, Baskar Ramdas, Nikolay V Dokholyan, Laura M Calvi, Jane L Liesveld, Craig T Jordan, Rakesh K Singh, Reuben Kapur, Michael W Becker.

Therapies for acute myeloid leukemia (AML) face formidable challenges due to relapse, often driven by leukemia stem cells (LSCs). Strategies targeting LSCs hold promise for enhancing outcomes, yet paired comparisons of functionally defined LSCs at diagnosis and relapse remain underexplored. We present transcriptome analyses of functionally defined LSC populations at diagnosis and relapse, revealing significant alterations in IL-1 signaling. Interleukin-1 receptor type I (IL1R1) and interleukin-1 receptor accessory protein (IL1RAP) were notably upregulated in leukemia stem and progenitor cells at both diagnosis and relapse. Knockdown of IL1R1 and IL1RAP reduced the clonogenicity and/or engraftment of primary human AML cells. In leukemic MLL-AF9 mice, Il1r1 knockout reduced LSC frequency and extended survival. To target IL-1 signaling at both diagnosis and relapse, we developed UR241-2, a novel interleukin-1 receptor-associated kinase 1 and 4 (IRAK1/4) inhibitor. UR241-2 robustly suppressed IL-1/IRAK1/4 signaling, including NF-κB activation and phosphorylation of p65 and p38, following IL-1 stimulation. UR241-2 selectively inhibited LSC clonogenicity in primary human AML cells at both diagnosis and relapse, while sparing normal hematopoietic stem and progenitor cells. It also reduced AML engraftment in leukemic mice. Our findings highlight the therapeutic potential of UR241-2 in targeting IL-1/IRAK1/4 signaling to eradicate LSCs and improve AML outcomes.

DOI: https://doi.org/10.1038/s41375-025-02816-y
Blood. 2025 Dec 15. pii: blood.2025032084. [Epub ahead of print]

Transient SP140 inhibition unlocks hematopoietic stem cell fate from human pluripotent stem cells.

Xingjie Liu, Zhiwei Zhang, Xinyu Cui, Rui Guo, Xiaoyan Ding, Liyang Ma, Pentao Liu, Yong Yu.

Efficient derivation of transplantable hematopoietic stem cells (HSCs) from human pluripotent stem cells (hPSCs) is constrained by epigenetic silencing. Through a CRISPR/Cas9 screen with a BCL11A-eGFP reporter, we identified epigenetic reader SP140 suppressing hematopoiesis. Transient genetic or pharmacologic inhibition of SP140 in hPSC-derived teratoma and embryoid body cultures promoted robust multilineage hematopoiesis and accelerated production of HSCs with serial transplantability and durable reconstitution in immunodeficient mice. Mechanistically, SP140 blockade unlocked transcription at endothelial-to-hematopoietic transition (EHT) loci through topoisomerase 1-dependent chromatin remodeling, activating key hematopoietic and stem cell programs. Transcriptomic analysis showed activation of these regulators upon SP140 inhibition, which was prevented by topoisomerase 1 blockade. CUT&Tag profiling identified SP140 binding at EHT and HSC-specification gene loci. SP140's function as an epigenetic gatekeeper was conserved in diverse hPSCs and murine embryo models, where its downregulation enhanced physiological HSC emergence. Importantly, selective SP140 inhibition in a chemically defined, scalable protocol enabled rapid in vitro generation of bona fide human HSCs suitable for transplantation. These findings identify transient SP140 inhibition as an effective strategy to overcome epigenetic barriers and unlock clinically relevant HSC specification from hPSCs, advancing regenerative hematopoiesis and cell therapy.

DOI: https://doi.org/10.1182/blood.2025032084
Cell Death Dis. 2025 Dec 18.

RPL5 deficiency-induced ribosomal stress targets a select subset of proteins and inhibits the PI3K-Akt-mTOR signaling pathway to eradicate leukemia stem cells.

Xiaofei He, Daijiao Ye, Jiayao He, Gangfeng Ding, Zihan Lin, Yaqian Qin, Bin Zhou, Liuzhi Shi, Xuanyu Yu, Chen Meng, Min Li, Chongyun Xing, Shenmeng Gao.

Ribosomal protein L5 (RPL5) is considered a haplo-insufficient tumor suppressor by upregulating p53 expression or promoting the inactivation of c-Myc in solid tumors upon tumor initiation. However, its detailed effect and mechanism in tumor maintenance were more complicated. Particularly, the specific role of RPL5 in acute myeloid leukemia (AML) remains unclear. In this study, we found that RPL5 expression was increased in primary AML blasts compared with normal controls, regardless of TP53 mutation. RPL5 knockdown reduced the survival and colony-forming ability of AML cells in vitro, as well as inhibited the engraftment of leukemia stem cells (LSCs) in vivo. It indicated that RPL5 was required for the survival of AML cells, especially for maintaining the stemness of LSCs. The data analysis of RNA-seq and proteomics revealed that RPL5 deficiency eradicated LSC by inducing a cellular stress response, i.e., ribosomal stress, rather than a specific function relating to RPL5. The inhibited PI3K-Akt-mTOR signaling pathway played a central role in the ribosomal stress induced by RPL5 deficiency. To investigate the selectivity of RPL5 depletion in eradicating LSCs, we found that RPL5 expression was highest in LSCs compared to AML cells and healthy controls. Moreover, ribosomal stress specifically affected transcripts with longer exon lengths and proteins with a lower isoleucine (Ile) to valine (Val) ratio. Ile and Val are glycogenic branched-chain amino acids (BCAAs) that regulate fundamental cell processes by affecting mTOR activation through BCAA metabolism. In conclusion, RPL5 depletion-induced ribosomal stress disrupted stemness maintenance by affecting BCAA metabolism in AML, specifically inhibiting the PI3K-Akt-mTOR signaling pathway, which resulted in LSC eradication.

DOI: https://doi.org/10.1038/s41419-025-08379-1
Cell Rep. 2025 Dec 12. pii: S2211-1247(25)01460-3. [Epub ahead of print]44(12): 116688

Ribosomal protein control of hematopoietic stem cell transformation through regulation of metabolism.

Bryan Harris, Dinesh K Singh, Billy Truong, Michele Rhodes, Rachael Price, Susan Shinton, Monika Verma, Bridget Aylward, Shawn P Fahl, Shanna R Sprinkle, Sarah Aminov, Minshi Wang, Yong Zhang, Jaqueline Perrigoue, Rachel Kessel, Suraj Peri, Joshua West, Orsi Giricz, Jacqueline Boultwood, Andrea Pellagatti, K H Ramesh, Cristina Montagna, Kith Pradhan, Jeffrey W Tyner, Brian K Kennedy, Michael Holinstat, Ulrich Steidl, Stephen Sykes, Amit Verma, David L Wiest.

  We report here that expression of the ribosomal protein RPL22 is frequently reduced in human myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML), and reduced RPL22 expression is associated with worse outcomes. Mice null for Rpl22 display characteristics of an MDS-like syndrome and develop leukemia at an accelerated rate. Rpl22-deficient mice also display enhanced hematopoietic stem cell (HSC) self-renewal and obstructed differentiation potential, which arises not from reduced protein synthesis but from altered metabolism, including increased fatty acid oxidation (FAO) and a striking induction of the stemness factor Lin28b in the resulting leukemia. Lin28b promotes a substantial increase in lipid content, upon which the survival of Rpl22-deficient leukemias depends. Altogether, these findings reveal that Rpl22 insufficiency enhances the leukemia potential of HSCs through regulation of FAO and promotes leukemogenesis through Lin28b promotion of lipid synthesis.

Keywords:  AML; CP: cancer; CP: molecular biology; Lin28b; MDS; Rpl22; fatty acid metabolism; hematopoietic stem cell; ribosomal protein; triglyceride

DOI:  https://doi.org/10.1016/j.celrep.2025.116688
Nat Commun. 2025 Dec 19.

Thrombopoietin increases susceptibility for EVI1 + KMT2A-MLLT3-driven AML expressing stem cell genes linked to poor outcome.

Hugues-Étienne Châtel-Soulet, Sabine Juge, Ana Luisa Pereira, Jonathan Seguin, Athimed El Taher, Federica Valigi, Zivojin Jevtic, Rathick Sivalingam, Frederik Otzen Bagger, Paul Büschl, Marwa Almosailleakh, Alexander Tzankov, Wei Tong, Mineo Kurokawa, César Nombela Arrieta, Juerg Schwaller.

To address the cellular origin of ecotropic virus integration site 1 (EVI1)-expressing aggressive KMT2A-rearranged acute myeloid leukaemia (AML) we integrate an Evi1-GFP reporter allele in the inducible iKMT2A-MLLT3 mouse model. We observe that a single injection of thrombopoietin (TPO) selectively increases the number of cycling Evi1+ haematopoietic stem cells (HSC) and accelerates AML initiation. Comparison of mouse Evi1+ KMT2-MLLT3+ AML originating from TPO-stimulated HSC with human EVI1+AML reveals higher expression of HSC genes including IL12Rβ2 and INPP4B linked to poor disease outcome of patients of four large AML cohorts. Knockdown experiments show exclusive MECOM-dependency of human EVI1high KMT2A-rearranged OCI-AML4 cells while reduction of IL12Rβ2 also impairs clonogenic growth of EVI1low MOLM-13, THP-1 or HL-60 AML cells. Collectively, we show that exogenous factors like TPO can increase the susceptibility for iKMT2A-MLLT3-driven HSC-originating Evi1+ AML expressing stem cell genes linked to transformation maintenance of cell lines, and poor disease outcome of patients.

DOI: https://doi.org/10.1038/s41467-025-67611-w
Elife. 2025 Dec 15. pii: RP105876. [Epub ahead of print]14

IL-27 limits HSPC differentiation during infection and protects from stem cell exhaustion.

Daniel L Aldridge, Zachary Lanzar, Anthony T Phan, David A Christian, Ryan D Pardy, Booki Min, Ross Kedl, Christopher A Hunter.

  Many inflammatory stimuli can induce progenitor cells in the bone marrow to produce increased numbers of myeloid cells as part of the process of emergency myelopoiesis. These events are associated with trained immunity and have long-term impacts on hematopoietic stem and progenitor cell (HSPC) development but can also compromise their function. While many cytokines support emergency myelopoiesis, less is known about the mechanisms that temper these events. When mice that lack the cytokine IL-27 were infected with Toxoplasma gondii, there was enhanced generation of monocyte progenitors and increased numbers of inflammatory monocytes. In the bone marrow of infected mice, there was increased production of IL-27 that localized with HSPCs, and a survey of cytokine receptor expression highlighted that HSPCs were uniquely poised to respond to IL-27. Furthermore, the use of in vitro differentiation assays and mixed bone marrow chimeras revealed that HSPCs from IL-27-deficient mice are predisposed toward the monocyte lineage. Additional studies highlighted that after infection, loss of the IL-27R resulted in reduced HSPC fitness that manifested as reduced proliferative responses and a decreased ability to reconstitute the hematopoietic system. Thus, the ability of IL-27 to act on HSPC provides a regulatory brake on differentiation to limit monocyte induction and preserve HSPC stemness.

Keywords:  IL-27; anti-inflammatory agents; haematopetic stem cells; host-defense system; immunology; inflammation; mouse; regenerative medicine; stem cells; toxoplasmosis

DOI:  https://doi.org/10.7554/eLife.105876
Blood. 2025 Dec 15. pii: blood.2025029875. [Epub ahead of print]

Pharmacological Inhibition of miR-126 Enhances Venetoclax Activity in Acute Myeloid Leukemia.

Lianjun Zhang, HyunJun Kang, Melissa Valerio, Dinh Hoa Hoang, Khyatiben V Pathak, Krystine Garcia-Mansfield, Xiyuan Lu, Wancheng Guo, Yu-Hsuan Fu, Xin He, Ying-Chieh Chen, Zhenhua Chen, Lucy Y Ghoda, Ralf Buettner, Zhuo Li, Amanda Blackmon, Ling Li, Bin Zhang, Patrick Pirrotte, Guido Marcucci, Ya-Huei Kuo, Le Xuan Truong Nguyen.

Leukemic stem cells (LSCs) in acute myeloid leukemia (AML) depend on oxidative phosphorylation (OXPHOS) sustained by fatty acid oxidation (FAO) and mitochondrial fusion (mitofusion). We demonstrate that miR-126 maintains LSC function by promoting BCL-2-dependent FAO, OXPHOS, and mitofusion, whereas its inhibition disrupts mitochondrial metabolism, induces mitochondrial fission (mitofission), and triggers apoptosis. Mechanistically, miR-126 stabilizes BCL-2 via the SPRED1/ERK axis, which upregulates CPT1B (FAO) and NRF2 (antioxidant response) while regulating mitochondrial dynamics through DRP1 phosphorylation (inhibiting mitofission) and MFN1/2 phosphorylation (enhancing mitofusion). miRisten, a CpG-conjugated anti-miR-126 oligonucleotide now in clinical trials (NCT07025564), synergized with venetoclax (VEN) to suppress FAO/OXPHOS, promote mitofission, and impair LSC homeostasis. In vivo, miRisten potentiated the VEN/azacitidine (AZA) regimen, an FDA-approved therapy for older or unfit AML patients, significantly prolonging survival in patient-derived xenograft models. VEN/miRisten combination also reduced LSC burden and restored VEN sensitivity, establishing miR-126 inhibition as a transformative therapeutic strategy in AML.

DOI: https://doi.org/10.1182/blood.2025029875
Leukemia. 2025 Dec 19.

Dynamics of clonal hematopoiesis and cellular responses to stress-induced toxicity in autologous stem cell transplantation.

Catarina M Stein, Raphael Hablesreiter, Friederike Christen, Pelle Löwe, Coral Fustero-Torre, Klara Kopp, Benjamin N Locher, Lena Nitsch, Robert Altwasser, Johanna Franziska Kerschbaum, Lars Bullinger, Leif S Ludwig, Paulina M Strzelecka, Frederik Damm.

Autologous stem cell transplantation (ASCT) involves harvesting hematopoietic stem and progenitor cells (HSPCs) prior to chemotherapy and subsequent repopulation of the bone marrow. This process imposes a bottleneck, providing a framework to dissect the unresolved short- and long-term clonal dynamics during hematopoietic reconstitution. By integrating bulk error-corrected targeted sequencing of clonal hematopoiesis (CH)-associated genes with mitochondrial single-cell Assay for Transposase-Accessible Chromatin sequencing (mtscATAC-seq), we characterized mutational trajectories in frequently altered hematological genes and traced clonal evolution through somatic mitochondrial DNA variants, revealing post-transplant cellular heterogeneity and clonal architecture. Among 60 patients (multiple myeloma, n = 51; non-Hodgkin lymphoma, n = 6; Hodgkin lymphoma, n = 3), CH-associated mutations were identified in 53% pre-ASCT, predominantly involving DNMT3A. A transient increase in mutation counts and gene diversity occurred 10-25 days post-ASCT, with a gradual clonal expansion two years post-transplantation. Tandem ASCT amplified clonal complexity, with a twofold increase in mutation count and gene-level diversity, while preserving clonal trajectories across both transplant courses. Mitochondrial single-cell profiling in longitudinal samples of 3 patients showed patient-specific immune reconstitution and clonal dynamics, with balanced multilineage output from graft HSPCs. Collectively, our findings provide a firsthand comprehensive view of ASCT-induced clonal dynamics and immune reconstitution, paving the way for targeted gene-specific post-transplant monitoring.

DOI: https://doi.org/10.1038/s41375-025-02823-z
Blood. 2025 Dec 17. pii: blood.2024028147. [Epub ahead of print]

The glycosaminoglycan oncofetal chondroitin sulfate represents a novel target for antibody drug-conjugate therapy for AML.

Joana Mujollari, Montserrat Estruch Alrich, Priya Khadgawat, Swati Choudhary, Tobias Gustavsson, Robert Dagil, Norbert Redlinger, Caroline Løppke, Elena Vidal Calvo, Mie Anemone Nordmaj, Thor Grundtvig Theander, Olaf Heidenreich, Yen Nguyen, Shuyu Qin, Anne Louise Tølbøll Sørensen, Kristen Grønbæk, Bo T Porse, Brigitte Kircher, Jan Mueller, Mette Agerbæk, Ali Salanti, Kim Theilgaard-Mönch.

Antibody-drug conjugates (ADCs) have emerged as promising targeted therapies in acute myeloid leukemia (AML). However, most ADCs exhibit off-target binding to normal hematopoietic stem and myeloid progenitor cells, resulting in adverse hemato-toxicity and narrow therapeutic windows, limiting their clinical application to young and fit AML patients eligible for intensive curative therapies. Proteoglycans with high levels of the glycosaminoglycan oncofetal chondroitin sulfate (ofCS), are abundantly expressed in solid cancers while being absent or lowly expressed in normal adult tissues. Here, we report high ofCS levels on bone marrow (BM) cells of AML patients and AML patient-derived xenografts (PDXs), while BM cells of healthy subjects showed low or undetectable ofCS levels. Consistently, an anti-ofCS antibody demonstrated binding and internalization into AML cells, and anti-ofCS ADCs effectively killed AML cells in vitro. Moreover, anti-ofCS ADC treatment significantly prolonged survival of AML PDXs compared to controls and was associated with low toxicity. Hence, anti-ofCS ADC could represent an effective therapy with acceptable toxicity applicable for all AML patients, including those ineligible or unresponsive to current intensive curative therapies. In conclusion, our study for the first time demonstrates that a glycosaminoglycan like ofCS represents a druggable target for development of effective antibody-based AML therapies.

DOI: https://doi.org/10.1182/blood.2024028147
J Clin Invest. 2025 Dec 15. pii: e193082. [Epub ahead of print]135(24):

Leukemia-expanded splenic CD81+ erythroblasts potentiate disease progression in mice by reshaping leukemic cell metabolism.

Yue Li, Jiaxuan Cao, Jingyuan Tong, Peixia Tang, Haoran Chen, Guohuan Sun, Zining Yang, Xiaoru Zhang, Fang Dong, Shangda Yang, Jie Gao, Xiangnan Zhao, Jinfa Ma, Di Wang, Lei Zhang, Lin Wang, Tao Cheng, Hui Cheng, Lihong Shi.

  During the progression of acute myeloid leukemia (AML), extramedullary hematopoiesis (EMH) compensates for impaired bone marrow hematopoiesis. However, the specific cellular dynamics of EMH and its influence on AML progression remain poorly understood. In this study, we identified a substantial expansion of the CD81+ erythroblast subpopulation (CD81+ Erys) in the spleens of AML mice, which promoted AML cell proliferation and reduced survival. Mechanistically, CD81+ Erys secrete elevated levels of macrophage migration-inhibitory factor (MIF), which interacted with the CD74 receptor on AML cells, activating the mTORC1 signaling pathway and upregulating Egln3. Consequently, AML cells cocultured with CD81+ Erys exhibited reprogrammed phospholipid metabolism, characterized by an increased phospholipid-to-lysophospholipid ratio. Modulating this metabolic shift, either by supplementing exogenous lysophospholipids or depleting Egln3 in AML cells, restored the phospholipid balance and mitigated the protumorigenic effects induced by CD81+ Erys. Overall, our findings elucidate the molecular crosstalk between erythroblasts and AML cells, extend our insights into the mechanisms driving AML progression, and suggest potential therapeutic strategies.

Keywords:  Cell biology; Hematology; Leukemias; Metabolism

DOI:  https://doi.org/10.1172/JCI193082
Cell Rep. 2025 Dec 17. pii: S2211-1247(25)01507-4. [Epub ahead of print]45(1): 116735

Afg3l2 couples mitochondrial vitamin B12 trafficking to amino acid metabolism to safeguard hematopoietic stem cell homeostasis.

Meng Zhang, Xiashiyao Zhang, Yandan Chen, Mengmeng Li, Qingwei Ding, Liang Zheng, Junke Zheng, Jun Wan, Bin Guo.

  Mitochondrial proteostasis is essential for hematopoietic stem cell (HSC) maintenance, yet how proteolytic regulation coordinates with metabolic pathways remains unclear. Here, we identify Afg3l2 as a key regulator of cobalamin metabolism and amino acid homeostasis in HSCs through its mediation of Mmadhc degradation. Loss of Afg3l2 leads to Mmadhc accumulation, driving excessive mitochondrial cobalamin import and its conversion to adenosylcobalamin. Elevated adenosylcobalamin levels hyperactivate methylmalonyl-CoA mutase, diverting branched-chain amino acid catabolism toward excessive succinyl-CoA production. This overstimulates the tricarboxylic acid cycle and creates a compensatory dependency on anaplerotic amino acid replenishment. Consequently, Afg3l2-deficient HSCs exhibit increased oxidative stress due to mitochondrial hyperactivation and reactive oxygen species accumulation, ultimately impairing their maintenance and engraftment capacity. Remarkably, Mmadhc overexpression phenocopies these defects, whereas Mmadhc knockdown partially restores HSC function in Afg3l2-deficient models. Our work defines a proteostatic-metabolic circuit in which Afg3l2-mediated Mmadhc degradation regulates cobalamin flux to maintain amino acid and energy balance in HSCs.

Keywords:  CP: Metabolism; CP: Stem cell research; TCA cycle; amino acid metabolism; cobalamin metabolism; hematopoietic stem cell; mitochondrial protease

DOI:  https://doi.org/10.1016/j.celrep.2025.116735
Leukemia. 2025 Dec 17.

The pathogenesis of therapy-related myeloid neoplasms from TP53-mutant clonal hematopoiesis.

Jonas Fullin, Ebru Topçu, Karolina A Zielińska, Roman R Schimmer, Nancy Klemm, Christian Koch, Francisco Caiado, Melissa Lock, Cyril Doerdelmann, Marco M Bühler, Joelle Tchinda, Kari J Kurppa, Lubor Borsig, Philip H Jones, Massimo Lopes, Markus G Manz, Steffen Boettcher.

Therapy-related acute myeloid leukemia and myelodysplastic neoplasms (t-AML/MDS) are devastating complications of chemo- or radiation therapy in patients treated for an unrelated primary malignancy. Cancer patients with TP53-mutant hematopoietic stem and progenitor cells (HSPCs) - a condition termed clonal hematopoiesis (CH) - are at a particularly high risk for t-AML/MDS. However, the pathogenesis of TP53-mutant t-AML/MDS, especially the role of the TP53 allelic state (i.e., mono- vs. biallelic), and its prognostic impact in AML/MDS have remained only poorly understood. We developed novel in vitro and in vivo mouse models to investigate how mono- or biallelic Trp53 mutations influence clonal expansion and leukemic progression from CH to t-AML/MDS. While HSPCs with monoallelic Trp53 mutations gain clonal fitness but retain their genomic integrity under chemo- or radiation therapy, biallelic Trp53 mutations result in genomic instability and are essential for leukemic transformation. Moreover, we provide proof of concept that non-mutational p53 inactivation, such as MDM2 overexpression, can replicate the effects of biallelic TP53 mutations, providing a possible explanation for cases of TP53-mutant AML/MDS that retain one wild-type TP53 allele. Our findings elucidate the pathogenesis of TP53-mutant t-AML/MDS and support the classification of biallelic TP53-mutant AML/MDS as distinct clinical entities.

DOI: https://doi.org/10.1038/s41375-025-02839-5
Leukemia. 2025 Dec 19.

BET inhibitor-based combinations targeting novel dependencies in MECOM-rearranged (r) AML.

Christine E Birdwell, Warren Fiskus, Christopher P Mill, Tapan M Kadia, Naval Daver, Courtney D DiNardo, Koji Sasaki, John A Davis, Kaberi Das, Hanxi Hou, Antrix Jain, Anna Malovannaya, Lauren B Flores, Rasoul Pourebrahim, Selina Yuan, Xiaoping Su, Michele Ceribelli, Kapil N Bhalla.

MECOM rearrangement in AML involves either inv(3)(q21;q26.2) or t(3;3)(q21;q26.2), where the dislocated GATA2 enhancer drives overexpression of the transcriptional regulator EVI1, causes concomitant GATA2 repression, and promotes AML progression, aggressive phenotype and therapy refractoriness. Treatment with BET protein inhibitor (BETi) induces in vitro and in vivo efficacy in MECOM-r AML cells. Utilizing an unbiased, high-throughput drug screen, focused on mechanistically-annotated drugs, we identified BRD4, PIK3CA, mTOR, BCL-xL and XIAP as dependencies in the MECOM-r AML cells. Monotherapy with mivebresib (BETi), dactolisib (PI3K/mTORi) and LCL161 (IAPi) dose-dependently induced greater lethality in PD MECOM-r versus non-MECOM-r AML cells. RNA-Seq and/or mass spectrometry analyses revealed that treatment with mivebresib or dactolisib downregulated MYC-targets and cell-cycle gene-sets whereas CyTOF and Western analyses also demonstrated reduction in the protein levels of EVI1, c-Myb, c-Myc in MECOM-r AML cells. Combination of mivebresib and dactolisib or LCL161 synergistically induced apoptosis. In a MECOM-r AML PDX model, mivebresib with dactolisib or LCL161, was superior to monotherapy or vehicle in reducing AML burden and increasing mouse survival. These findings highlight that cotreatment with BETi and PI3K/mTOR or IAP inhibitor exerts superior in vitro and in vivo efficacy in MECOM-r AML cells and support further evaluation of these BETi-based combinations.

DOI: https://doi.org/10.1038/s41375-025-02842-w
Nat Genet. 2025 Dec 18.

Nucleophosmin supports WNT-driven hyperproliferation and tumor initiation.

Georgios Kanellos, Chiara Giacomelli, Alexander Raven, Nikola Vlahov, Hu Jin, Pauline Herviou, Sudhir B Malla, Nadia Nasreddin, Patricia P Centeno, Constantinos Alexandrou, Kathryn Gilroy, Rachel L Baird, Kathryn Pennel, June Munro, Joseph A Waldron, Holly Hall, Leah Officer-Jones, Sheila Bryson, Douglas Strathdee, Sergio Lilla, Sara Zanivan, Vivienne Morrison, Colin Nixon, Rachel A Ridgway, Crispin Miller, John R P Knight, Andrew D Campbell, Philip D Dunne, John Le Quesne, Joanne Edwards, Peter J Park, Martin Bushell, Owen J Sansom.

Nucleophosmin (NPM1), a nucleolar protein frequently mutated in hematopoietic malignancies, is overexpressed in several solid tumors with poorly understood functional roles. Here, we demonstrate that Npm1 is upregulated after APC loss in WNT-responsive tissues and supports WNT-driven intestinal and liver tumorigenesis. Mechanistically, NPM1 loss induces ribosome pausing and accumulation at the 5'-end of coding sequences, triggering a protein synthesis stress response and p53 activation, which mediate this antitumorigenic effect. Collectively, our data identify NPM1 as a critical WNT effector that sustains WNT-driven hyperproliferation and tumorigenesis by attenuating the integrated stress response and p53 activation. Notably, NPM1 expression correlates with elevated WNT signaling and proliferation in human colorectal cancer (CRC), while CRCs harboring NPM1 deletions exhibit preferential TP53 inactivation, underscoring the clinical relevance of our findings. Being dispensable for adult epithelial homeostasis, NPM1 represents a promising therapeutic target in p53-proficient WNT-driven tumors, including treatment-refractory KRAS-mutant CRC, and hepatic cancers.

DOI: https://doi.org/10.1038/s41588-025-02408-7
Nat Commun. 2025 Dec 14.

Compression-induced NF-κB activation sustains tumor cell survival in confinement by detoxifying aldehydes and promotes metastasis.

Bing Liu, Min Liu, Yajuan Zhang, Yifei Zhu, Dingpei Zhou, Hong Gao, Fan Yang, Dong Gao, Yun Zhao, BangBao Tao, Feng Yao, Weiwei Yang.

Metastasis remains the primary cause of cancer-related mortality. During dissemination, cancer cells must navigate spatially confined microenvironments, yet the underlying metabolic adaptations that facilitate this process remain unclear. Here, through an in vivo CRISPR screen targeting metabolic enzymes, we identify aldehyde dehydrogenase 1 family member B1 (ALDH1B1) as essential for tumor cell survival in confining capillaries. Mechanistically, compressive force induces casein kinase 2 alpha 3 (CSK23) to phosphorylate kappa-B kinase subunit beta (IKKβ) at Ser177/181, which activates the nuclear factor kappa B (NF-κB) pathway and upregulates ALDH1B1. The upregulation of ALDH1B1 enhances aldehyde detoxification, which suppresses ferroptosis and promotes tumor cell survival during migration through the capillaries, thereby facilitating metastasis. Importantly, genetic or pharmacological inhibition of CSK23 or ALDH1B1 effectively impairs metastasis. In lung cancer patients, confined tumor cells exhibit higher levels of ALDH1B1 and NF-κB activation, which correlates with metastatic recurrence. Our findings reveal a mechano-metabolic pathway that promotes metastasis and suggest CSK23 and ALDH1B1 as potential therapeutic targets.

DOI: https://doi.org/10.1038/s41467-025-67452-7