bims-scepro 2024-08-18 papers

bims-scepro

Biomed News

on Stem cell proteostasis

Issue of 2024‒08‒18
27 papers selected by
William Grey, University of York

A novel study on CXXC5: unraveling its regulatory mechanisms in hematopoietic stem cell biology through proteomics and gene editing.
IL1RAP-specific T cell engager depletes acute myeloid leukemia stem cells.
Heterotypic interaction promotes asymmetric division of human hematopoietic progenitors.
The tandem CD33-CLL1 CAR-T as an approach to treat acute myeloid leukemia.
Arsenic trioxide and p97 inhibitor synergize against acute myeloid leukemia by targeting nascent polypeptides and activating the ZAKα-JNK pathway.
The Leukemic Isocitrate Dehydrogenase (IDH) 1/2 Mutations Impair Myeloid and Erythroid Cell Differentiation of Primary Human Hematopoietic Stem and Progenitor Cells (HSPCs).
Super enhancer acquisition drives expression of oncogenic PPP1R15B that regulates protein homeostasis in multiple myeloma.
The crosstalk between lung cancer and the bone marrow niche fuels emergency myelopoiesis.
Brief cycling intervals incrementally increase the number of hematopoietic stem and progenitor cells in human peripheral blood.
Mitochondrial permeability transition dictates mitochondrial maturation upon switch in cellular identity of hematopoietic precursors.
Cullin 4B-RING E3 ligase negatively regulates the immunosuppressive capacity of mesenchymal stem cells by suppressing iNOS.
The Aryl Hydrocarbon Receptor Regulates Invasiveness and Motility in Acute Myeloid Leukemia Cells through Expressional Regulation of Non-Muscle Myosin Heavy Chain IIA.
Lys-63-specific deubiquitinase BRCC36 enhances the sensitivity of multiple myeloma cells to lenalidomide by inhibiting lysosomal degradation of cereblon.
Age and dose dependent changes to the bone and bone marrow microenvironment after cytotoxic conditioning with busulfan.
Chidamide induces cell cycle arrest via NR4A3/P21 axis upregulation to suppress relapsed and refractory acute myeloid leukemia.
OPA1 promotes ferroptosis by augmenting mitochondrial ROS and suppressing an integrated stress response.
ZBTB46 coordinates angiogenesis and immunity to control tumor outcome.
Chemotaxis Assay of Bone Marrow-Derived Macrophages.
OTUD6 deubiquitination of RPS7/eS7 on the free 40 S ribosome regulates global protein translation and stress.
Genetically Encoded Microtubule Binders for Single-Cell Interrogation of Cytoskeleton Dynamics and Protein Activity.
P-NADs: PUX-based NAnobody degraders for ubiquitin-independent degradation of target proteins.
Genetic risk classification for adults with AML receiving less-intensive therapies: the 2024 ELN recommendations.
Dissecting the functional behavior of the differentially phosphorylated prolyl isomerase, Pin1.
Degradability tunes ECM stress relaxation and cellular mechanics.
Fast and deep phosphoproteome analysis with the Orbitrap Astral mass spectrometer.
Hydrogel crosslinking modulates macrophages, fibroblasts, and their communication, during wound healing.
Therapeutic advances of targeting receptor tyrosine kinases in cancer.

Genes Genomics. 2024 Aug 16.

A novel study on CXXC5: unraveling its regulatory mechanisms in hematopoietic stem cell biology through proteomics and gene editing.

Shanshan Liu, Yan Gao, Xianqi Feng, Yujie Xu, Minghui Hu, Hairong Fei, Hongying Zheng, Junxia Huang, Tianlan Li, Chunting Zhao, Lingjie Sun.

  BACKGROUND: This study investigates the role of CXXC5 in the self-renewal and differentiation of hematopoietic stem cells (HSCs) within the bone marrow microenvironment, utilizing advanced methodologies such as single-cell RNA sequencing (scRNA-seq), CRISPR-Cas9, and proteomic analysis.METHODS: We employed flow cytometry to isolate HSCs from bone marrow samples, followed by scRNA-seq analysis using the 10x Genomics platform to examine cell clustering and CXXC5 expression patterns. CRISPR-Cas9 and lentiviral vectors facilitated the knockout and overexpression of CXXC5 in HSCs. The impact on HSCs was assessed through qRT-PCR, Western blot, CCK-8, CFU, and LTC-IC assays, alongside flow cytometry to measure apoptosis and cell proportions. A mouse model was also used to evaluate the effects of CXXC5 manipulation on HSC engraftment and survival rates.
RESULTS: Our findings highlight the diversity of cell clustering and the significant role of CXXC5 in HSC regulation. Knockout experiments showed reduced proliferation and accelerated differentiation, whereas overexpression led to enhanced proliferation and delayed differentiation. Proteomic analysis identified key biological processes influenced by CXXC5, including cell proliferation, differentiation, and apoptosis. In vivo results demonstrated that CXXC5 silencing impaired HSC engraftment in a bone marrow transplantation model.
CONCLUSION: CXXC5 is crucial for the regulation of HSC self-renewal and differentiation in the bone marrow microenvironment. Its manipulation presents a novel approach for enhancing HSC function and provides a potential therapeutic target for hematological diseases.

Keywords:  Bone marrow microenvironment; CRISPR-Cas9; CXXC5; Cell differentiation; Hematopoietic stem cells; Proteomics; Self-renewal; Single-cell RNA sequencing

DOI:  https://doi.org/10.1007/s13258-024-01540-8
J Hematol Oncol. 2024 Aug 14. 17(1): 67

IL1RAP-specific T cell engager depletes acute myeloid leukemia stem cells.

Yi Zhang, Miso Park, Lucy Y Ghoda, Dandan Zhao, Melissa Valerio, Ebtesam Nafie, Asaul Gonzalez, Kevin Ly, Bea Parcutela, Hyeran Choi, Xubo Gong, Fang Chen, Kaito Harada, Zhenhua Chen, Le Xuan Truong Nguyen, Flavia Pichiorri, Jianjun Chen, Joo Song, Stephen J Forman, Idoroenyi Amanam, Bin Zhang, Jie Jin, John C Williams, Guido Marcucci.

  BACKGROUND: The interleukin-1 receptor accessory protein (IL1RAP) is highly expressed on acute myeloid leukemia (AML) bulk blasts and leukemic stem cells (LSCs), but not on normal hematopoietic stem cells (HSCs), providing an opportunity to target and eliminate the disease, while sparing normal hematopoiesis. Herein, we report the activity of BIF002, a novel anti-IL1RAP/CD3 T cell engager (TCE) in AML.METHODS: Antibodies to IL1RAP were isolated from CD138+ B cells collected from the immunized mice by optoelectric positioning and single cell sequencing. Individual mouse monoclonal antibodies (mAbs) were produced and characterized, from which we generated BIF002, an anti-human IL1RAP/CD3 TCE using Fab arm exchange. Mutations in human IgG1 Fc were introduced to reduce FcγR binding. The antileukemic activity of BIF002 was characterized in vitro and in vivo using multiple cell lines and patient derived AML samples.
RESULTS: IL1RAP was found to be highly expressed on most human AML cell lines and primary blasts, including CD34+ LSC-enriched subpopulation from patients with both de novo and relapsed/refractory (R/R) leukemia, but not on normal HSCs. In co-culture of T cells from healthy donors and IL1RAPhigh AML cell lines and primary blasts, BIF002 induced dose- and effector-to-target (E:T) ratio-dependent T cell activation and leukemic cell lysis at subnanomolar concentrations. BIF002 administered intravenously along with human T cells led to depletion of leukemic cells, and significantly prolonged survival of IL1RAPhigh MOLM13 or AML patient-derived xenografts with no off-target side effects, compared to controls. Of note, BiF002 effectively redirects T cells to eliminate LSCs, as evidenced by the absence of disease initiation in secondary recipients of bone marrow (BM) from BIF002+T cells-treated donors (median survival not reached; all survived > 200 days) compared with recipients of BM from vehicle- (median survival: 26 days; p = 0.0004) or isotype control antibody+T cells-treated donors (26 days; p = 0.0002).
CONCLUSIONS: The novel anti-IL1RAP/CD3 TCE, BIF002, eradicates LSCs and significantly prolongs survival of AML xenografts, representing a promising, novel treatment for AML.

Keywords:  Acute myeloid leukemia; IL1RAP; Immunotherapy; Leukemic stem cells; T cell engager

DOI:  https://doi.org/10.1186/s13045-024-01586-x
Development. 2024 Aug 13. pii: dev.203088. [Epub ahead of print]

Heterotypic interaction promotes asymmetric division of human hematopoietic progenitors.

Adrian Candelas, Benoit Vianay, Matthieu Gelin, Lionel Faivre, Jerome Larghero, Laurent Blanchoin, Manuel Théry, Stéphane Brunet.

  Hematopoietic Stem and Progenitor Cells (HSPCs) give rise to all cell types of the hematopoietic system through various processes including asymmetric divisions. However, the contribution of stromal cells of the hematopoietic niches in the control of HSPC asymmetric divisions remains unknown. Using polyacrylamide microwells as minimalist niches, we show that specific heterotypic interaction with osteoblast and endothelial cell promote asymmetric division of human HSPC. Upon interaction, HSPCs polarize in interphase with the centrosome, the Golgi apparatus, and lysosomes positioned close to the site of contact. Subsequently, during mitosis, HSPCs orient their spindle perpendicular to the plane of contact. This division mode gives rise to siblings with unequal amounts of lysosomes and of CD34 differentiation marker. Such asymmetric inheritance generates heterogeneity in the progeny, which is likely to contribute to the plasticity of the early steps of hematopoiesis.

Keywords:  Asymmetric division; Hematopoiesis; Heterotypic interaction; Microfabrication; Niches; Stem cells

DOI:  https://doi.org/10.1242/dev.203088
Blood Transfus. 2024 Aug 06.

The tandem CD33-CLL1 CAR-T as an approach to treat acute myeloid leukemia.

Huiru Wang, Shanglong Feng, Yanliang Zhu, Yafeng Zhang, Ziwei Zhou, Zhigang Nian, Xueqin Lu, Peng Peng, Shu Wu, Li Zhou.

BACKGROUND: Acute myeloid leukemia (AML) is characterized by high heterogeneity, poor long-term survival, and a propensity for relapse. Exceptional efficacy in treating recurrent or refractory B-lymphoid malignancies has been demonstrated by Chimeric antigen receptor T cells (CAR-T cells). Given the therapeutic potential of targeting both CD33 and C-type lectin-like molecule-1 (CLL1) in AML, the development of a dual-targeting CD33-CLL1 CAR-T cells assumes significant importance.MATERIALS AND METHODS: The expressions of CD33 and CLL-1 antigens in peripheral blood cells and bone marrow cells from AML patients was assessed. Subsequently, a Chimeric Antigen Receptor (CAR) incorporating a dual-specific single-chain variable fragment targeting CLL1 and CD33 (CD33-CLL1-CAR-T) was engineered. The anti-tumor efficacy and potential side effects of CD33-CLL1-CAR-T cells were comprehensively investigated in both in vitro and in vivo settings.
RESULTS: The constructed tandem CD33-CLL1 CAR-T exhibited potent cytotoxicity against leukemia cell lines and human primary AML cells in vitro. Co-cultivation of AML blasts with CD33-CLL1-CAR-T cells resulted in effective proliferation and the secretion of substantial quantities of GM-CSF and IFN-γ. Importantly, the impact of CD33-CLL1-CAR-T cells on normal hematopoietic stem cells was minimal, ensuring safety in vivo mouse models. Notably, significant anti-leukemic activity was observed in the mouse model, with CD33-CLL1-CAR-T cells leading to tumor eradication and prolonged survival.
DISCUSSION: The tandem CD33-CLL1 CAR-T cells not only efficiently eliminated AML blasts but also exhibited low cytotoxicity toward normal hematopoietic stem cells (HSCs). These findings underscore the potential clinical applicability of the tandem CD33-CLL1 CAR-T cells as an effective and safe treatment strategy for AML, representing a noteworthy advancement in the field of CAR-T cells therapy.

DOI: https://doi.org/10.2450/BloodTransfus.786
Cancer Gene Ther. 2024 Aug 09.

Arsenic trioxide and p97 inhibitor synergize against acute myeloid leukemia by targeting nascent polypeptides and activating the ZAKα-JNK pathway.

Shufeng Xie, Hui Liu, Shouhai Zhu, Zhihong Chen, Ruiheng Wang, Wenjie Zhang, Huajian Xian, Rufang Xiang, Xiaoli Xia, Yong Sun, Jinlan Long, Yuanli Wang, Minghui Wang, Yixin Wang, Yaoyifu Yu, Zixuan Huang, Chaoqun Lu, Zhenshu Xu, Han Liu.

Arsenic trioxide (ATO) has exhibited remarkable efficacy in treating acute promyelocytic leukemia (APL), primarily through promoting the degradation of the PML-RARα fusion protein. However, ATO alone fails to confer any survival benefit to non-APL acute myeloid leukemia (AML) patients and exhibits limited efficacy when used in combination with other agents. Here, we explored the general toxicity mechanisms of ATO in APL and potential drugs that could be combined with ATO to exhibit synergistic lethal effects on other AML. We demonstrated that PML-RARα degradation and ROS upregulation were insufficient to cause APL cell death. Based on the protein synthesis of different AML cells and their sensitivity to ATO, we established a correlation between ATO-induced cell death and protein synthesis. Our findings indicated that ATO induced cell death by damaging nascent polypeptides and causing ribosome stalling, accompanied by the activation of the ZAKα-JNK pathway. Furthermore, ATO-induced stress activated the GCN2-ATF4 pathway, and ribosome-associated quality control cleared damaged proteins with the assistance of p97. Importantly, our data revealed that inhibiting p97 enhanced the effectiveness of ATO in killing AML cells. These explorations paved the way for identifying optimal synthetic lethal drugs to enhance ATO treatment on non-APL AML.

DOI: https://doi.org/10.1038/s41417-024-00818-z
Cancers (Basel). 2024 Jul 27. pii: 2675. [Epub ahead of print]16(15):

The Leukemic Isocitrate Dehydrogenase (IDH) 1/2 Mutations Impair Myeloid and Erythroid Cell Differentiation of Primary Human Hematopoietic Stem and Progenitor Cells (HSPCs).

Sara Pierangeli, Serena Donnini, Valerio Ciaurro, Francesca Milano, Valeria Cardinali, Sofia Sciabolacci, Gaetano Cimino, Ilaria Gionfriddo, Roberta Ranieri, Sabrina Cipriani, Eleonora Padiglioni, Roberta Iacucci Ostini, Tiziana Zei, Antonio Pierini, Maria Paola Martelli.

  How hematopoietic stem and progenitor cell (HSPC) fate decisions are affected by genetic alterations acquired during AML leukemogenesis is poorly understood and mainly explored in animal models. Here, we study isocitrate dehydrogenase (IDH) gene mutations in the human model of HSPC and discuss the available literature on this topic. IDH1/2 mutations occur in ~20% of AML cases, are recognized among the mutations earliest acquired during leukemogenesis, and are targets of specific inhibitors (ivosidenib and enasidenib, respectively). In order to investigate the direct effects of these mutations on HSPCs, we expressed IDH1-R132H or IDH2-R140Q mutants into human CD34+ healthy donor cells via lentiviral transduction and analyzed the colony-forming unit (CFU) ability. CFU ability was dramatically compromised with a complete trilineage block of differentiation. Strikingly, the block was reversed by specific inhibitors, confirming that it was a specific effect induced by the mutants. In line with this observation, the CD34+ leukemic precursors isolated from a patient with IDH2-mutated AML at baseline and during enasidenib treatment showed progressive and marked improvements in their fitness over time, in terms of CFU ability and propensity to differentiate. They attained clonal trilinear reconstitution of hematopoiesis and complete hematological remission.

Keywords:  IDH1/2 mutation; acute myeloid leukemia; human HSPC modeling

DOI:  https://doi.org/10.3390/cancers16152675
Nat Commun. 2024 Aug 09. 15(1): 6810

Super enhancer acquisition drives expression of oncogenic PPP1R15B that regulates protein homeostasis in multiple myeloma.

Sinan Xiong, Jianbiao Zhou, Tze King Tan, Tae-Hoon Chung, Tuan Zea Tan, Sabrina Hui-Min Toh, Nicole Xin Ning Tang, Yunlu Jia, Yi Xiang See, Melissa Jane Fullwood, Takaomi Sanda, Wee-Joo Chng.

Multiple myeloma is a hematological malignancy arising from immunoglobulin-secreting plasma cells. It remains poorly understood how chromatin rewiring of regulatory elements contributes to tumorigenesis and therapy resistance in myeloma. Here we generate a high-resolution contact map of myeloma-associated super-enhancers by integrating H3K27ac ChIP-seq and HiChIP from myeloma cell lines, patient-derived myeloma cells and normal plasma cells. Our comprehensive transcriptomic and phenomic analyses prioritize candidate genes with biological and clinical implications in myeloma. We show that myeloma cells frequently acquire SE that transcriptionally activate an oncogene PPP1R15B, which encodes a regulatory subunit of the holophosphatase complex that dephosphorylates translation initiation factor eIF2α. Epigenetic silencing or knockdown of PPP1R15B activates pro-apoptotic eIF2α-ATF4-CHOP pathway, while inhibiting protein synthesis and immunoglobulin production. Pharmacological inhibition of PPP1R15B using Raphin1 potentiates the anti-myeloma effect of bortezomib. Our study reveals that myeloma cells are vulnerable to perturbation of PPP1R15B-dependent protein homeostasis, highlighting a promising therapeutic strategy.

DOI: https://doi.org/10.1038/s41467-024-50910-z
Front Immunol. 2024 ;15 1397469

The crosstalk between lung cancer and the bone marrow niche fuels emergency myelopoiesis.

Evelyn Calderon-Espinosa, Kirsten De Ridder, Thomas Benoot, Yanina Jansen, Domien Vanhonacker, Robbe Heestermans, Ann De Becker, Ivan Van Riet, Lore Decoster, Cleo Goyvaerts.

  Modest response rates to immunotherapy observed in advanced lung cancer patients underscore the need to identify reliable biomarkers and targets, enhancing both treatment decision-making and efficacy. Factors such as PD-L1 expression, tumor mutation burden, and a 'hot' tumor microenvironment with heightened effector T cell infiltration have consistently been associated with positive responses. In contrast, the predictive role of the abundantly present tumor-infiltrating myeloid cell (TIMs) fraction remains somewhat uncertain, partly explained by their towering variety in terms of ontogeny, phenotype, location, and function. Nevertheless, numerous preclinical and clinical studies established a clear link between lung cancer progression and alterations in intra- and extramedullary hematopoiesis, leading to emergency myelopoiesis at the expense of megakaryocyte/erythroid and lymphoid differentiation. These observations affirm that a continuous crosstalk between solid cancers such as lung cancer and the bone marrow niche (BMN) must take place. However, the BMN, encompassing hematopoietic stem and progenitor cells, differentiated immune and stromal cells, remains inadequately explored in solid cancer patients. Subsequently, no clear consensus has been reached on the exact breadth of tumor installed hematopoiesis perturbing cues nor their predictive power for immunotherapy. As the current era of single-cell omics is reshaping our understanding of the hematopoietic process and the subcluster landscape of lung TIMs, we aim to present an updated overview of the hierarchical differentiation process of TIMs within the BMN of solid cancer bearing subjects. Our comprehensive overview underscores that lung cancer should be regarded as a systemic disease in which the cues governing the lung tumor-BMN crosstalk might bolster the definition of new biomarkers and druggable targets, potentially mitigating the high attrition rate of leading immunotherapies for NSCLC.

Keywords:  biomarkers; bone marrow; emergency myelopoiesis; hematopoiesis; immunotherapy; lung cancer

DOI:  https://doi.org/10.3389/fimmu.2024.1397469
Front Physiol. 2024 ;15 1327269

Brief cycling intervals incrementally increase the number of hematopoietic stem and progenitor cells in human peripheral blood.

Fendi Pradana, Tarondeep Nijjar, Phoebe A Cox, Paul T Morgan, Tim Podlogar, Samuel J E Lucas, Mark T Drayson, Francesca A M Kinsella, Alex J Wadley.

  Introduction: Peripheral blood stem cell (PBSC) donation is the primary procedure used to collect hematopoietic stem and progenitor cells (HSPCs) for hematopoietic stem cell transplantation. Single bouts of exercise transiently enrich peripheral blood with HSPCs and cytolytic natural killer cells (CD56dim), which are important in preventing post-transplant complications. To provide a rationale to investigate the utility of exercise in a PBSC donation setting (≈3 h), this study aimed to establish whether interval cycling increased peripheral blood HSPC and CD56dim concentrations to a greater degree than continuous cycling.Methods: In a randomised crossover study design, eleven males (mean ± SD: age 25 ± 7 years) undertook bouts of moderate intensity continuous exercise [MICE, 30 min, 65%-70% maximum heart rate (HRmax)], high-volume high intensity interval exercise (HV-HIIE, 4 × 4 min, 80%-85% HRmax) and low-volume HIIE (LV-HIIE, 4 × 2 min, 90%-95% HRmax). The cumulative impact of each interval on circulating HSPC (CD34+CD45dimSSClow) and CD56dim concentrations (cells/µL), and the bone marrow homing potential of HSPCs (expression of CXCR-4 and VLA-4) were determined.
Results: There was an increase in HSPC concentration after two intervals of LV-HIIE (Rest: 1.84 ± 1.55 vs. Interval 2: 2.94 ± 1.34, P = 0.01) and three intervals of HV-HIIE only (Rest: 2.05 ± 0.86 vs. Interval 3: 2.51 ± 1.05, P = 0.04). The concentration of all leukocyte subsets increased after each trial, with this greatest for CD56dim NK cells, and in HIIE vs. MICE (LV-HIIE: 4.77 ± 2.82, HV-HIIE: 4.65 ± 2.06, MICE: 2.44 ± 0.77, P < 0.0001). These patterns were observed for concentration, not frequency of CXCR-4+ and VLA-4+ HSPCs, which was unaltered. There was a marginal decrease in VLA-4, but not CXCR-4 expression on exercise-mobilised HSPCs after all trials (P < 0.0001).
Discussion: The results of the present study indicate that HIIE caused a more marked increase in HSPC and CD56dim NK cell concentrations than MICE, with mobilised HSPCs maintaining their bone marrow homing phenotype. LV-HIIE evoked an increase in HSPC concentration after just 2 × 2-minute intervals. The feasibility and clinical utility of interval cycling in a PBSC donation context should therefore be evaluated.

Keywords:  HSPC; exercise; interval cycling; natural killer cell; peripheral blood stem cell donation; transplantation

DOI:  https://doi.org/10.3389/fphys.2024.1327269
Commun Biol. 2024 Aug 09. 7(1): 967

Mitochondrial permeability transition dictates mitochondrial maturation upon switch in cellular identity of hematopoietic precursors.

Sandeep P Dumbali, Paulina D Horton, Travis I Moore, Pamela L Wenzel.

The mitochondrial permeability transition pore (mPTP) is a supramolecular channel that regulates exchange of solutes across cristae membranes, with executive roles in mitochondrial function and cell death. The contribution of the mPTP to normal physiology remains debated, although evidence implicates the mPTP in mitochondrial inner membrane remodeling in differentiating progenitor cells. Here, we demonstrate that strict control over mPTP conductance shapes metabolic machinery as cells transit toward hematopoietic identity. Cells undergoing the endothelial-to-hematopoietic transition (EHT) tightly control chief regulatory elements of the mPTP. During EHT, maturing arterial endothelium restricts mPTP activity just prior to hematopoietic commitment. After transition in cellular identity, mPTP conductance is restored. In utero treatment with NIM811, a molecule that blocks sensitization of the mPTP to opening by Cyclophilin D (CypD), amplifies oxidative phosphorylation (OXPHOS) in hematopoietic precursors and increases hematopoiesis in the embryo. Additionally, differentiating pluripotent stem cells (PSCs) acquire greater organization of mitochondrial cristae and hematopoietic activity following knockdown of the CypD gene, Ppif. Conversely, knockdown of Opa1, a GTPase critical for proper cristae architecture, induces cristae irregularity and impairs hematopoiesis. These data elucidate a mechanism that regulates mitochondrial maturation in hematopoietic precursors and underscore a role for the mPTP in the acquisition of hematopoietic fate.

DOI: https://doi.org/10.1038/s42003-024-06671-y
Cell Death Differ. 2024 Aug 14.

Cullin 4B-RING E3 ligase negatively regulates the immunosuppressive capacity of mesenchymal stem cells by suppressing iNOS.

Ruiqi Yu, Hong Han, Shuxian Chu, Liping Qin, Mengying Du, Yanyan Ma, Yufeng Wang, Wei Jiang, Yu Song, Yongxin Zou, Molin Wang, Qiao Liu, Baichun Jiang, Yaoqin Gong, Gongping Sun.

Mesenchymal stem cells (MSCs) are multipotent stem cells that can exert immunomodulatory capacity upon stimulation with pro-inflammatory cytokines. Our previous work has identified Cullin 4B (CUL4B), a scaffold protein in the CUL4B-RING E3 ligase (CRL4B) complex, as a key regulator in the differentiation of MSCs. Here, we demonstrate the critical role of CUL4B in regulating the immunosuppressive function of MSCs. When stimulated with pro-inflammatory cytokines, MSCs lacking CUL4B display enhanced immunosuppressive capacity, which is mediated by the elevated inducible nitric oxide synthase (iNOS). TGF-β signaling can suppress iNOS by inhibiting its transcription as well as promoting its protein degradation. We show that the CRL4B complex cooperates with PRC2 complex and HDACs to repress transcription of Dlx1 and Pmepa1, two inhibitors of TGF-β signaling, leading to decreased expression and accelerated degradation of iNOS. Our study unveils the CRL4B complex as a potential therapeutic target in promoting the immunosuppressive capacity of MSCs.

DOI: https://doi.org/10.1038/s41418-024-01359-6
Int J Mol Sci. 2024 Jul 26. pii: 8147. [Epub ahead of print]25(15):

The Aryl Hydrocarbon Receptor Regulates Invasiveness and Motility in Acute Myeloid Leukemia Cells through Expressional Regulation of Non-Muscle Myosin Heavy Chain IIA.

Fengjiao Chang, Lele Wang, Youngjoon Kim, Minkyoung Kim, Sunwoo Lee, Sang-Woo Lee.

  Acute myeloid leukemia (AML) is the most prevalent type of hematopoietic malignancy. Despite recent therapeutic advancements, the high relapse rate associated with extramedullary involvement remains a challenging issue. Moreover, therapeutic targets that regulate the extramedullary infiltration of AML cells are still not fully elucidated. The Aryl Hydrocarbon Receptor (AHR) is known to influence the progression and migration of solid tumors; however, its role in AML is largely unknown. This study explored the roles of AHR in the invasion and migration of AML cells. We found that suppressed expression of AHR target genes correlated with an elevated relapse rate in AML. Treatment with an AHR agonist on patient-derived AML cells significantly decreased genes associated with leukocyte trans-endothelial migration, cell adhesion, and regulation of the actin cytoskeleton. These results were further confirmed in THP-1 and U937 AML cell lines using AHR agonists (TCDD and FICZ) and inhibitors (SR1 and CH-223191). Treatment with AHR agonists significantly reduced Matrigel invasion, while inhibitors enhanced it, regardless of the Matrigel's stiffness. AHR agonists significantly reduced the migration rate and chemokinesis of both cell lines, but AHR inhibitors enhanced them. Finally, we found that the activity of AHR and the expression of NMIIA are negatively correlated. These findings suggest that AHR activity regulates the invasiveness and motility of AML cells, making AHR a potential therapeutic target for preventing extramedullary infiltration in AML.

Keywords:  acute myeloid leukemia; aryl hydrocarbon receptor; chemokinesis; extramedullary infiltration; invasion; non-muscle myosin heavy chain IIA

DOI:  https://doi.org/10.3390/ijms25158147
Cell Mol Life Sci. 2024 Aug 13. 81(1): 349

Lys-63-specific deubiquitinase BRCC36 enhances the sensitivity of multiple myeloma cells to lenalidomide by inhibiting lysosomal degradation of cereblon.

Busong Wang, Min Li, Dan Cao, Qing Sun, Wenjun Yu, Jingjing Ma, Haigang Ren, Guoqiang Xu, Liang Zhou.

  Multiple myeloma (MM) is the second most common hematological tumor in adults. Immunomodulatory drugs (IMiDs), such as thalidomide and lenalidomide (Len), are effective drugs for the treatment of multiple myeloma. Len can recruit IKZF1 and IKZF3 to cereblon (CRBN), a substrate receptor of the cullin 4-RING E3 ligase (CRL4), promote their ubiquitination and degradation, and finally inhibit the proliferation of myeloma cells. However, MM patients develop resistance to IMiDs over time, leading to disease recurrence and deterioration. To explore the possible approaches that may enhance the sensitivity of IMiDs to MM, in this study, we used the proximity labeling technique TurboID and quantitative proteomics to identify Lys-63-specific deubiquitinase BRCC36 as a CRBN-interacting protein. Biochemical experiments demonstrated that BRCC36 in the BRISC complex protects CRBN from lysosomal degradation by specifically cleaving the K63-linked polyubiquitin chain on CRBN. Further studies found that a small-molecule compound SHIN1, which binds to BRISC complex subunit SHMT2, can upregulate CRBN by elevating BRCC36. The combination of SHIN1 and Len can further increase the sensitivity of MM cells to IMiDs. Therefore, this study provides the basis for the exploration of a possible strategy for the SHIN1 and Len combination treatment for MM.

Keywords:  Antimyeloma effect; BRCC36; Cell viability; Cereblon (CRBN); Lenalidomide; Multiple myeloma (MM)

DOI:  https://doi.org/10.1007/s00018-024-05390-1
Front Cell Dev Biol. 2024 ;12 1441381

Age and dose dependent changes to the bone and bone marrow microenvironment after cytotoxic conditioning with busulfan.

Nastaran Abbasizadeh, Christian S Burns, Ruth Verrinder, Farhad Ghazali, Negar Seyedhassantehrani, Joel A Spencer.

  Preparative regimens before Hematopoietic Cell Transplantation (HCT) damage the bone marrow (BM) microenvironment, potentially leading to secondary morbidity and even mortality. The precise effects of cytotoxic preconditioning on bone and BM remodeling, regeneration, and subsequent hematopoietic recovery over time remain unclear. Moreover, the influence of recipient age and cytotoxic dose have not been fully described. In this study, we longitudinally investigated bone and BM remodeling after busulfan treatment with low intensity (LI) and high intensity (HI) regimens as a function of animal age. As expected, higher donor chimerism was observed in young mice in both LI and HI regimens compared to adult mice. Noticeably in adult mice, significant engraftment was only observed in the HI group. The integrity of the blood-bone marrow barrier in calvarial BM blood vessels was lost after busulfan treatment in the young mice and remained altered even 6 weeks after HCT. In adult mice, the severity of vascular leakage appeared to be dose-dependent, being more pronounced in HI compared to LI recipients. Interestingly, no noticeable change in blood flow velocity was observed following busulfan treatment. Ex vivo imaging of the long bones revealed a reduction in the frequency and an increase in the diameter and density of the blood vessels shortly after treatment, a phenomenon that largely recovered in young mice but persisted in older mice after 6 weeks. Furthermore, analysis of bone remodeling indicated a significant alteration in bone turnover at 6 weeks compared to earlier timepoints in both young and adult mice. Overall, our results reveal new aspects of bone and BM remodeling, as well as hematopoietic recovery, which is dependent on the cytotoxic dose and recipient age.

Keywords:  bone marrow microenvironment; bone remodeling; cytotoxic conditioning intensity; hematopoietic aging; hematopoietic cell transplantation; hematopoietic recovery

DOI:  https://doi.org/10.3389/fcell.2024.1441381
Biochem Biophys Res Commun. 2024 Aug 05. pii: S0006-291X(24)01029-5. [Epub ahead of print]737 150493

Chidamide induces cell cycle arrest via NR4A3/P21 axis upregulation to suppress relapsed and refractory acute myeloid leukemia.

Xuefeng Feng, Fuyi Luo, Shuyu Wang, Feng Zhu, Yifan Gao, Jianmin Luo, Jiazi Zhou.

  (1) Currently, the survival prognosis for patients with relapsed and refractory acute myeloid leukemia (R/R AML) is extremely poor. Therefore, the exploration of novel drugs is imperative to enhance the prognosis of patients with R/R AML. The therapeutic efficacy and mechanism of Chidamide, a novel epigenetic regulatory drug, in the treatment of R/R AML remain unclear.METHODS: The mechanism of action of Chidamide has been explored in various AML cell lines through various methods such as cell apoptosis, cell cycle analysis, high-throughput transcriptome sequencing, gene silencing, and xenograft models.
RESULTS: Here, we have discovered that chidamide potently induces apoptosis, G0/G1 phase arrest, and mitochondrial membrane potential depolarization in R/R AML cells, encompassing both primary cells and cell lines. Through RNA-seq analysis, we further revealed that chidamide epigenetically regulates the upregulation of differentiation-related pathways while suppressing those associated with cell replication and cell cycle progression. Notably, our screening identified NR4A3 as a key suppressor gene whose upregulation by chidamide leads to P21-dependent cell cycle arrest in the G0/G1 phase.
CONCLUSIONS: We have discovered a novel epigenetic regulatory mechanism of chidamide in the treatment of relapsed and refractory acute myeloid leukemia (R/R AML).

Keywords:  Acute myeloid leukemia; Cell cycle; Epigenetic regulation; NR4A3; P21; Prognostic

DOI:  https://doi.org/10.1016/j.bbrc.2024.150493
Mol Cell. 2024 Aug 09. pii: S1097-2765(24)00618-X. [Epub ahead of print]

OPA1 promotes ferroptosis by augmenting mitochondrial ROS and suppressing an integrated stress response.

Felix G Liang, Fereshteh Zandkarimi, Jaehoon Lee, Joshua L Axelrod, Ryan Pekson, Yisang Yoon, Brent R Stockwell, Richard N Kitsis.

  Ferroptosis, an iron-dependent form of nonapoptotic cell death mediated by lipid peroxidation, has been implicated in the pathogenesis of multiple diseases. Subcellular organelles play pivotal roles in the regulation of ferroptosis, but the mechanisms underlying the contributions of the mitochondria remain poorly defined. Optic atrophy 1 (OPA1) is a mitochondrial dynamin-like GTPase that controls mitochondrial morphogenesis, fusion, and energetics. Here, we report that human and mouse cells lacking OPA1 are markedly resistant to ferroptosis. Reconstitution with OPA1 mutants demonstrates that ferroptosis sensitization requires the GTPase activity but is independent of OPA1-mediated mitochondrial fusion. Mechanistically, OPA1 confers susceptibility to ferroptosis by maintaining mitochondrial homeostasis and function, which contributes both to the generation of mitochondrial lipid reactive oxygen species (ROS) and suppression of an ATF4-mediated integrated stress response. Together, these results identify an OPA1-controlled mitochondrial axis of ferroptosis regulation and provide mechanistic insights for therapeutically manipulating this form of cell death in diseases.

Keywords:  ATF4; GPx4; OPA1; cell death; ferroptosis; integrated stress response; mitochondria; system X(c)(−); xCT

DOI:  https://doi.org/10.1016/j.molcel.2024.07.020
Nat Immunol. 2024 Aug 12.

ZBTB46 coordinates angiogenesis and immunity to control tumor outcome.

Ashraf Ul Kabir, Carisa Zeng, Madhav Subramanian, Jun Wu, Minseo Kim, Karen Krchma, Xiaoli Wang, Carmen M Halabi, Hua Pan, Samuel A Wickline, Daved H Fremont, Maxim N Artyomov, Kyunghee Choi.

Tumor angiogenesis and immunity show an inverse correlation in cancer progression and outcome1. Here, we report that ZBTB46, a repressive transcription factor and a widely accepted marker for classical dendritic cells (DCs)2,3, controls both tumor angiogenesis and immunity. Zbtb46 was downregulated in both DCs and endothelial cells by tumor-derived factors to facilitate robust tumor growth. Zbtb46 downregulation led to a hallmark pro-tumor microenvironment (TME), including dysfunctional vasculature and immunosuppressive conditions. Analysis of human cancer data revealed a similar association of low ZBTB46 expression with an immunosuppressive TME and a worse prognosis. In contrast, enforced Zbtb46 expression led to TME changes to restrict tumor growth. Mechanistically, Zbtb46-deficient endothelial cells were highly angiogenic, and Zbtb46-deficient bone marrow progenitors upregulated Cebpb and diverted the DC program to immunosuppressive myeloid lineage output, potentially explaining the myeloid lineage skewing phenomenon in cancer4. Conversely, enforced Zbtb46 expression normalized tumor vessels and, by suppressing Cebpb, skewed bone marrow precursors toward immunostimulatory myeloid lineage output, leading to an immune-hot TME. Remarkably, Zbtb46 mRNA treatment synergized with anti-PD1 immunotherapy to improve tumor management in preclinical models. These findings identify ZBTB46 as a critical factor for angiogenesis and for myeloid lineage skewing in cancer and suggest that maintaining its expression could have therapeutic benefits.

DOI: https://doi.org/10.1038/s41590-024-01936-4
Methods Mol Biol. 2024 ;2828 1-9

Chemotaxis Assay of Bone Marrow-Derived Macrophages.

Hannah Donnelly, Abhimanyu Kiran, Robert Insall.

  Immune responses rely on efficient and coordinated migration of immune cells to the site of infection or injury. To reach the site of immunological threat often requires long-range navigation of immune cells through complex tissue and vascular networks. Chemotaxis, cell migration steered by gradients of cell-attractive chemicals that bind sensory receptors, is central to this response. Chemoattractant receptors mostly belong to the G-protein-coupled receptor (GPCR) family, but the way attractant-receptor signaling directs cell migration is not fully understood. Direct-viewing chemotaxis chambers combined with time-lapse microscopy give a powerful tool to study the dynamic details of cells' responses to different attractant landscapes. Here, we describe the application of one such chamber (the Dunn chamber) to study bone marrow-derived macrophage chemotaxis to gradients of complement C5a.

Keywords:  Bone marrow-derived macrophages; Cell migration; Chemotaxis; Complement C5a; Dunn chemotaxis chamber; Time-lapse microscopy

DOI:  https://doi.org/10.1007/978-1-0716-4023-4_1
Nat Commun. 2024 Aug 11. 15(1): 6873

OTUD6 deubiquitination of RPS7/eS7 on the free 40 S ribosome regulates global protein translation and stress.

Sammy Villa, Pankaj Dwivedi, Aaron Stahl, Trent Hinkle, Christopher M Rose, Donald S Kirkpatrick, Seth M Tomchik, Vishva M Dixit, Fred W Wolf.

Ribosomes are regulated by evolutionarily conserved ubiquitination/deubiquitination events. We uncover the role of the deubiquitinase OTUD6 in regulating global protein translation through deubiquitination of the RPS7/eS7 subunit on the free 40 S ribosome in vivo in Drosophila. Coimmunoprecipitation and enrichment of monoubiquitinated proteins from catalytically inactive OTUD6 flies reveal RPS7 as the ribosomal substrate. The 40 S protein RACK1 and E3 ligases CNOT4 and RNF10 function upstream of OTUD6 to regulate alkylation stress. OTUD6 interacts with RPS7 specifically on the free 40 S, and not on 43 S/48 S initiation complexes or the translating ribosome. Global protein translation levels are bidirectionally regulated by OTUD6 protein abundance. OTUD6 protein abundance is physiologically regulated in aging and in response to translational and alkylation stress. Thus, OTUD6 may promote translation initiation, the rate limiting step in protein translation, by titering the amount of 40 S ribosome that recycles.

DOI: https://doi.org/10.1038/s41467-024-51284-y
ACS Sens. 2024 Aug 15.

Genetically Encoded Microtubule Binders for Single-Cell Interrogation of Cytoskeleton Dynamics and Protein Activity.

Joseph Zhou, Xiaoxuan Liu, Dekai Zhang, Guolin Ma.

  Microtubule (MT) dynamics is tightly regulated by microtubule-associated proteins (MAPs) and various post-translational modifications (PTMs) of tubulin. Here, we introduce OligoMT and OligoTIP as genetically encoded oligomeric MT binders designed for real-time visualization and manipulation of MT behaviors within living cells. OligoMT acts as a reliable marker to label the MT cytoskeleton, while OligoTIP allows for live monitoring of the growing MT plus-ends. These engineered MT binders have been successfully utilized to label the MT network, monitor cell division, track MT plus-ends, and assess the effect of tubulin acetylation on the MT stability at the single-cell level. Moreover, OligoMT and OligoTIP can be repurposed as biosensors for quantitative assessment of drug actions and for reporting enzymatic activity. Overall, these engineered MT binders hold promise for advancing the mechanistic dissection of MT biology and have translational applications in cell-based high-throughput drug discovery efforts.

Keywords:  biosensor; cytoskeleton; drug discovery; high-throughput screening; microtubule; protein−protein interactions

DOI:  https://doi.org/10.1021/acssensors.4c01167
Heliyon. 2024 Jul 30. 10(14): e34487

P-NADs: PUX-based NAnobody degraders for ubiquitin-independent degradation of target proteins.

Jun Wang, Georgy Chistov, Junrui Zhang, Brandon Huntington, Israa Salem, Anandsukeerthi Sandholu, Stefan T Arold.

  Targeted protein degradation (TPD) allows cells to maintain a functional proteome and to rapidly adapt to changing conditions. Methods that repurpose TPD for the deactivation of specific proteins have demonstrated significant potential in therapeutic and research applications. Most of these methods are based on proteolysis targeting chimaeras (PROTACs) which link the protein target to an E3 ubiquitin ligase, resulting in the ubiquitin-based degradation of the target protein. In this study, we introduce a method for ubiquitin-independent TPD based on nanobody-conjugated plant ubiquitin regulatory X domain-containing (PUX) adaptor proteins. We show that the PUX-based NAnobody Degraders (P-NADs) can unfold a target protein through the Arabidopsis and human orthologues of the CDC48 unfoldase without the need for ubiquitination or initiating motifs. We demonstrate that P-NAD plasmids can be transfected into a human cell line, where the produced P-NADs use the endogenous CDC48 machinery for ubiquitin-independent TPD of a 143 kDa multidomain protein. Thus, P-NADs pave the road for ubiquitin-independent therapeutic TPD approaches. In addition, the modular P-NAD design combined with in vitro and cellular assays provide a versatile platform for elucidating functional aspects of CDC48-based TPD in plants and animals.

Keywords:  CDC48; PROTAC; Plant ubiquitin regulatory X domain-containing; Targeted protein degradation; p97

DOI:  https://doi.org/10.1016/j.heliyon.2024.e34487
Blood. 2024 Aug 12. pii: blood.2024025409. [Epub ahead of print]

Genetic risk classification for adults with AML receiving less-intensive therapies: the 2024 ELN recommendations.

Hartmut Döhner, Courtney D DiNardo, Andrew H Wei, Bob Löwenberg, Frederick Appelbaum, Charles Craddock, Hervé Dombret, Benjamin L Ebert, Pierre Fenaux, Lucy A Godley, Robert P Hasserjian, Richard A Larson, Ross L Levine, Yasushi Miyazaki, Dietger Niederwieser, Gert J Ossenkoppele, Christoph Röllig, Jorge Sierra, Eytan M Stein, Martin S Tallman, Hwei-Fang Tien, Jianxiang Wang, Agnieszka Wierzbowska.

The European LeukemiaNet (ELN) genetic risk classifications were developed based on data from younger adults receiving intensive chemotherapy. Emerging analyses from patients receiving less-intensive therapies prompted a proposal for an ELN genetic risk classification specifically for this patient population.

DOI: https://doi.org/10.1182/blood.2024025409
Protein Sci. 2024 Sep;33(9): e5138

Dissecting the functional behavior of the differentially phosphorylated prolyl isomerase, Pin1.

Danielle F Kay, Adem Ozleyen, Cristina Matas De Las Heras, Richard G Doveston, Aneika C Leney.

  Protein post-translational modifications (PTMs) play an intricate role in a diverse range of cellular processes creating a complex PTM code that governs cell homeostasis. Understanding the molecular build-up and the critical factors regulating this PTM code is essential for targeted therapeutic design whereby PTM mis-regulation is prevalent. Here, we focus on Pin1, a peptidyl-prolyl cis-trans isomerase whose regulatory function is altered by a diverse range of PTMs. Through employing advanced mass spectrometry techniques in combination with fluorescence polarization and enzyme activity assays, we elucidate the impact of combinatorial phosphorylation on Pin1 function. Moreover, two phosphorylation sites were identified whereby Ser71 phosphorylation preceded Ser16 phosphorylation, leading to the deactivation of Pin1's prolyl isomerase activity before affecting substrate binding. Together, these findings shed light on the regulatory mechanisms underlying Pin1 function and emphasize the importance of understanding PTM landscapes in health and disease.

Keywords:  native mass spectrometry; phosphorylation; post‐translational modifications; prolyl isomerase; proteomics

DOI:  https://doi.org/10.1002/pro.5138
bioRxiv. 2024 Jul 29. pii: 2024.07.28.605514. [Epub ahead of print]

Degradability tunes ECM stress relaxation and cellular mechanics.

Badri Narayanan Narasimhan, Stephanie I Fraley.

In native extracellular matrices (ECM), cells can use matrix metalloproteinases (MMPs) to degrade and remodel their surroundings. Likewise, synthetic matrices have been engineered to facilitate MMP-mediated cleavage that enables cell spreading, migration, and interactions. However, the intersection of matrix degradability and mechanical properties has not been fully considered. We hypothesized that immediate mechanical changes result from the action of MMPs on the ECM and that these changes are sensed by cells. Using atomic force microscopy (AFM) to measure cell-scale mechanical properties, we find that both fibrillar collagen and synthetic degradable matrices exhibit enhanced stress relaxation after MMP exposure. Cells respond to these relaxation differences by altering their spreading and focal adhesions. We demonstrate that stress relaxation can be tuned through the rational design of matrix degradability. These findings establish a fundamental link between matrix degradability and stress relaxation, which may impact a range of biological applications.

DOI: https://doi.org/10.1101/2024.07.28.605514
Nat Commun. 2024 Aug 15. 15(1): 7016

Fast and deep phosphoproteome analysis with the Orbitrap Astral mass spectrometer.

Noah M Lancaster, Pavel Sinitcyn, Patrick Forny, Trenton M Peters-Clarke, Caroline Fecher, Andrew J Smith, Evgenia Shishkova, Tabiwang N Arrey, Anna Pashkova, Margaret Lea Robinson, Nicholas Arp, Jing Fan, Juli Hansen, Andrea Galmozzi, Lia R Serrano, Julie Rojas, Audrey P Gasch, Michael S Westphall, Hamish Stewart, Christian Hock, Eugen Damoc, David J Pagliarini, Vlad Zabrouskov, Joshua J Coon.

Owing to its roles in cellular signal transduction, protein phosphorylation plays critical roles in myriad cell processes. That said, detecting and quantifying protein phosphorylation has remained a challenge. We describe the use of a novel mass spectrometer (Orbitrap Astral) coupled with data-independent acquisition (DIA) to achieve rapid and deep analysis of human and mouse phosphoproteomes. With this method, we map approximately 30,000 unique human phosphorylation sites within a half-hour of data collection. The technology is benchmarked to other state-of-the-art MS platforms using both synthetic peptide standards and with EGF-stimulated HeLa cells. We apply this approach to generate a phosphoproteome multi-tissue atlas of the mouse. Altogether, we detect 81,120 unique phosphorylation sites within 12 hours of measurement. With this unique dataset, we examine the sequence, structural, and kinase specificity context of protein phosphorylation. Finally, we highlight the discovery potential of this resource with multiple examples of phosphorylation events relevant to mitochondrial and brain biology.

DOI: https://doi.org/10.1038/s41467-024-51274-0
Nat Commun. 2024 Aug 09. 15(1): 6820

Hydrogel crosslinking modulates macrophages, fibroblasts, and their communication, during wound healing.

Sergei Butenko, Raji R Nagalla, Christian F Guerrero-Juarez, Francesco Palomba, Li-Mor David, Ronald Q Nguyen, Denise Gay, Axel A Almet, Michelle A Digman, Qing Nie, Philip O Scumpia, Maksim V Plikus, Wendy F Liu.

Biomaterial wound dressings, such as hydrogels, interact with host cells to regulate tissue repair. This study investigates how crosslinking of gelatin-based hydrogels influences immune and stromal cell behavior and wound healing in female mice. We observe that softer, lightly crosslinked hydrogels promote greater cellular infiltration and result in smaller scars compared to stiffer, heavily crosslinked hydrogels. Using single-cell RNA sequencing, we further show that heavily crosslinked hydrogels increase inflammation and lead to the formation of a distinct macrophage subpopulation exhibiting signs of oxidative activity and cell fusion. Conversely, lightly crosslinked hydrogels are more readily taken up by macrophages and integrated within the tissue. The physical properties differentially affect macrophage and fibroblast interactions, with heavily crosslinked hydrogels promoting pro-fibrotic fibroblast activity that drives macrophage fusion through RANKL signaling. These findings suggest that tuning the physical properties of hydrogels can guide cellular responses and improve healing, offering insights for designing better biomaterials for wound treatment.

DOI: https://doi.org/10.1038/s41467-024-50072-y
Signal Transduct Target Ther. 2024 Aug 14. 9(1): 201

Therapeutic advances of targeting receptor tyrosine kinases in cancer.

Ciprian Tomuleasa, Adrian-Bogdan Tigu, Raluca Munteanu, Cristian-Silviu Moldovan, David Kegyes, Anca Onaciu, Diana Gulei, Gabriel Ghiaur, Hermann Einsele, Carlo M Croce.

Receptor tyrosine kinases (RTKs), a category of transmembrane receptors, have gained significant clinical attention in oncology due to their central role in cancer pathogenesis. Genetic alterations, including mutations, amplifications, and overexpression of certain RTKs, are critical in creating environments conducive to tumor development. Following their discovery, extensive research has revealed how RTK dysregulation contributes to oncogenesis, with many cancer subtypes showing dependency on aberrant RTK signaling for their proliferation, survival and progression. These findings paved the way for targeted therapies that aim to inhibit crucial biological pathways in cancer. As a result, RTKs have emerged as primary targets in anticancer therapeutic development. Over the past two decades, this has led to the synthesis and clinical validation of numerous small molecule tyrosine kinase inhibitors (TKIs), now effectively utilized in treating various cancer types. In this manuscript we aim to provide a comprehensive understanding of the RTKs in the context of cancer. We explored the various alterations and overexpression of specific receptors across different malignancies, with special attention dedicated to the examination of current RTK inhibitors, highlighting their role as potential targeted therapies. By integrating the latest research findings and clinical evidence, we seek to elucidate the pivotal role of RTKs in cancer biology and the therapeutic efficacy of RTK inhibition with promising treatment outcomes.

DOI: https://doi.org/10.1038/s41392-024-01899-w