bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2023–05–14
twelve papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and purine biosynthesis.
  2. Moving beyond traditional clinical trial endpoints: patient-reported outcomes illuminate the patient experience of novel AML therapies.
  3. CD69 marks a subpopulation of acute myeloid leukemia with enhanced colony forming capacity and a unique signaling activation state.
  4. A novel approach to overcome drug resistance in acute myeloid leukemia.
  5. Analysis and functional relevance of the chaperone TRAP-1 interactome in the metabolic regulation and mitochondrial integrity of cancer cells.
  6. Treating CD33-Positive de novo Acute Myeloid Leukemia in Pediatric Patients: Focus on the Clinical Value of Gemtuzumab Ozogamicin.
  7. Single-Cell Profiling of CD8+ T Cells in Acute Myeloid Leukemia Reveals a Continuous Spectrum of Differentiation and Clonal Hyperexpansion.
  8. Acute myeloid leukemia in the medically unfit elderly patients.
  9. Sox13 and M2-like leukemia-associated macrophages contribute to endogenous IL-34 caused accelerated progression of acute myeloid leukemia.
  10. Identification of a novel small-molecule inhibitor targeting TIM-3 for cancer immunotherapy.
  11. Hematopoietic stem cell microtransplantation in patients aged over 70 with acute myeloid leukemia: a multicenter study.
  12. Real-world genomic profiling of acute myeloid leukemia and the impact of European LeukemiaNet risk stratification 2022 update.
  1. Res Sq. 2023 Apr 28. pii: rs.3.rs-2843025. [Epub ahead of print]
    Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and purine biosynthesis.
    Natalia Baran, Katie Hurrish, Yongwei Su, Shraddha Patel, Cassandra Ramage, Jenna Carter, Holly Edwards, Steven Buck, Sandra Wiley, Maik Hüttemann, Lisa Polin, Juiwanna Kushner, Sijana Dzinic, Kathryn White, Xun Bao, Jing Li, Jay Yang, Julie Boerner, Zhanjun Hou, Gheath Al-Atrash, Sergej Konoplev, Jonathan Busquets, Stefano Tiziani, Larry Matherly, Jeffrey Taub, Marina Konopleva, Yubin Ge.
      Venetoclax (VEN), in combination with low dose cytarabine (AraC) or a hypomethylating agent, is FDA approved to treat acute myeloid leukemia (AML) in patients who are over the age of 75 or cannot tolerate standard chemotherapy. Despite high response rates to these combination therapies, most patients succumb to the disease due to relapse and/or drug resistance, providing an unmet clinical need for novel therapies to improve AML patient survival. ME-344 is a potent isoflavone with demonstrated inhibitory activity toward oxidative phosphorylation (OXPHOS) and clinical activity in solid tumors. Given that OXPHOS inhibition enhances VEN antileukemic activity against AML, we hypothesized that ME-344 could enhance the anti-AML activity of VEN. Here we report that ME-344 synergized with VEN to target AML cell lines and primary patient samples while sparing normal hematopoietic cells. Cooperative suppression of OXPHOS was detected in a subset of AML cell lines and primary patient samples. Metabolomics analysis revealed a significant reduction of purine biosynthesis metabolites by ME-344. Further, lometrexol, an inhibitor of purine biosynthesis, synergistically enhanced VEN-induced apoptosis in AML cell lines. Interestingly, AML cells with acquired resistance to AraC showed significantly increased purine biosynthesis metabolites and sensitivities to ME-344. Furthermore, synergy between ME-344 and VEN was preserved in these AraC-resistant AML cells. These results translated into significantly prolonged survival upon combination of ME-344 and VEN in NSGS mice bearing parental or AraC-resistant MV4-11 leukemia. This study demonstrates that ME-344 enhances VEN antileukemic activity against preclinical models of AML by suppressing OXPHOS and/or purine biosynthesis.
    DOI:  https://doi.org/10.21203/rs.3.rs-2843025/v1
  2. Leuk Lymphoma. 2023 May 11. 1-3
    Moving beyond traditional clinical trial endpoints: patient-reported outcomes illuminate the patient experience of novel AML therapies.
    Thomas W LeBlanc.
      
    DOI:  https://doi.org/10.1080/10428194.2023.2208696
  3. Leuk Lymphoma. 2023 May 10. 1-13
    CD69 marks a subpopulation of acute myeloid leukemia with enhanced colony forming capacity and a unique signaling activation state.
    Marie Lue Antony, Daniel Chang, Klara E Noble-Orcutt, Anna Kay, Jeffrey L Jensen, Hesham Mohei, Chad L Myers, Karen Sachs, Zohar Sachs.
      In acute myeloid leukemia (AML), leukemia stem cells (LSCs) have self-renewal potential and are responsible for relapse. We previously showed that, in Mll-AF9/NRASG12V murine AML, CD69 expression marks an LSC-enriched subpopulation with enhanced in vivo self-renewal capacity. Here, we used CyTOF to define activated signaling pathways in LSC subpopulations in Mll-AF9/NRASG12V AML. Furthermore, we compared the signaling activation states of CD69High and CD36High subsets of primary human AML. The human CD69High subset expresses low levels of Ki67 and high levels of NFκB and pMAPKAPKII. Additionally, the human CD69High AML subset also has enhanced colony-forming capacity. We applied Bayesian network modeling to compare the global signaling network within the human AML subsets. We find that distinct signaling states, distinguished by NFκB and pMAPKAPKII levels, correlate with divergent functional subsets, defined by CD69 and CD36 expression, in human AML. Targeting NFκB with proteasome inhibition diminished colony formation.
    Keywords:  Bayesian network; Leukemia stem cells; Neoplasia; Signal transduction; signaling
    DOI:  https://doi.org/10.1080/10428194.2023.2207698
  4. Haematologica. 2023 May 11.
    A novel approach to overcome drug resistance in acute myeloid leukemia.
    Candice Mazewski, Leonidas C Platanias.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2023.283099
  5. Sci Rep. 2023 May 10. 13(1): 7584
    Analysis and functional relevance of the chaperone TRAP-1 interactome in the metabolic regulation and mitochondrial integrity of cancer cells.
    Shrikant Purushottam Dharaskar, Khanderao Paithankar, Sreedhar Amere Subbarao.
      The 90 kDa heat shock protein, Hsp90, functions as a cancer chaperone contributing to tumor proliferation. We have encountered the mitochondrial homolog of Hsp90, the TRAP-1, regulating mitochondrial dynamics, metabolism, and tumor metastasis. Although Hsp90 is associated with a broad network of proteins regulating various cellular processes, TRAP-1-mediated cellular networks are unclear. Therefore, using TRAP-1 knockdown (KD) and overexpression (OE) systems, we compared their quantitative transcriptome (RNA Sequencing) and proteomic (LC-MS/MS) patterns to obtain molecular signatures that are altered in response to TRAP-1 KD or OE. We report TRAP-1 modulating vital metabolic pathways such as the tricarboxylic acid cycle, oxidative phosphorylation, electron transport chain, glycolysis, and gluconeogenesis. In addition, TRAP-1 facilitated the pentose phosphate pathway to shunt carbons back to glycolysis or gluconeogenesis, a much-solicited tumor response. Subsequently, we examined the TRAP-1 interactome using the tandem affinity purification system and identified 255 unique proteins. These diverse proteins appear to regulate several cellular processes, including energy metabolism, suggesting that TRAP-1, in addition to metabolic rewiring, maintains mitochondrial integrity. Our study exposes the unknown functions of TRAP-1 in cancer cells. Systematic evaluation of TRAP-1 interactors may uncover novel regulatory mechanisms in disease aggression. Since metabolic inhibitors are emerging as potential anticancer agents, our study gains importance.
    DOI:  https://doi.org/10.1038/s41598-023-34728-1
  6. Onco Targets Ther. 2023 ;16 297-308
    Treating CD33-Positive de novo Acute Myeloid Leukemia in Pediatric Patients: Focus on the Clinical Value of Gemtuzumab Ozogamicin.
    Noa E Wijnen, Joost B Koedijk, Kim Klein, Maaike Luesink, Bianca F Goemans, C Michel Zwaan, Gertjan J L Kaspers.
      Although survival in pediatric acute myeloid leukemia (AML) has increased considerably over the past decades, refractory disease and relapse rates remain high. Refractory and relapsed disease are difficult to treat, with overall survival rates less than 40-50%. Preventing relapse should, therefore, be one of the highest priorities. Current conventional chemotherapy regimens are hard to intensify due to associated toxic complications, hence more effective therapies that do not increase toxicity are needed. A promising targeted agent is the CD33-directed antibody-drug conjugate gemtuzumab ozogamicin (GO). Because CD33 is highly expressed on leukemic cells in the majority of AML patients, GO can be useful for a broad range of patients. Better relapse-free survival (RFS) after therapy including GO has been reported in several pediatric clinical trials; however, ambiguity about the clinical value of GO in newly diagnosed children remains. Treatment with GO in de novo AML patients aged ≥1 month, in combination with standard chemotherapy is approved in the United States, whereas in Europe, GO is only approved for newly diagnosed patients aged ≥15 years. In this review, we aimed to clarify the clinical value of GO for treatment of newly diagnosed pediatric AML patients. Based on current literature, GO seems to have additional value, in terms of RFS, and acceptable toxicity when used in addition to chemotherapy during initial treatment. Moreover, in KMT2A-rearranged patients, the clinical value of GO was even more evident. Also, we addressed predictors of response, being CD33 expression and SNPs, PgP-1 and Annexin A5. The near finalized intent-to-file clinical trial in the MyeChild consortium investigates whether fractionated dosing has additional value for pediatric AML, which may pave the way for a broader application of GO in pediatric AML.
    Keywords:  antibody–drug conjugates; calicheamicin; immunotherapy; single-nucleotide polymorphism; tailored therapy
    DOI:  https://doi.org/10.2147/OTT.S263829
  7. Cancer Immunol Res. 2023 May 10. pii: CIR-22-0961. [Epub ahead of print]
    Single-Cell Profiling of CD8+ T Cells in Acute Myeloid Leukemia Reveals a Continuous Spectrum of Differentiation and Clonal Hyperexpansion.
    Poonam N Desai, Bofei Wang, Andre Fonseca, Pamella Borges, Fatima Zahra Jelloul, Patrick K Reville, Eric Lee, Christopher Ly, Akshay Basi, Jessica Root, Natalia Baran, Sean M Post, Qing Deng, Hanxiao Sun, Arif O Harmanci, Jared K Burks, Javier A Gomez, Courtney D DiNardo, Naval G Daver, Gheath Alatrash, Marina Konopleva, Michael R Green, Dinler A Antunes, Andrew Futreal, Dapeng Hao, Hussein A Abbas.
      Comprehensive investigation of CD8+ T cells in acute myeloid leukemia (AML) is essential for developing immunotherapeutic strategies beyond immune checkpoint blockade. Herein, we performed single-cell RNA profiling of CD8+ T cells from 3 healthy bone marrow donors and 23 newly diagnosed (NewlyDx) and 8 relapsed/refractory (RelRef) AML patients. Cells co-expressing canonical exhaustion markers formed a cluster constituting <1% of all CD8+ T cells. We identified two effector CD8+ T cell subsets characterized by distinct cytokine and metabolic profiles that were differentially enriched in NewlyDx and RelRef patients. We refined a 25-gene CD8-derived signature correlating with therapy resistance, including genes associated with activation, chemoresistance, and terminal differentiation. Pseudotemporal trajectory analysis supported enrichment of a terminally differentiated state in CD8+ T cells with high CD8-derived signature expression at relapse or refractory disease. Higher expression of the 25-gene CD8 AML signature correlated with poorer outcomes in previously untreated AML patients, suggesting that the bona fide state of CD8+ T cells and their degree of differentiation are clinically relevant. Immune clonotype tracking revealed more phenotypic transitions in CD8 clonotypes in NewlyDx than in RelRef patients. Furthermore, CD8+ T cells from RelRef patients had a higher degree of clonal hyperexpansion associated with terminal differentiation and higher CD8-derived signature expression. Clonotype-derived antigen prediction revealed that most previously unreported clonotypes were patient-specific, suggesting significant heterogeneity in AML immunogenicity. Thus, immunologic reconstitution in AML is likely to be most successful at earlier disease stages when CD8+ T cells are less differentiated and have greater capacity for clonotype transitions.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-22-0961
  8. Leuk Res. 2023 May 05. pii: S0145-2126(23)00571-4. [Epub ahead of print]130 107306
    Acute myeloid leukemia in the medically unfit elderly patients.
    Joseph Edmund, Liz Joemon Thaliath, Kapil Meleveedu.
      Acute Myeloid Leukemia is a clonal proliferative disorder whose incidence increases with age. While studies have shown that the elderly medically unfit patients have poorer outcomes with intensive chemotherapy, a vast majority of them are deemed ineligible for intensive chemotherapy. Multiple studies have also shown that poor performance status prior to treatment initiation affects the prognosis. An accurate comprehensive assessment is hence vital to the selection of such patients. The chemotherapy agents that have been used for AML in the medically unfit patients have also changed significantly in the past few years. In this review we focus on the importance of comprehensive geriatric assessment prior to chemotherapy initiation among patients who are 75 years and older and the treatment approaches available for the medically unfit, Acute Myeloid Leukemia patients.
    Keywords:  Acute myeloid leukemia; Comorbidities; Elderly; Geriatric assessment; New agents; Treatment
    DOI:  https://doi.org/10.1016/j.leukres.2023.107306
  9. Cell Death Dis. 2023 05 06. 14(5): 308
    Sox13 and M2-like leukemia-associated macrophages contribute to endogenous IL-34 caused accelerated progression of acute myeloid leukemia.
    Dongyue Zhang, Xiaoxi Cui, Yifei Li, Rong Wang, Hao Wang, Yibo Dai, Qian Ren, Lina Wang, Guoguang Zheng.
      Interleukin 34 (IL-34) mainly plays physiologic and pathologic roles through the sophisticated multi-ligand signaling system, macrophage colony-stimulating factor (M-CSF, CSF-1)/IL-34-CSF-1R axis, which exhibits functional redundancy, tissue-restriction and diversity. This axis is vital for the survival, differentiation and function of monocytic lineage cells and plays pathologic roles in a broad range of diseases. However, the role of IL-34 in leukemia has not been established. Here MLL-AF9 induced mouse acute myeloid leukemia (AML) model overexpressing IL-34 (MA9-IL-34) was used to explore its role in AML. MA9-IL-34 mice exhibited accelerated disease progression and short survival time with significant subcutaneous infiltration of AML cells. MA9-IL-34 cells showed increased proliferation. In vitro colony forming assays and limiting dilution transplantation experiments demonstrated that MA9-IL-34 cells had elevated leukemia stem cell (LSC) levels. Gene expression microarray analysis revealed a panel of differential expressed genes including Sex-determining region Y (SRY)-box 13 (Sox13). Furthermore, a positive correlation between the expressions of IL-34 and Sox13 was detected human datasets. Knockdown of Sox13 rescued the enhanced proliferation, high LSC level and subcutaneous infiltration in MA9-IL-34 cells. Moreover, more leukemia-associated macrophages (LAMs) were detected in MA9-IL-34 microenvironment. Additionally, those LAMs showed M2-like phenotype since they expressed high level of M2-associated genes and had attenuated phagocytic potential, suggesting that LAMs should also contribute to IL-34 caused adverse phenotypes. Therefore, our findings uncover the intrinsic and microenvironmental mechanisms of IL-34 in AML and broadens the knowledge of M-CSF/IL-34-CSF-1R axis in malignancies.
    DOI:  https://doi.org/10.1038/s41419-023-05822-z
  10. Biochem Pharmacol. 2023 May 04. pii: S0006-2952(23)00174-0. [Epub ahead of print]212 115583
    Identification of a novel small-molecule inhibitor targeting TIM-3 for cancer immunotherapy.
    Menghan Wu, Aijun Wu, Xiangrui Zhang, Yang Li, Beibei Li, Shengzhe Jin, Qingyu Dong, Xiaoshuang Niu, Lihan Zhang, Xiaowen Zhou, Jiangfeng Du, Yahong Wu, Wenjie Zhai, Xiuman Zhou, Lu Qiu, Yanfeng Gao, Wenshan Zhao.
      PD-1/PD-L1 blockade has achieved substantial clinical results in cancer treatment. However, the expression of other immune checkpoints leads to resistance and hinders the efficacy of PD-1/PD-L1 blockade. T cell immunoglobulin and mucin domain 3 (TIM-3), a non-redundant immune checkpoint, synergizes with PD-1 to mediate T cell dysfunction in tumor microenvironment. Development of small molecules targeting TIM-3 is a promising strategy for cancer immunotherapy. Here, to identify small molecule inhibitors targeting TIM-3, the docking pocket in TIM-3 was analyzed by Molecular Operating Environment (MOE) and the Chemdiv compound database was screened. The small molecule SMI402 could bind to TIM-3 with high affinity and prevent the ligation of PtdSer, HMGB1, and CEACAM1. SMI402 reinvigorated T cell function in vitro. In the MC38-bearing mouse model, SMI402 inhibited tumor growth by increasing CD8+ T and natural killing (NK) cells infiltration at the tumor site, as well as restoring the function of CD8+ T and NK cells. In conclusions, the small molecule SMI402 shows promise as a leading compound which targets TIM-3 for cancer immunotherapy.
    Keywords:  Cancer immunotherapy; Immune checkpoint; Small molecule; TIM-3; Virtual screening
    DOI:  https://doi.org/10.1016/j.bcp.2023.115583
  11. Am J Cancer Res. 2023 ;13(4): 1509-1521
    Hematopoietic stem cell microtransplantation in patients aged over 70 with acute myeloid leukemia: a multicenter study.
    Kai-Xun Hu, Mei Guo, Chang-Lin Yu, Jian-Hui Qiao, Qi-Yun Sun, Bo Cai, Xing-Rong Zhan, Xu-Liang Shen, Chuan-Bao Fan, Hui-Sheng Ai, Yi Wang.
      In the era of molecular targeted drugs, elderly patients with acute myeloid leukemia (AML) are still very difficult to treat, especially those older than 70 years. The decline in immune function leads to serious infection and disease recurrence. The microtransplant treatment regimen (MST) chemotherapy combined with allogeneic hematopoietic stem cell infusion is a new cell therapy regimen. The aim of this MST study was to improve the survival of elderly patients by graft versus leukemia action and improving T-cell immune function. From May 2012 to July 2020, one hundred and eleven patients aged 70 to 88 years with de novo AML were analyzed retrospectively. After induction chemotherapy, patients whom complete remission (CR) was achieved were given another 2 cycles of postremission therapy. The MST groups were given allogeneic stem cell infusion after each chemotherapy cycle. CR, leukemia-free survival, and overall survival (OS) were compared between groups. Additionally, the immune function and the T cell receptor (TCR) library of T cells were detected and analyzed. The MST group exhibited an encouragingly high CR rate (63.8%), even in high-risk patients (54%), and this rate was significantly higher than that in the chemotherapy alone group. The 1-year OS of MST patients was 57.7%, and it was 55.9% in the high-risk group. It was only 37.3% in the chemotherapy alone group. Higher numbers of naive T cells were found in the MST population than in the chemotherapy alone group. More updated T-cell clones were observed in MST patients by T-cell receptor repertoire analysis with a next-generation sequencing methodology. These results suggest that MST is a safe and practical regimen conducive to longer-term survival in patients of a highly advanced age with AML. Furthermore, it has broad clinical value in the recovery of immune function in elderly patients.
    Keywords:  Acute myeloid leukemia; T cell receptor repertoire; elderly patients; hematopoietic stem cell; micro-transplantation
  12. Clin Transl Oncol. 2023 May 11.
    Real-world genomic profiling of acute myeloid leukemia and the impact of European LeukemiaNet risk stratification 2022 update.
    Susana Elaine Alves da Rosa, Larissa Barbosa de Lima, Caroline Nunes Silveira, Luiz Gustavo Ferreira Cortes, João Bosco de Oliveira Filho, Rodrigo de Souza Reis, Murilo Castro Cervato, Pedro Henrique Sebe Rodrigues, Karla de Oliveira Pelegrino, Roberta Cardoso Petroni, Erica da Silva Araujo, Paulo Vidal Campregher.
       BACKGROUND: Acute myeloid leukemia (AML) is a myeloid neoplasm associated with a high morbidity and mortality. The diagnosis, risk stratification and therapy selection in AML have changed substantially in the last decade with the progressive incorporation of clinically relevant molecular markers.
    METHODS: In this work, our aim was to describe a real-world genomic profiling experience in AML and to demonstrate the impact of the European Leukemia Net 2022 update on risk stratification in AML.
    RESULTS AND DISCUSSION: One hundred and forty-one patients were evaluated with an amplicon-based multi-gene next-generation sequencing (NGS) panel. The most commonly mutated genes were FLT3, DNMT3A, RUNX1, IDH2, NPM1, ASXL1, SRSF2, NRAS, TP53 and TET2. Detection of FLT3 ITD with NGS had a sensitivity of 96.3% when compared to capillary electrophoresis. According to ELN 2017, 26.6%, 20.1%, and 53.3% of patients were classified as having a good, moderate, or unfavorable risk. When ELN 2022 was used, 15.6%, 27.8%, and 56.6% of patients were classified as favorable, moderate, or unfavorable risk, respectively. When ELN 2022 was compared to ELN 2017, thirteen patients (14.4%) exhibited a different risk classification, with a significant decrease in the number of favorable risk patients, what has immediate clinical impact.
    CONCLUSIONS: In conclusion, we have described a real-world genomic profiling experience in AML and the impact of the 2022 ELN update on risk stratification.
    Keywords:  Acute myeloid leukemia; Genetics
    DOI:  https://doi.org/10.1007/s12094-023-03195-5
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