bims-scepro 2024-12-29 papers

bims-scepro

Biomed News

on Stem cell proteostasis

Issue of 2024–12–29
seventeen papers selected by
William Grey, University of York

Bone-Marrow-Targeted Nanocomposite Abrogates C-Myb-Survivin Cross Talk in MLL-AF9-Rearranged Acute Myeloid Leukemia in In Vitro and In Vivo Patient-Derived Xenograft Models.
Deciphering hematopoietic stem cell development: key signaling pathways and mechanisms.
c-JUN interacts with HDAC1 as a potential combinatorial therapeutic target in acute myeloid leukemia.
Hematopoietic stem cell a reservoir of innate immune memory.
TIM-3 marks measurable residual leukemic stem cells responsible for relapse after allogeneic stem cell transplantation.
Multi-niche human bone marrow on-a-chip for studying the interactions of adoptive CAR-T cell therapies with multiple myeloma.
Different effects of fatty acid oxidation on hematopoietic stem cells based on age and diet.
Metabolic Adaptations To Acute Glucose Uptake Inhibition Converge Upon Mitochondrial Respiration For Leukemia Cell Survival.
Reduced elastin in multiple myeloma niche promotes cell proliferation.
Reconsidering the usual suspects in age-related hematologic disorders: is stem cell dysfunction a root cause of aging?
A novel human pluripotent stem cell gene activation system identifies IGFBP2 as a mediator in the production of haematopoietic progenitors in vitro.
Enhanced engraftment of human haematopoietic stem cells via mechanical remodelling mediated by the corticotropin-releasing hormone.
Menin inhibitors in the treatment of acute myeloid leukemia.
Genome-wide CRISPR screen identifies AraC-Dauno-Eto (ADE) response modulators that predicts outcome in pediatric AML.
SLC25A21 correlates with the prognosis of adult acute myeloid leukemia through inhibiting the growth of leukemia cells via downregulating CXCL8.
Cells Prioritize the Regulation of Cell Mass Density.
HMGA2 overexpression with specific chromosomal abnormalities predominate in CALR and ASXL1 mutated myelofibrosis.

ACS Appl Mater Interfaces. 2024 Dec 22.

Bone-Marrow-Targeted Nanocomposite Abrogates C-Myb-Survivin Cross Talk in MLL-AF9-Rearranged Acute Myeloid Leukemia in In Vitro and In Vivo Patient-Derived Xenograft Models.

Avinash Chandra Kushwaha, Boddu Mrunalini, Pankaj Malhotra, Surajit Karmakar, Subhasree Roy Choudhury.

  The heterogeneous form of malignancy in the myeloid lineage of normal hematopoietic stem cells (HSCs) is characterized as acute myeloid leukemia (AML). The t(9;11) reciprocal translocation (p22;q23) generates MLL-AF9 oncogene, which results in myeloid-based monoblastic AML with frequent relapse and poor survival. MLL-AF9 binds with the C-Myb promoter and regulates AML onset, maintenance, and survival. The bone marrow microenvironment (BMM) protects leukemia stem cells (LSCs) from therapeutic agents, which can lead to relapsed condition. Targeting leukemia BMM can be a viable therapeutics approach for AML treatment, wherein bone homing bisphosphonate, ibandronic acid (IBD), can localize to the BMM. In order to target the BMM of AML, C-Myb siRNA was entrapped in Vitamin D nanoemulsion-functionalized with BMM-targeted IBD, which exhibited binding with ex vivo bone slices and localization into mice bone marrow. IBD functionalization and C-Myb siRNA nanotherapy enhanced the suppression of LSCs (c-Kit+) and the upregulation of myeloid differentiation markers CD11b and Gr-1 in peripheral blood and bone marrow of athymic nude mice and patient-derived xenograft models. IBD functionalization enhanced the downregulation of C-Myb and C-Myb-Survivin cross talk in bone marrow and spleen tissue responsible for AML onset, maintenance, and pathogenesis. Further C-Myb binding to Survivin promoter was abrogated by the present bone-marrow-targeted nanotherapy, signifying its translational potential for AML therapeutics.

Keywords:  AML; MLL-AF9; PDX; bone marrow microenvironment; siRNA nanotherapy; xenograft

DOI:  https://doi.org/10.1021/acsami.4c18737
Front Cell Dev Biol. 2024 ;12 1510198

Deciphering hematopoietic stem cell development: key signaling pathways and mechanisms.

Saori Morino-Koga, Tomomasa Yokomizo.

  Most blood cells derive from hematopoietic stem cells (HSCs), originating from endothelial cells. The induction of HSCs from endothelial cells occurs during mid-gestation, and research has revealed multiple steps in this induction process. Hemogenic endothelial cells emerge within the endothelium, transition to hematopoietic cells (pre-HSCs), and subsequently mature into functional HSCs. Reports indicate transcription factors and external signals are involved in these processes. In this review, we discuss the timing and role of these transcription factors and summarize the external signals that have demonstrated efficacy in an in vitro culture. A precise understanding of the signals at each step is expected to advance the development of methods for inducing HSCs from pluripotent stem cells.

Keywords:  aorta-gonad-mesonephros (AGM); endothelial-to-hematopoietic transition (EHT); erythro-myeloid progenitor (EMP); hematopoietic stem cell (HSC); hematopoietic stem cell precursor (pre-HSC); intra-aortic hematopoietic cluster (IAHC)

DOI:  https://doi.org/10.3389/fcell.2024.1510198
Int Immunopharmacol. 2024 Dec 24. pii: S1567-5769(24)02449-4. [Epub ahead of print]146 113927

c-JUN interacts with HDAC1 as a potential combinatorial therapeutic target in acute myeloid leukemia.

Ke Wu, Xiaoyu Xu, Wei Wei, Jie Wen, Haixi Hu.

  Acute myeloid leukemia (AML) is a biologically heterogeneous disease originating from the clonal expansion of hematopoietic stem cells (HSCs). Clonal expansion of hematopoietic stem cell progenitors (HSC-Prog), along with a block in differentiation, are hallmark features of AML. The disease is characterized by poor clinical outcomes, highlighting the urgent need for effective therapeutic strategies and suitable drug targets. We conducted multi-omics analyses, including single-cell RNA sequencing (scRNA-seq), Mendelian randomization (MR), and bulk RNA-seq, to investigate HDAC1's oncogenic role in AML. We identified specific gene signatures at the single-cell level. MR with eQTL data established causal links, and TCGA-LAML RNA-seq provided prognostic insights. Analysis of cellular communication and transcription factors revealed high c-JUN activity in HSC-Prog. We confirmed the association of c-JUN with HDAC1 through Western blotting and Co-immunoprecipitation (Co-IP). Functional validation of c-JUN in AML cells was performed via flow cytometry in vitro. The effectiveness of drugs targeting c-JUN and HDAC1 was assessed in mouse models using live imaging methods like in vivo imaging system (IVIS) and iSMAART. We identified the activity of c-JUN is specifically enhanced in HSC-Prog in AML patients. We suggest a potential regulatory relationship between c-JUN and HDAC1 in AML tumor cells. Inhibition of c-JUN can suppress cell proliferation and CD33 expression in AML, enhancing susceptibility to natural killer (NK) cell-mediated cytotoxicity. The combination of agents targeting c-JUN (Ailanthone) and HDAC1 (Panobinostat) showed robust efficacy in treating AML in xenograft mouse models, outperforming monotherapy. We also observed that the combination of Ailanthone and Panobinostat therapy displayed a safe pharmacological profile without dose-dependent toxicity, suggesting its potential as a therapeutic strategy.

Keywords:  Acute myeloid leukemia; Combination therapy; HDAC1; Mendelian randomization; Single cell RNA-seq; c-JUN

DOI:  https://doi.org/10.1016/j.intimp.2024.113927
Front Immunol. 2024 ;15 1491729

Hematopoietic stem cell a reservoir of innate immune memory.

Lucas Ruffinatto, Yann Groult, Johanna Iacono, Sandrine Sarrazin, Bérengère de Laval.

  Hematopoietic stem cells (HSCs) are a rare, long-lived and multipotent population that give rise to majority of blood cells and some tissue-resident immune cells. There is growing evidence that inflammatory stimuli can trigger persistent reprogramming in HSCs that enhances or inhibits the cellular functions of these HSCs and their progeny in response to subsequent infections. This newly discovered property makes HSCs a reservoir for innate immune memory. The molecular mechanisms underlying innate immune memory in HSCs are similar to those observed in innate immune cells, although their full elucidation is still pending. In this review, we examine the current state of knowledge on how an inflammatory response leads to reprogramming of HSCs. Understanding the full spectrum of consequences of reshaping early hematopoiesis is critical for assessing the potential benefits and risks under physiological and pathological conditions.

Keywords:  emergency hematopoiesis; epigenetic; hematopoietic stem and progenitor cells (HSPCs); inflammation; innate immune memory; metabolism; myelopoiesis

DOI:  https://doi.org/10.3389/fimmu.2024.1491729
Cancer Sci. 2024 Dec 26.

TIM-3 marks measurable residual leukemic stem cells responsible for relapse after allogeneic stem cell transplantation.

Teppei Sakoda, Yoshikane Kikushige, Hidetoshi Irifune, Gentaro Kawano, Takuya Harada, Yuichiro Semba, Masayasu Hayashi, Takahiro Shima, Yasuo Mori, Tetsuya Eto, Tomohiko Kamimura, Hiromi Iwasaki, Ryosuke Ogawa, Goichi Yoshimoto, Koji Kato, Takahiro Maeda, Toshihiro Miyamoto, Koichi Akashi.

  In this study, we investigated the measurable residual leukemic stem cell (MR-LSC) population after allogeneic stem cell transplantation (allo-SCT) for high-risk acute myeloid leukemia (AML), utilizing T-cell immunoglobulin mucin-3 (TIM-3) expression as a functional marker of AML leukemic stem cells (LSCs). Analysis of the CD34+CD38- fraction of bone marrow cells immediately after achievement of engraftment revealed the presence of both TIM-3+LSCs and TIM-3- donor hematopoietic stem cells (HSCs) at varying ratios. Genetic analysis confirmed that TIM-3+ cells harbored patient-specific mutations identical to those found in AML clones, whereas TIM-3- cells did not, indicating that TIM-3+CD34+CD38- cells represent residual AML LSCs. In 92 allo-SCT occasions involving 83 AML patients, we enumerated the frequencies of TIM-3+LSCs immediately after achieving hematologic complete remission with complete donor cell chimerism. Notably, only 22.2% of patients who achieved a TIM-3+MR-LSClow status (<60%) experienced relapse, with a median event-free survival (EFS) of 1581 days (median follow-up duration was 2177 days among event-free survivors). Conversely, 87.5% of patients with TIM-3+MR-LSCint/high (≥60%) relapsed, with a median EFS of 140.5 days. Furthermore, MR-LSC status emerged as a significant independent risk factor for relapse (hazard ratio, 8.56; p < 0.0001), surpassing the impact of patient disease status prior to allo-SCT, including failure to achieve complete remission (hazard ratio, 1.98; p = 0.048). These findings suggest that evaluating TIM-3+ MR-LSCs immediately after engraftment, which reflects the competitive reconstitution of residual TIM-3+ LSCs and donor HSCs, may be valuable for predicting outcomes in AML patients undergoing allo-SCT.

Keywords:  TIM‐3; acute myeloid leukemia; allogeneic stem cell transplantation; leukemic stem cells; measurable residual disease

DOI:  https://doi.org/10.1111/cas.16431
Biomaterials. 2024 Dec 15. pii: S0142-9612(24)00552-0. [Epub ahead of print]316 123016

Multi-niche human bone marrow on-a-chip for studying the interactions of adoptive CAR-T cell therapies with multiple myeloma.

Delta Ghoshal, Ingrid Petersen, Rachel Ringquist, Liana Kramer, Eshant Bhatia, Thomas Hu, Ariane Richard, Reda Park, Jenna Corbin, Savi Agarwal, Abel Thomas, Sebastian Ramirez, Jacob Tharayil, Emma Downey, Frank Ketchum, Abigail Ochal, Neha Sonthi, Sagar Lonial, James N Kochenderfer, Reginald Tran, Mandy Zhu, Wilbur A Lam, Ahmet F Coskun, Krishnendu Roy.

Multiple myeloma (MM), a cancer of bone marrow plasma cells, is the second-most common hematological malignancy. However, despite immunotherapies like chimeric antigen receptor (CAR)-T cells, relapse is nearly universal. The bone marrow (BM) microenvironment influences how MM cells survive, proliferate, and resist treatment. Yet, it is unclear which BM niches give rise to MM pathophysiology. Here, we present a 3D microvascularized culture system, which models the endosteal and perivascular bone marrow niches, allowing us to study MM-stroma interactions in the BM niche and model responses to therapeutic CAR-T cells. We demonstrated the prolonged survival of cell line-based and patient-derived multiple myeloma cells within our in vitro system and successfully perfused in donor-matched CAR-T cells. We then measured T cell survival, differentiation, and cytotoxicity against MM cells using a variety of analysis techniques. Our MM-on-a-chip system could elucidate the role of the BM microenvironment in MM survival and therapeutic evasion and inform the rational design of next-generation therapeutics.

DOI: https://doi.org/10.1016/j.biomaterials.2024.123016
Cell Stem Cell. 2024 Dec 12. pii: S1934-5909(24)00413-2. [Epub ahead of print]

Different effects of fatty acid oxidation on hematopoietic stem cells based on age and diet.

Salma Merchant, Animesh Paul, Amanda Reyes, Daniel Cassidy, Ashley Leach, Dohun Kim, Sarah Muh, Gerik Grabowski, Gerta Hoxhaj, Zhiyu Zhao, Sean J Morrison.

  Fatty acid oxidation is of uncertain importance in most stem cells. We show by 14C-palmitate tracing and metabolomic analysis that hematopoietic stem/progenitor cells (HSPCs) engage in long-chain fatty acid oxidation that depends upon carnitine palmitoyltransferase 1a (CPT1a) and hydroxyacyl-CoA dehydrogenase (HADHA) enzymes. CPT1a or HADHA deficiency had little or no effect on HSPCs or hematopoiesis in young adult mice. Young HSPCs had the plasticity to oxidize other substrates, including glutamine, and compensated for loss of fatty acid oxidation by decreasing pyruvate dehydrogenase phosphorylation, which should increase function. This metabolic plasticity declined as mice aged, when CPT1a or HADHA deficiency altered hematopoiesis and impaired hematopoietic stem cell (HSC) function upon serial transplantation. A high-fat diet increased fatty acid oxidation and reduced HSC function. This was rescued by CPT1a or HADHA deficiency, demonstrating that increased fatty acid oxidation can undermine HSC function. Long-chain fatty acid oxidation is thus dispensable in young HSCs but necessary during aging and deleterious with a high-fat diet.

Keywords:  aging; fatty acid; hematopoiesis; high-fat diet; metabolic plasticity; metabolism; mitochondria; β-oxidation

DOI:  https://doi.org/10.1016/j.stem.2024.11.014
bioRxiv. 2024 Nov 22. pii: 2024.11.20.624567. [Epub ahead of print]

Metabolic Adaptations To Acute Glucose Uptake Inhibition Converge Upon Mitochondrial Respiration For Leukemia Cell Survival.

Monika Komza, Jesminara Khatun, Jesse D Gelles, Andrew P Trotta, Ioana Abraham-Enachescu, Juan Henao, Ahmed Elsaadi, Andriana G Kotini, Cara Clementelli, JoAnn Arandela, Sebastian El Ghaity-Beckley, Agneesh Barua, Yiyang Chen, Bridget K Marcellino, Eirini P Papapetrou, Masha V Poyurovsky, Jerry Edward Chipuk.

One hallmark of cancer is the upregulation and dependency on glucose metabolism to fuel macromolecule biosynthesis and rapid proliferation. Despite significant pre-clinical effort to exploit this pathway, additional mechanistic insights are necessary to prioritize the diversity of metabolic adaptations upon acute loss of glucose metabolism. Here, we investigated a potent small molecule inhibitor to Class I glucose transporters, KL-11743, using glycolytic leukemia cell lines and patient-based model systems. Our results reveal that while several metabolic adaptations occur in response to acute glucose uptake inhibition, the most critical is increased mitochondrial oxidative phosphorylation. KL-11743 treatment efficiently blocks the majority of glucose uptake and glycolysis, yet markedly increases mitochondrial respiration via enhanced Complex I function. Compared to partial glucose uptake inhibition, dependency on mitochondrial respiration is less apparent suggesting robust blockage of glucose uptake is essential to create a metabolic vulnerability. When wild-type and oncogenic RAS patient-derived induced pluripotent stem cell acute myeloid leukemia (AML) models were examined, KL-11743 mediated induction of mitochondrial respiration and dependency for survival associated with oncogenic RAS. Furthermore, we examined the therapeutic potential of these observations by treating a cohort of primary AML patient samples with KL-11743 and witnessed similar dependency on mitochondrial respiration for sustained cellular survival. Together, these data highlight conserved adaptations to acute glucose uptake inhibition in diverse leukemic models and AML patient samples, and position mitochondrial respiration as a key determinant of treatment success.

DOI: https://doi.org/10.1101/2024.11.20.624567
Exp Cell Res. 2024 Dec 24. pii: S0014-4827(24)00486-5. [Epub ahead of print]444(2): 114395

Reduced elastin in multiple myeloma niche promotes cell proliferation.

Mozayan Zoabi, Elina Orbuch, Oded Komemi, Osnat Jarchowsky-Dolberg, Yaron Shraga Brin, Shelly Tartakover-Matalon, Metsada Pasmanik-Chor, Michael Lishner, Liat Drucker.

  Multiple myeloma (MM) malignant plasma cells accumulate in the bone marrow (BM) where their interactions with the microenvironment promote disease progression and drug resistance. Previously, we have shown that bone marrow mesenchymal stem cells (BM-MSCs) (MM and normal donors- ND) derived extracellular matrix (ECM) affected MM cell lines differentially with a pro-MM effect attributed to MM-MSCs' ECM. Here we studied the composition of BM-MSC's ECM (ND versus MM) with focus on elastin (ELN). Isolated BM-MSCs' ECM mass spectrometry (proteomics) demonstrated distinct differences in proteins repertoire in a source dependent manner (MM or ND-MSCs) with ELN being the most significantly decreased protein in MM-MSCs ECM. To study this observation, we cultured MM cell lines (MM1S, RPMI-8226) and BM-MSCs with/without ELN and assayed the cells' phenotype. We demonstrated that supplementing ELN to MM cell lines reduced live cell counts and increased cell adhesion. ELN also decreased MM-MSCs' proliferation but did not affect ND-MSCs. Importantly, ELN addition to MM-MSC ECM abrogated its pro-MM effect on MM cells' proliferation. These novel findings underscore a suppressive role for ELN in MM and suggest it may hold potential diagnostic and therapeutic purposes.

Keywords:  Bone marrow mesenchymal stem cells; Elastin; Extracellular matrix; Multiple myeloma

DOI:  https://doi.org/10.1016/j.yexcr.2024.114395
Exp Hematol. 2024 Dec 24. pii: S0301-472X(24)00562-9. [Epub ahead of print] 104698

Reconsidering the usual suspects in age-related hematologic disorders: is stem cell dysfunction a root cause of aging?

Foteini Fotopoulou, Esther Rodriguez-Correa, Charles Dussiau, Michael D Milsom.

  Aging exerts a profound impact on the hematopoietic system, leading to increased susceptibility to infections, autoimmune diseases, chronic inflammation, anemia, thrombotic events, and hematologic malignancies. Within the field of experimental hematology, the functional decline of hematopoietic stem cells (HSCs) is often regarded as a primary driver of age-related hematologic conditions. However, aging is clearly a complex multifaceted process involving not only HSCs but also mature blood cells and their interactions with other tissues. This review reappraises an HSC-centric view of hematopoietic aging by exploring how the entire hematopoietic hierarchy, from stem cells to mature cells, contributes to age-related disorders. It highlights the decline of both innate and adaptive immunity, leading to increased susceptibility to infections and cancer, and the rise of autoimmunity as peripheral immune cells undergo aging-induced changes. It explores the concept of "inflammaging," where persistent, low-grade inflammation driven by old immune cells creates a cycle of tissue damage and disease. Additionally, this review delves into the roles of inflammation and homeostatic regulation in age-related conditions such as thrombotic events and anemia, arguing that these issues arise from broader dysfunctions rather than stemming from HSC functional attrition alone. In summary, this review highlights the importance of taking a holistic approach to studying hematopoietic aging and its related pathologies. By looking beyond just stem cells and considering the full spectrum of age-associated changes, one can better capture the complexity of aging and attempt to develop preventative or rejuvenative strategies that better target multiple facets of this process.

Keywords:  CHIP; HSC; Hematopoietic stem cells; Inflammation; aging; anemia; clonal hematopoiesis; immune compromised; inflammaging; myeloid bias

DOI:  https://doi.org/10.1016/j.exphem.2024.104698
Elife. 2024 Dec 23. pii: RP94884. [Epub ahead of print]13

A novel human pluripotent stem cell gene activation system identifies IGFBP2 as a mediator in the production of haematopoietic progenitors in vitro.

Paolo Petazzi, Telma Ventura, Francesca Paola Luongo, Heather McClafferty, Alisha May, Helen Alice Taylor, Michael J Shipston, Nicola Romanò, Lesley M Forrester, Pablo Menendez, Antonella Fidanza.

  A major challenge in the stem cell biology field is the ability to produce fully functional cells from induced pluripotent stem cells (iPSCs) that are a valuable resource for cell therapy, drug screening, and disease modelling. Here, we developed a novel inducible CRISPR-mediated activation strategy (iCRISPRa) to drive the expression of multiple endogenous transcription factors (TFs) important for in vitro cell fate and differentiation of iPSCs to haematopoietic progenitor cells. This work has identified a key role for IGFBP2 in developing haematopoietic progenitors. We first identified nine candidate TFs that we predicted to be involved in blood cell emergence during development, then generated tagged gRNAs directed to the transcriptional start site of these TFs that could also be detected during single-cell RNA sequencing (scRNAseq). iCRISPRa activation of these endogenous TFs resulted in a significant expansion of arterial-fated endothelial cells expressing high levels of IGFBP2, and our analysis indicated that IGFBP2 is involved in the remodelling of metabolic activity during in vitro endothelial to haematopoietic transition. As well as providing fundamental new insights into the mechanisms of haematopoietic differentiation, the broader applicability of iCRISPRa provides a valuable tool for studying dynamic processes in development and for recapitulating abnormal phenotypes characterised by ectopic activation of specific endogenous gene expression in a wide range of systems.

Keywords:  CRISPR activation; developmental biology; haematopoiesis; human; pluripotent stem cells; regenerative medicine; stem cells

DOI:  https://doi.org/10.7554/eLife.94884
Nat Biomed Eng. 2024 Dec 23.

Enhanced engraftment of human haematopoietic stem cells via mechanical remodelling mediated by the corticotropin-releasing hormone.

Mingming Wu, Haoxiang Yang, Senquan Liu, Lai Jiang, Tingting Liang, Yan Wang, Mingming Zhu, Xian Song, Hao Liu, Jinghao Shen, Shuangzi Wang, Xiaoyu Zhu, Cheng-Kui Qu, Linzhao Cheng, Hongyuan Jiang, Fang Ni.

The engraftment of haematopoietic stem and progenitor cells (HSPCs), particularly in cord-blood transplants, remains challenging. Here we report the role of the corticotropin-releasing hormone (CRH) in enhancing the homing and engraftment of human-cord-blood HSPCs in bone marrow through mechanical remodelling. By using microfluidics, intravital two-photon imaging and long-term-engraftment assays, we show that treatment with CRH substantially enhances HSPC adhesion, motility and mechanical remodelling, ultimately leading to improved bone-marrow homing and engraftment in immunodeficient mice. CRH induces Ras homologue gene family member A (RhoA)-dependent nuclear translocation of the yes-associated protein (YAP), which upregulates the expression of genes encoding extracellular-matrix proteins (notably, thrombospondin-2 (THBS2)). This process guides the mechanical remodelling of HSPCs via modulation of the actin cytoskeleton and the extracellular matrix, with THBS2 interacting with the integrin αvβ3 and coordinating the nuclear translocation of YAP upon CRH/CRH-receptor-1 (CRH/CRHR1) signalling. Overall, the CRH/CRHR1/RhoA/YAP/THBS2/αvβ3 axis has a central role in modulating HSPC behaviour via a mechanical feedback loop involving THBS2, αvβ3, the actin cytoskeleton and YAP signalling. Our findings may suggest avenues for optimizing the transplantation of HSPCs.

DOI: https://doi.org/10.1038/s41551-024-01316-1
Blood. 2024 Dec 24. pii: blood.2024026232. [Epub ahead of print]

Menin inhibitors in the treatment of acute myeloid leukemia.

Gerwin A Huls, Carolien M Woolthuis, Jan Jacob Schuringa.

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the (oligo)clonal expansion of myeloid progenitor cells. Despite advances in treatment, AML remains challenging to cure, particularly in patients with specific genetic abnormalities. Menin inhibitors have emerged as a promising therapeutic approach, targeting key genetic drivers of AML such as KMT2A rearrangements and NPM1 mutations. Here, we review the clinical value of menin inhibitors, highlighting their mechanism of action, efficacy, safety, and potential to transform AML treatment.

DOI: https://doi.org/10.1182/blood.2024026232
Blood Adv. 2024 Dec 23. pii: bloodadvances.2024014157. [Epub ahead of print]

Genome-wide CRISPR screen identifies AraC-Dauno-Eto (ADE) response modulators that predicts outcome in pediatric AML.

Nam Hk Nguyen, Roya Rafiee, Phani Krishan Parcha, Abderrahmane Tagmount, Jeffrey Rubnitz, Raul C Ribeiro, Xueyuan Cao, Stanley B Pounds, Christopher D Vulpe, Jatinder Kaur Lamba.

Cytarabine, daunorubicin, and etoposide (ADE) have been the standard backbone of induction chemotherapy regimens for acute myeloid leukemia (AML) patients for over five decades. However, chemoresistance is still a major concern, and a significant proportion of AML becomes resistant to ADE treatment leading to relapse and poor survival. Therefore, there is a significant need to identify mechanisms mediating drug resistance to overcome chemoresistance. Herein, we performed genome-wide synthetic lethal CRISPR/Cas9 screens using araC, daunorubicin and etoposide. We further integrated significant findings from the CRISPR screen with outcome in pAML patients treated with standard ADE regimen on 3 independent clinical trials to identify drug response biomarkers of prognostic significance. We identified seveal mediators that would represent clinically and biologically significant genes for ADE treatment, such as BCL2, CLIP2, and VAV3, which are resistant genes with high expression associated with poor outcomes in pAML treated with ADE, and GRPEL1, HCFC1, and TAF10, which are sensitive genes with high expression showing beneficial outcomes. Notably, knockdowns of the BCL2, CLIP2, and VAV3 genes sensitize the ADE component in AML cell lines, suggesting that these genes should be further studied as potential therapeutic targets to overcome chemoresistance.

DOI: https://doi.org/10.1182/bloodadvances.2024014157
Cell Death Dis. 2024 Dec 20. 15(12): 921

SLC25A21 correlates with the prognosis of adult acute myeloid leukemia through inhibiting the growth of leukemia cells via downregulating CXCL8.

Yu Liu, Yan Xu, Qianqian Hao, Luyao Shi, Yufei Chen, Yajun Liu, Mengya Li, Yu Zhang, Tao Li, Yafei Li, Zhongxing Jiang, Yanfang Liu, Chong Wang, Zhilei Bian, Lu Yang, Shujuan Wang.

In recent years, targeting mitochondrial apoptosis has emerged as a promising therapeutic strategy for Acute Myeloid Leukemia (AML). The SLC25 family of mitochondrial carriers plays a critical role in maintaining mitochondrial function and regulating apoptosis. However, the role of SLC25A21, an oxodicarboxylate carrier, in AML progression and its potential as a prognostic biomarker remain underexplored. This study aimed to further investigate the role, molecular mechanism, and potential clinical value of SLC25A21 in AML progression. The transcript levels of SLC25A21 in bone marrow specimens were analyzed using real-time quantitative polymerase chain reaction. The correlation between SLC25A21 expression and the prognosis of AML was assessed through survival analysis. Findings revealed that SLC25A21 was downregulated in adult AML, and the low expression of SLC25A21 was correlated with worse prognosis for AML patients. Furthermore, overexpression of SLC25A21 inhibited cell proliferation and cell cycle progression, and was correlated with apoptosis through mitochondrial apoptosis signaling pathway. C-X-C motif chemokine ligand 8 (CXCL8) was identified as a downstream target of SLC25A21. These functions of SLC25A21 could be rescued by the overexpression of CXCL8. Moreover, SLC25A21 overexpression significantly suppressed the growth of xenograft tumors. In conclusion, the low SLC25A21 expression is correlated with poor clinical outcome. The overexpression of SLC25A21 inhibited the AML cell survival and proliferation by dysregulating the expression of CXCL8. SLC25A21 might be a potential prognostic marker and a treatment target for AML.

DOI: https://doi.org/10.1038/s41419-024-07308-y
bioRxiv. 2024 Dec 12. pii: 2024.12.10.627803. [Epub ahead of print]

Cells Prioritize the Regulation of Cell Mass Density.

Jinyu Fu, Qin Ni, Yufei Wu, Anoushka Gupta, Zhuoxu Ge, Hongru Yang, Yasin Afrida, Ishan Barman, Sean X Sun.

A cell's global physical state is characterized by its volume and dry mass. The ratio of cell mass to volume is the cell mass density (CMD), which is also a measure of macromolecular crowding and concentrations of all proteins. Using the Fluorescence eXclusion method (FXm) and Quantitative Phase Microscopy (QPM), we investigate CMD dynamics after exposure to sudden media osmolarity change. We find that while the cell volume and mass exhibit complex behavior after osmotic shock, CMD follows a straightforward monotonic recovery in 48 hours. The recovery is cell-cycle independent and relies on a coordinated adjustment of protein synthesis and volume growth rates. Surprisingly, we find that the protein synthesis rate decreases when CMD increases. This result is explained by CMD-dependent nucleoplasm-cytoplasm transport, which serves as negative regulatory feedback on CMD. The Na + /H + exchanger NHE plays a role in regulating CMD by affecting both protein synthesis and volume change. Taken together, we reveal that cells possess a robust control system that actively regulates CMD during environmental change.

DOI: https://doi.org/10.1101/2024.12.10.627803
Leukemia. 2024 Dec 23.

HMGA2 overexpression with specific chromosomal abnormalities predominate in CALR and ASXL1 mutated myelofibrosis.

Shivani Handa, Christoph Schaniel, Joseph Tripodi, Daiva Ahire, Md Babu Mia, Sophie Klingborg, Douglas Tremblay, Bridget K Marcellino, Ronald Hoffman, Vesna Najfeld.

Although multiple genetic events are thought to play a role in promoting progression of the myeloproliferative neoplasms (MPN), the individual events that are associated with the development of more aggressive disease phenotypes remain poorly defined. Here, we report that novel genomic deletions at chromosome 12q14.3, as detected by a high-resolution array comparative genomic hybridization plus single nucleotide polymorphisms platform, occur in 11% of MPN patients with myelofibrosis (MF) and MPN-accelerated/blast phase (AP/BP) but was not detected in patients with polycythemia vera or essential thrombocythemia. These 12q14.3 deletions resulted in the loss of most of the non-coding region of exon 5 and MIRLET7 binding sites in the 3'UTR of the high mobility group AT hook 2 (HMGA2), which negatively regulate HMGA2 expression. These acquired 12q14.3 deletions were predominately detected in MF patients with CALR and ASXL1 co-mutations and led to a greater degree of HMGA2 transcript overexpression, independent of the presence of an ASXL1 mutation. Patients with 12q structural abnormalities involving HMGA2 exhibited a more aggressive clinical course, with a higher frequency of MPN-AP/BP evolution. These findings indicate that HMGA2 overexpression associated with genomic deletion of its 3'UTR region is a newly recognized genetic event that contributes to MPN progression.

DOI: https://doi.org/10.1038/s41375-024-02496-0