bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2023–05–07
seventeen papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Amino acid metabolism, redox balance and epigenetic regulation in cancer.
  2. ENPP4 and HOXA3 as potential leukaemia stem cell markers in acute myeloid leukaemia.
  3. Mitochondria in cancer stem cells: Achilles heel or hard armor.
  4. [Prognostic value of residual disease detection in acute myeloid leukemia with normal karyotype and negative FLT3-ITD].
  5. Cancer stem cells: an insight into the development of metastatic tumors and therapy resistance.
  6. The 'omics of obesity in B-cell acute lymphoblastic leukemia.
  7. Blocking fatty acid synthesis beats resistance.
  8. Childhood hematopoietic stem cells constitute the permissive window for RUNX1-ETO leukemogenesis.
  9. Methionine consumption by cancer cells drives a progressive upregulation of PD-1 expression in CD4 T cells.
  10. Identification and validation of a novel CD8+ T cell-associated prognostic model based on ferroptosis in acute myeloid leukemia.
  11. Metabonomic analysis of tumor microenvironments: a mini-review.
  12. Integrated bioinformatic analysis of mitochondrial metabolism-related genes in acute myeloid leukemia.
  13. Inter-organelle cross-talk supports acetyl-coenzyme A homeostasis and lipogenesis under metabolic stress.
  14. Acetyl-CoA biosynthesis drives resistance to histone acetyltransferase inhibition.
  15. Maintenance therapy in acute myeloid leukemia: advances and controversies.
  16. Multi-targeted immunotherapeutics to treat B cell malignancies.
  17. Acetylcarnitine shuttling links mitochondrial metabolism to histone acetylation and lipogenesis.
  1. FEBS J. 2023 May 02.
    Amino acid metabolism, redox balance and epigenetic regulation in cancer.
    Xiang Li, Hong-Sheng Zhang.
      Amino acids act as the versatile nutrients driving cell growth and survival, especially in cancer cells. Amino acid metabolism comprises numerous metabolic networks and is closely linked with intracellular redox balance and epigenetic regulation. Reprogrammed amino acid metabolism has been recognized as a ubiquitous feature in tumor cells. This review outlines the metabolism of several primary amino acids in cancer cells and highlights the pivotal role of amino acid metabolism in sustaining redox homeostasis and regulating epigenetic modification in response to oxidative and genetic stress in cancer cells.
    Keywords:  amino acids; cancer; epigenetic regulation; metabolism; redox balance
    DOI:  https://doi.org/10.1111/febs.16803
  2. Malays J Pathol. 2023 Apr;45(1): 65-76
    ENPP4 and HOXA3 as potential leukaemia stem cell markers in acute myeloid leukaemia.
    A Mohd Amin, N Panneerselvan, S Md Noor, N Mohtaruddin, J Sathar, W S Norbaya, R Osman, L H Kee, W H Mohd Yaakub, S K Cheong, M Abdullah.
       INTRODUCTION: Acute myeloid leukaemia (AML) is a heterogeneous malignant disease with a high degree of treatment failure using chemotherapy. Leukaemia stem cells (LSCs) are CD34+CD38- early progenitors associated with poor prognosis in AML. A unique LSC phenotype that excludes rare normal haematopoietic stem cells (HSC) is still elusive. This study aimed to determine expression of selected potential LSC markers in normal and leukaemic myeloid cells and correlate prognosis in AML patients.
    MATERIALS AND METHODS: Flow cytometry and RT-qPCR measured expressions of ALDH, IL3RA/CD123, CLEC12A/CLL-1/CD371, HOXA3 and ENPP4. Normal cord blood (n=3) and blood monocytes (n=5) represented HSC and mature cells, respectively. Myeloid leukaemia cell lines (THP-1, KG-1a, K562 and HL-60) represented progenitor cells at various stages of maturation. AML samples included chemo-resistant (n=8), early relapse (n=2) and late relapse (n=18).
    RESULTS: Combining protein/gene expressions, CD34+CD38- was a feature of immature cells seen in cord blood, KG-1a, and K562 but not more mature cells (blood monocytes and HL-60). Normal cells expressed CD371 while mature cells (blood monocytes and HL-60) lacked CD123. ENPP4 was not expressed on normal cells while HOXA3 was expressed only on cord blood and THP-1. In AML, CD123, HOXA3, ENPP4 (but not CD371) were significantly increased in the CD34+CD38- fraction of chemo-resistant patients while ALDH was associated with chemo-resistance.
    CONCLUSION: CD34+CD38- presented an immature phenotype and with ALDH were associated with poor prognosis. CD123, HOXA3 and ENPP4 further enriched the LSC population. ENPP4 has not been reported and has the advantage of not being expressed on HSC and normal monocytes.
  3. Trends Cell Biol. 2023 May 01. pii: S0962-8924(23)00050-8. [Epub ahead of print]
    Mitochondria in cancer stem cells: Achilles heel or hard armor.
    Xiao-Xia Zheng, Jun-Jie Chen, Yi-Bo Sun, Tian-Qing Chen, Jun Wang, Shi-Cang Yu.
      Previous studies have shown that mitochondria play core roles in not only cancer stem cell (CSC) metabolism but also the regulation of CSC stemness maintenance and differentiation, which are key regulators of cancer progression and therapeutic resistance. Therefore, an in-depth study of the regulatory mechanism of mitochondria in CSCs is expected to provide a new target for cancer therapy. This article mainly introduces the roles played by mitochondria and related mechanisms in CSC stemness maintenance, metabolic transformation, and chemoresistance. The discussion mainly focuses on the following aspects: mitochondrial morphological structure, subcellular localization, mitochondrial DNA, mitochondrial metabolism, and mitophagy. The manuscript also describes the recent clinical research progress on mitochondria-targeted drugs and discusses the basic principles of their targeted strategies. Indeed, an understanding of the application of mitochondria in the regulation of CSCs will promote the development of novel CSC-targeted strategies, thereby significantly improving the long-term survival rate of patients with cancer.
    Keywords:  anticancer therapeutics; cancer stem cells; metabolism; mitochondria; mitochondrial morphology
    DOI:  https://doi.org/10.1016/j.tcb.2023.03.009
  4. Ann Biol Clin (Paris). 2023 May 05. 81(2): 136-144
    [Prognostic value of residual disease detection in acute myeloid leukemia with normal karyotype and negative FLT3-ITD].
    Samiha Jaddaoui, Hanaa Bencharef, Sara Addakiri, Hind Dehbi, Amal Tazzite, Mouna Lamchahab, Bouchra Oukkache.
       INTRODUCTION: Complete remission (CR) in patients with acute myeloid leukemia (AML) is still morphologicaly defined, thus corresponding to a wide range of tumor burden.
    OBJECTIVES: we aimed to evaluate the residual disease (MRD) status in patients with AML, as well as perform a molecular analysis of the FLT3/ITD gene in patients with normal karyotype.
    MATERIAL AND METHODS: adult patients with AML, diagnosed according to the WHO 2016 criteria, were included. MRD was detected using flow cytometric techniques after induction treatment resulting in CR.
    RESULTS: thirty patients met our inclusion criteria. 83 % of them had an intermediate risk status, 67 % of which (20/30) having a normal karyotype. MRD and leukemic stem cell (LSC) positivity in this group was predominant with considerable decrease in benign progenitor count. The relapse-free survival (RFS) in the group of MRD negative patients with normal cytogenetics and non-mutated FLT3 gene was better than the RFS in all of our patients studied.
    CONCLUSION: MRD and LSC are powerful prognostic factors for relapse. They should be routinely integrated to guide better management of AML.
    Keywords:  FLT3-ITD mutation; acute myeloblastic leukemia; residual disease
    DOI:  https://doi.org/10.1684/abc.2023.1798
  5. Stem Cell Rev Rep. 2023 May 02.
    Cancer stem cells: an insight into the development of metastatic tumors and therapy resistance.
    Tahsin Nairuz, Zimam Mahmud, Rasel Khan Manik, Yearul Kabir.
      The term "cancer stem cells" (CSCs) refers to cancer cells that exhibit traits parallel to normal stem cells, namely the potential to give rise to every type of cell identified in a tumor microenvironment. It has been found that CSCs usually develops from other neoplastic cells or non-cancerous somatic cells by acquiring stemness and malignant characteristics through particular genetic modifications. A trivial number of CSCs, identified in solid and liquid cancer, can give rise to an entire tumor population with aggressive anticancer drug resistance, metastasis, and invasiveness. Besides, cancer stem cells manipulate their intrinsic and extrinsic features, regulate the metabolic pattern of the cell, adjust efflux-influx efficiency, modulate different signaling pathways, block apoptotic signals, and cause genetic and epigenetic alterations to retain their pluripotency and ability of self-renewal. Notably, to keep the cancer stem cells' ability to become malignant cells, mesenchymal stem cells, tumor-associated fibroblasts, immune cells, etc., interact with one another. Furthermore, CSCs are characterized by the expression of particular molecular markers that carry significant diagnostic and prognostic significance. Because of this, scientific research on CSCs is becoming increasingly imperative, intending to understand the traits and behavior of cancer stem cells and create more potent anticancer therapeutics to fight cancer at the CSC level. In this review, we aimed to elucidate the critical role of CSCs in the onset and spread of cancer and the characteristics of CSCs that promote severe resistance to targeted therapy.
    Keywords:  Cancer biomarkers; Cancer metastasis; Cancer stem cells; Therapy resistance; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12015-023-10529-x
  6. J Natl Cancer Inst Monogr. 2023 May 04. 2023(61): 12-29
    The 'omics of obesity in B-cell acute lymphoblastic leukemia.
    Delaney K Geitgey, Miyoung Lee, Kirsten A Cottrill, Maya Jaffe, William Pilcher, Swati Bhasin, Jessica Randall, Anthony J Ross, Michelle Salemi, Marisol Castillo-Castrejon, Matthew B Kilgore, Ayjha C Brown, Jeremy M Boss, Rich Johnston, Anne M Fitzpatrick, Melissa L Kemp, Robert English, Eric Weaver, Pritha Bagchi, Ryan Walsh, Christopher D Scharer, Manoj Bhasin, Joshua D Chandler, Karmella A Haynes, Elizabeth A Wellberg, Curtis J Henry.
      The obesity pandemic currently affects more than 70 million Americans and more than 650 million individuals worldwide. In addition to increasing susceptibility to pathogenic infections (eg, SARS-CoV-2), obesity promotes the development of many cancer subtypes and increases mortality rates in most cases. We and others have demonstrated that, in the context of B-cell acute lymphoblastic leukemia (B-ALL), adipocytes promote multidrug chemoresistance. Furthermore, others have demonstrated that B-ALL cells exposed to the adipocyte secretome alter their metabolic states to circumvent chemotherapy-mediated cytotoxicity. To better understand how adipocytes impact the function of human B-ALL cells, we used a multi-omic RNA-sequencing (single-cell and bulk transcriptomic) and mass spectroscopy (metabolomic and proteomic) approaches to define adipocyte-induced changes in normal and malignant B cells. These analyses revealed that the adipocyte secretome directly modulates programs in human B-ALL cells associated with metabolism, protection from oxidative stress, increased survival, B-cell development, and drivers of chemoresistance. Single-cell RNA sequencing analysis of mice on low- and high-fat diets revealed that obesity suppresses an immunologically active B-cell subpopulation and that the loss of this transcriptomic signature in patients with B-ALL is associated with poor survival outcomes. Analyses of sera and plasma samples from healthy donors and those with B-ALL revealed that obesity is associated with higher circulating levels of immunoglobulin-associated proteins, which support observations in obese mice of altered immunological homeostasis. In all, our multi-omics approach increases our understanding of pathways that may promote chemoresistance in human B-ALL and highlight a novel B-cell-specific signature in patients associated with survival outcomes.
    DOI:  https://doi.org/10.1093/jncimonographs/lgad014
  7. Nat Rev Drug Discov. 2023 May 04.
    Blocking fatty acid synthesis beats resistance.
    Sarah Crunkhorn.
      
    DOI:  https://doi.org/10.1038/d41573-023-00071-3
  8. Int J Hematol. 2023 May 02.
    Childhood hematopoietic stem cells constitute the permissive window for RUNX1-ETO leukemogenesis.
    Mohamed Gaber Abdallah, Vania Swee Imm Teoh, Bibek Dutta, Tomomasa Yokomizo, Motomi Osato.
      Cancer is a very rare event at the cellular level, although it is a common disease at the body level as one third of humans die of cancer. A small subset of cells in the body harbor the cellular features that constitute a permissive window for a particular genetic change to induce cancer. The significance of a permissive window is ironically best shown by a large number of failures in generating the animal model for acute myeloid leukemia (AML) with t(8;21). Over the decades, the RUNX1-ETO fusion gene created by t(8;21) has been introduced into various types of hematopoietic cells, largely at adult stage, in mice; however, all the previous attempts failed to generate tractable AML models. In stark contrast, we recently succeeded in inducing AML with the clinical features seen in human patients by specifically introducing RUNX1-ETO in childhood hematopoietic stem cells (HSCs). This result in mice is consistent with adolescent and young adult (AYA) onset in human t(8;21) patients, and suggests that childhood HSCs constitute the permissive window for RUNX1-ETO leukemogenesis. If loss of a permissive window is induced pharmacologically, cancer cells might be selectively targeted. Such a permissive window modifier may serve as a novel therapeutic drug.
    Keywords:  Acute myeloid leukemia; Hematopoietic stem cell; Permissive window; RUNX; t(8;21)
    DOI:  https://doi.org/10.1007/s12185-023-03605-y
  9. Nat Commun. 2023 May 05. 14(1): 2593
    Methionine consumption by cancer cells drives a progressive upregulation of PD-1 expression in CD4 T cells.
    Mahesh Pandit, Yun-Seo Kil, Jae-Hee Ahn, Ram Hari Pokhrel, Ye Gu, Sunil Mishra, Youngjoo Han, Yung-Taek Ouh, Ben Kang, Myeong Seon Jeong, Jong-Oh Kim, Joo-Won Nam, Hyun-Jeong Ko, Jae-Hoon Chang.
      Programmed cell death protein 1 (PD-1), expressed on tumor-infiltrating T cells, is a T cell exhaustion marker. The mechanisms underlying PD-1 upregulation in CD4 T cells remain unknown. Here we develop nutrient-deprived media and a conditional knockout female mouse model to study the mechanism underlying PD-1 upregulation. Reduced methionine increases PD-1 expression on CD4 T cells. The genetic ablation of SLC43A2 in cancer cells restores methionine metabolism in CD4 T cells, increasing the intracellular levels of S-adenosylmethionine and yielding H3K79me2. Reduced H3K79me2 due to methionine deprivation downregulates AMPK, upregulates PD-1 expression and impairs antitumor immunity in CD4 T cells. Methionine supplementation restores H3K79 methylation and AMPK expression, lowering PD-1 levels. AMPK-deficient CD4 T cells exhibit increased endoplasmic reticulum stress and Xbp1s transcript levels. Our results demonstrate that AMPK is a methionine-dependent regulator of the epigenetic control of PD-1 expression in CD4 T cells, a metabolic checkpoint for CD4 T cell exhaustion.
    DOI:  https://doi.org/10.1038/s41467-023-38316-9
  10. Front Immunol. 2023 ;14 1149513
    Identification and validation of a novel CD8+ T cell-associated prognostic model based on ferroptosis in acute myeloid leukemia.
    Ge Jiang, Peng Jin, Xiao Xiao, Jie Shen, Ran Li, Yunxiang Zhang, Xiaoyang Li, Kai Xue, Junmin Li.
      Acute myeloid leukemia (AML) is a highly aggressive cancer with great heterogeneity and variability in prognosis. Though European Leukemia Net (ELN) 2017 risk classification has been widely used, nearly half of patients were stratified to "intermediate" risk and requires more accurate classification via excavating biological features. As new evidence showed that CD8+ T cell can kill cancer cells through ferroptosis pathway. We firstly use CIBERSORT algorithm to divide AMLs into CD8+ high and CD8+ low T cell groups, then 2789 differentially expressed genes (DEGs) between groups were identified, of which 46 ferroptosis-related genes associated with CD8+ T cell were sorted out. GO, KEGG analysis and PPI network were conducted based on these 46 DEGs. By jointly using LASSO algorithm and Cox univariate regression, we generated a 6-gene prognostic signature comprising VEGFA, KLHL24, ATG3, EIF2AK4, IDH1 and HSPB1. Low-risk group shows a longer overall survival. We then validated the prognostic value of this 6-gene signature using two independent external datasets and patient sample collection dataset. We also proved that incorporation of the 6-gene signature obviously enhanced the accuracy of ELN risk classification. Finally, gene mutation analysis, drug sensitive prediction, GSEA and GSVA analysis were conducted between high-risk and low-risk AML patients. Collectively, our findings suggested that the prognostic signature based on CD8+ T cell-related ferroptosis genes can optimize the risk stratification and prognostic prediction of AML patients.
    Keywords:  CD8+ T cell; European Leukemia Net (ELN) 2017; acute myeloid leukemia (AML); ferroptosis; prognosis
    DOI:  https://doi.org/10.3389/fimmu.2023.1149513
  11. Front Oncol. 2023 ;13 1164266
    Metabonomic analysis of tumor microenvironments: a mini-review.
    Zeng Zeng, Cong-Xian Chen.
      Metabolomic analysis is a vital part of studying cancer progression. Metabonomic crosstalk, such as nutrient availability, physicochemical transformation, and intercellular interactions can affect tumor metabolism. Many original studies have demonstrated that metabolomics is important in some aspects of tumor metabolism. In this mini-review, we summarize the definition of metabolomics and how it can help change a tumor microenvironment, especially in pathways of three metabonomic tumors. Just as non-invasive biofluids have been identified as early biomarkers of tumor development, metabolomics can also predict differences in tumor drug response, drug resistance, and efficacy. Therefore, metabolomics is important for tumor metabolism and how it can affect oncology drugs in cancer therapy.
    Keywords:  drug resistance; metabolism; metabolomic; metabonomic; tumor
    DOI:  https://doi.org/10.3389/fonc.2023.1164266
  12. Front Immunol. 2023 ;14 1120670
    Integrated bioinformatic analysis of mitochondrial metabolism-related genes in acute myeloid leukemia.
    Xiqin Tong, Fuling Zhou.
       Background: Acute myeloid leukemia (AML) is a common hematologic malignancy characterized by poor prognoses and high recurrence rates. Mitochondrial metabolism has been increasingly recognized to be crucial in tumor progression and treatment resistance. The purpose of this study was to examined the role of mitochondrial metabolism in the immune regulation and prognosis of AML.
    Methods: In this study, mutation status of 31 mitochondrial metabolism-related genes (MMRGs) in AML were analyzed. Based on the expression of 31 MMRGs, mitochondrial metabolism scores (MMs) were calculated by single sample gene set enrichment analysis. Differential analysis and weighted co-expression network analysis were performed to identify module MMRGs. Next, univariate Cox regression and the least absolute and selection operator regression were used to select prognosis-associated MMRGs. A prognosis model was then constructed using multivariate Cox regression to calculate risk score. We validated the expression of key MMRGs in clinical specimens using immunohistochemistry (IHC). Then differential analysis was performed to identify differentially expressed genes (DEGs) between high- and low-risk groups. Functional enrichment, interaction networks, drug sensitivity, immune microenvironment, and immunotherapy analyses were also performed to explore the characteristic of DEGs.
    Results: Given the association of MMs with prognosis of AML patients, a prognosis model was constructed based on 5 MMRGs, which could accurately distinguish high-risk patients from low-risk patients in both training and validation datasets. IHC results showed that MMRGs were highly expressed in AML samples compared to normal samples. Additionally, the 38 DEGs were mainly related to mitochondrial metabolism, immune signaling, and multiple drug resistance pathways. In addition, high-risk patients with more immune-cell infiltration had higher Tumor Immune Dysfunction and Exclusion scores, indicating poor immunotherapy response. mRNA-drug interactions and drug sensitivity analyses were performed to explore potential druggable hub genes. Furthermore, we combined risk score with age and gender to construct a prognosis model, which could predict the prognosis of AML patients.
    Conclusion: Our study provided a prognostic predictor for AML patients and revealed that mitochondrial metabolism is associated with immune regulation and drug resistant in AML, providing vital clues for immunotherapies.
    Keywords:  acute myeloid leukemia; drug sensitivity; mitochondrial metabolism; prognostic model; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1120670
  13. Sci Adv. 2023 May 03. 9(18): eadf0138
    Inter-organelle cross-talk supports acetyl-coenzyme A homeostasis and lipogenesis under metabolic stress.
    Ramya S Kuna, Avi Kumar, Karl A Wessendorf-Rodriguez, Hector Galvez, Courtney R Green, Grace H McGregor, Thekla Cordes, Reuben J Shaw, Robert U Svensson, Christian M Metallo.
      Proliferating cells rely on acetyl-CoA to support membrane biogenesis and acetylation. Several organelle-specific pathways are available for provision of acetyl-CoA as nutrient availability fluctuates, so understanding how cells maintain acetyl-CoA homeostasis under such stresses is critically important. To this end, we applied 13C isotope tracing cell lines deficient in these mitochondrial [ATP-citrate lyase (ACLY)]-, cytosolic [acetyl-CoA synthetase (ACSS2)]-, and peroxisomal [peroxisomal biogenesis factor 5 (PEX5)]-dependent pathways. ACLY knockout in multiple cell lines reduced fatty acid synthesis and increased reliance on extracellular lipids or acetate. Knockout of both ACLY and ACSS2 (DKO) severely stunted but did not entirely block proliferation, suggesting that alternate pathways can support acetyl-CoA homeostasis. Metabolic tracing and PEX5 knockout studies link peroxisomal oxidation of exogenous lipids as a major source of acetyl-CoA for lipogenesis and histone acetylation in cells lacking ACLY, highlighting a role for inter-organelle cross-talk in supporting cell survival in response to nutrient fluctuations.
    DOI:  https://doi.org/10.1126/sciadv.adf0138
  14. Nat Chem Biol. 2023 May 01.
    Acetyl-CoA biosynthesis drives resistance to histone acetyltransferase inhibition.
    Timothy R Bishop, Chitra Subramanian, Eric M Bilotta, Leopold Garnar-Wortzel, Anissa R Ramos, Yuxiang Zhang, Joshua N Asiaban, Christopher J Ott, Charles O Rock, Michael A Erb.
      Histone acetyltransferases (HATs) are implicated as both oncogene and nononcogene dependencies in diverse human cancers. Acetyl-CoA-competitive HAT inhibitors have emerged as potential cancer therapeutics and the first clinical trial for this class of drugs is ongoing (NCT04606446). Despite these developments, the potential mechanisms of therapeutic response and evolved drug resistance remain poorly understood. Having discovered that multiple regulators of de novo coenzyme A (CoA) biosynthesis can modulate sensitivity to CBP/p300 HAT inhibition (PANK3, PANK4 and SLC5A6), we determined that elevated acetyl-CoA concentrations can outcompete drug-target engagement to elicit acquired drug resistance. This not only affects structurally diverse CBP/p300 HAT inhibitors, but also agents related to an investigational KAT6A/B HAT inhibitor that is currently in Phase 1 clinical trials. Altogether, this work uncovers CoA metabolism as an unexpected liability of anticancer HAT inhibitors and will therefore buoy future efforts to optimize the efficacy of this new form of targeted therapy.
    DOI:  https://doi.org/10.1038/s41589-023-01320-7
  15. Haematologica. 2023 May 04.
    Maintenance therapy in acute myeloid leukemia: advances and controversies.
    Jayastu Senapati, Tapan M Kadia, Farhad Ravandi.
      The last decade has seen a steadfast progression in drug development in acute myeloid leukemia (AML) which have moved progressively towards genomics-based therapy. With these advancements, outcomes in AML have improved but remains far from satisfactory. An approach towards preventing relapse in AML is the use of a maintenance therapy in patients, after attaining remission. Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective post-remission therapy that has been proven to reduce the risk of relapse. However, in patients who are ineligible for HSCT or have a high risk of relapse, other effective measures to prevent relapse are needed. There also exists a need for post HSCT maintenance to reduce relapse in high-risk subsets. Over the last 3 decades maintenance therapy in AML has evolved from the use of chemotherapeutic agents to more targeted therapies and better modulation of the immune system. Unfortunately, improvement in survival outcomes from these agents have not been consistently demonstrated in clinical trials. To derive the optimum benefit from maintenance therapy the time points of therapy initiation need to be defined and therapy selection must be precise with respect to the AML genetics and risk stratification, prior treatment exposure, transplant eligibility, expected toxicity and patient's clinical profile and desires. The far-reaching goal is to facilitate patients with AML in remission to achieve a normal quality of life while improving remission duration and overall survival. The QUAZAR trial was a welcome step towards a safe maintenance drug with ease of administration and showed survival benefit but leaves many open issues for discussion. In this review we will discuss these issues, highlighting the development of AML maintenance therapies over the last 3 decades.
    DOI:  https://doi.org/10.3324/haematol.2022.281810
  16. J Control Release. 2023 Apr 28. pii: S0168-3659(23)00298-5. [Epub ahead of print]
    Multi-targeted immunotherapeutics to treat B cell malignancies.
    M Tommy Gambles, Jiyuan Yang, Jindřich Kopeček.
      The concept of multi-targeted immunotherapeutic systems has propelled the field of cancer immunotherapy into an exciting new era. Multi-effector molecules can be designed to engage with, and alter, the patient's immune system in a plethora of ways. The outcomes can vary from effector cell recruitment and activation upon recognition of a cancer cell, to a multipronged immune checkpoint blockade strategy disallowing evasion of the cancer cells by immune cells, or to direct cancer cell death upon engaging multiple cell surface receptors simultaneously. Here, we review the field of multi-specific immunotherapeutics implemented to treat B cell malignancies. The mechanistically diverse strategies are outlined and discussed; common B cell receptor antigen targeting strategies are outlined and summarized; and the challenges of the field are presented along with optimistic insights for the future.
    Keywords:  B cell malignancies; Drug-free macromolecular therapeutics; Immunotherapy; Leukemia; Lymphoma; Multi-specific antibody constructs; Receptor crosslinking
    DOI:  https://doi.org/10.1016/j.jconrel.2023.04.048
  17. Sci Adv. 2023 May 03. 9(18): eadf0115
    Acetylcarnitine shuttling links mitochondrial metabolism to histone acetylation and lipogenesis.
    Luke T Izzo, Sophie Trefely, Christina Demetriadou, Jack M Drummond, Takuya Mizukami, Nina Kuprasertkul, Aimee T Farria, Phuong T T Nguyen, Nivitha Murali, Lauren Reich, Daniel S Kantner, Joshua Shaffer, Hayley Affronti, Alessandro Carrer, Andrew Andrews, Brian C Capell, Nathaniel W Snyder, Kathryn E Wellen.
      The metabolite acetyl-CoA is necessary for both lipid synthesis in the cytosol and histone acetylation in the nucleus. The two canonical precursors to acetyl-CoA in the nuclear-cytoplasmic compartment are citrate and acetate, which are processed to acetyl-CoA by ATP-citrate lyase (ACLY) and acyl-CoA synthetase short-chain 2 (ACSS2), respectively. It is unclear whether other substantial routes to nuclear-cytosolic acetyl-CoA exist. To investigate this, we generated cancer cell lines lacking both ACLY and ACSS2 [double knockout (DKO) cells]. Using stable isotope tracing, we show that both glucose and fatty acids contribute to acetyl-CoA pools and histone acetylation in DKO cells and that acetylcarnitine shuttling can transfer two-carbon units from mitochondria to cytosol. Further, in the absence of ACLY, glucose can feed fatty acid synthesis in a carnitine responsive and carnitine acetyltransferase (CrAT)-dependent manner. The data define acetylcarnitine as an ACLY- and ACSS2-independent precursor to nuclear-cytosolic acetyl-CoA that can support acetylation, fatty acid synthesis, and cell growth.
    DOI:  https://doi.org/10.1126/sciadv.adf0115
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