bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021–05–30
thirteen papers selected by
Ayesh Seneviratne, University of Toronto
  1. Outcomes of second allogeneic hematopoietic cell transplantation for patients with acute myeloid leukemia.
  2. Hematopoietic versus leukemic stem cell quiescence: Challenges and therapeutic opportunities.
  3. Impact of the Natural Compound Urolithin A on Health, Disease, and Aging.
  4. Venetoclax Combined With FLAG-IDA Induction and Consolidation in Newly Diagnosed and Relapsed or Refractory Acute Myeloid Leukemia.
  5. Aged hematopoietic stem cells are refractory to bloodborne systemic rejuvenation interventions.
  6. Restoration of energy homeostasis by SIRT6 extends healthy lifespan.
  7. Mediterranean diet enriched in extra-virgin olive oil or nuts modulates circulating exosomal non-coding RNAs.
  8. Regenerative Medicine and the Hope for a Cure.
  9. MMP2 and TLRs modulate immune responses in the tumor microenvironment.
  10. Statin use and incident cardiovascular events in renal transplant recipients.
  11. N6-Methyladenosine on mRNA facilitates a phase-separated nuclear body that suppresses myeloid leukemic differentiation.
  12. Roles of tRNA metabolism in aging and lifespan.
  13. SGLT-2 inhibitors and protection from cardiovascular death: is it all about heart failure?
  1. Transplant Cell Ther. 2021 May 20. pii: S2666-6367(21)00898-8. [Epub ahead of print]
    Outcomes of second allogeneic hematopoietic cell transplantation for patients with acute myeloid leukemia.
    Fevzi F Yalniz, Rima M Saliba, Uri Greenbaum, Jeremy Ramdial, Uday Popat, Betul Oran, Amin Alousi, Amanda Olson, Gheath Alatrash, David Marin, Katy Rezvani, Chitra Hosing, Jin Im, Rohtesh Mehta, Muzaffar Qazilbash, Jacinth Joy Joseph, Gabriela Rondon, Rashmi Kanagal-Shamanna, Elizabeth Shpall, Richard Champlin, Partow Kebriaei.
       BACKGROUND: Relapse after allogeneic hematopoietic cell transplantation (HCT) leads to poor survival in patients with acute myeloid leukemia (AML). A second HCT (HCT2) may achieve durable remission.
    OBJECTIVES: To determine the outcomes of patients who received an HCT2 for relapsed AML and to evaluate the predictors of overall survival (OS) and progression-free survival (PFS).
    STUDY DESIGN: We retrospectively reviewed medical records of adult patients who underwent an HCT2 for relapsed AML at our institution during 2000-2019.
    RESULTS: Ninety-one patients were identified with a median age of 44 years (range, 18-73) at HCT2. Donor types were HLA-identical sibling (n=37, 41%), HLA-matched-unrelated (n=34, 37%), haploidentical (n=19, 21%), and cord-blood (n=1, 1%). Donors were different at HCT2 in 53% of patients. The majority of patients received reduced intensity conditioning (n=71, 78%) and were in remission (n=56, 61%) at HCT2. The median remission duration after HCT1 was 8.4 months (range, 1-70) and the median time between transplants was 14 months (range, 3-73). The median follow-up of surviving patients after HCT2 was 66 months (range, 2-171), with 32% alive at time of analysis. The most common cause of death was disease recurrence (n=45, 73%). At 2 years, the rates of OS, PFS, progression, and non-relapse mortality were 36%, 27%, 42%, and 18%, respectively. The development of chronic GVHD after first HCT and HCT comorbidity index (HCT-CI) ≥2 at HCT2 were associated with inferior PFS and OS after HCT2.
    CONCLUSION: A second HCT is feasible in selected patients with AML who have relapsed after HCT1. Long-term survival benefit is possible in patients without chronic GVHD after HCT1 and HCT-CI <2 at HCT2.
    Keywords:  Acute myeloid leukemia; second allogeneic stem cell transplantation; survival
    DOI:  https://doi.org/10.1016/j.jtct.2021.05.007
  2. Blood Rev. 2021 May 12. pii: S0268-960X(21)00056-4. [Epub ahead of print] 100850
    Hematopoietic versus leukemic stem cell quiescence: Challenges and therapeutic opportunities.
    Eimear O'Reilly, Hojjat Alizadeh Zeinabad, Eva Szegezdi.
      Hematopoietic stem cells (HSC) are responsible for the production of mature blood cells. To ensure that the HSC pool does not get exhausted over the lifetime of an individual, most HSCs are in a state of quiescence with only a small proportion of HSCs dividing at any one time. HSC quiescence is carefully controlled by both intrinsic and extrinsic, niche-driven mechanisms. In acute myeloid leukemia (AML), the leukemic cells overtake the hematopoietic bone marrow niche where they acquire a quiescent state. These dormant AML cells are resistant to chemotherapeutics. Because they can re-establish the disease after therapy, they are often termed as quiescent leukemic stem cells (LSC) or leukemia-initiating cells. While advancements are being made to target particular driver mutations in AML, there is less focus on how to tackle the drug resistance of quiescent LSCs. This review summarises the current knowledge on the biochemical characteristics of quiescent HSCs and LSCs, the intracellular signaling pathways and the niche-driven mechanisms that control quiescence and the key differences between HSC- and LSC-quiescence that may be exploited for therapy.
    Keywords:  Acute myeloid leukemia (AML); Bone marrow microenvironment; Cytokines, Chemokines; Drug resistance; Hematopoietic niche; Hematopoietic stem cells (HSC); Leukemic stem cells (LSC); Quiescence; Relapse
    DOI:  https://doi.org/10.1016/j.blre.2021.100850
  3. Trends Mol Med. 2021 May 21. pii: S1471-4914(21)00118-0. [Epub ahead of print]
    Impact of the Natural Compound Urolithin A on Health, Disease, and Aging.
    Davide D'Amico, Pénélope A Andreux, Pamela Valdés, Anurag Singh, Chris Rinsch, Johan Auwerx.
      Urolithin A (UA) is a natural compound produced by gut bacteria from ingested ellagitannins (ETs) and ellagic acid (EA), complex polyphenols abundant in foods such as pomegranate, berries, and nuts. UA was discovered 40 years ago, but only recently has its impact on aging and disease been explored. UA enhances cellular health by increasing mitophagy and mitochondrial function and reducing detrimental inflammation. Several preclinical studies show how UA protects against aging and age-related conditions affecting muscle, brain, joints, and other organs. In humans, benefits of UA supplementation in the muscle are supported by recent clinical trials in elderly people. Here, we review the state of the art of UA's biology and its translational potential as a nutritional intervention in humans.
    Keywords:  aging; inflammation; mitochondria; mitophagy; muscle health; urolithin A
    DOI:  https://doi.org/10.1016/j.molmed.2021.04.009
  4. J Clin Oncol. 2021 May 27. JCO2003736
    Venetoclax Combined With FLAG-IDA Induction and Consolidation in Newly Diagnosed and Relapsed or Refractory Acute Myeloid Leukemia.
    Courtney D DiNardo, Curtis A Lachowiez, Koichi Takahashi, Sanam Loghavi, Lianchun Xiao, Tapan Kadia, Naval Daver, Maria Adeoti, Nicholas J Short, Koji Sasaki, Sa Wang, Gautam Borthakur, Ghayas Issa, Abhishek Maiti, Yesid Alvarado, Naveen Pemmaraju, Guillermo Montalban Bravo, Lucia Masarova, Musa Yilmaz, Nitin Jain, Michael Andreeff, Elias Jabbour, Guillermo Garcia-Manero, Steven Kornblau, Farhad Ravandi, Marina Y Konopleva, Hagop M Kantarjian.
       PURPOSE: Sixty percent of newly diagnosed patients with acute myeloid leukemia (ND-AML) receiving frontline therapy attain a complete response (CR), yet 30%-40% of patients relapse. Relapsed or refractory AML (R/R-AML) remains a particularly adverse population necessitating improved therapeutic options. This phase Ib/II study evaluated the safety and efficacy of fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin combined with the B-cell lymphoma-2 inhibitor venetoclax in ND-AML and R/R-AML.
    MATERIALS AND METHODS: The phase IB portion (PIB) enrolled patients with R/R-AML using a 3 + 3 dose escalation and de-escalation algorithm for identification of maximum tolerated dose and dose-limiting toxicities. The phase II portion enrolled patients into two arms to evaluate response and time-to-event end points: phase IIA (PIIA): ND-AML and phase IIB (PIIB): R/R-AML.
    RESULTS: Sixty-eight patients have enrolled to date (PIB, 16; PIIA, 29; PIIB, 23). Median age was 46 years (range, 20-73). Grade 3 and 4 adverse events occurring in ≥ 10% of patients included febrile neutropenia (50%), bacteremia (35%), pneumonia (28%), and sepsis (12%). The overall response rate for PIB, PIIA, and PIIB was 75%, 97%, and 70% with 75%, 90%, and 61%, respectively, achieving a composite CR. Measurable residual disease-negative composite CR was attained in 96% of ND-AML and 69% of R/R-AML patients. After a median follow-up of 12 months, median overall survival (OS) for both PII cohorts was not reached. Fifty-six percent of patients proceeded to allogeneic hematopoietic stem-cell transplantation (ND-AML, 69%; R/R-AML, 46%). In R/R-AML, allogeneic hematopoietic stem-cell transplantation resulted in a significant improvement in OS (median OS, NR; 1-year OS, 87%). One-year survival post-HSCT was 94% in ND-AML and 78% in R/R-AML.
    CONCLUSION: Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin + venetoclax represents an effective intensive treatment regimen in ND-AML and R/R-AML patients, associated with deep remissions and a high rate of transition to successful transplantation.
    DOI:  https://doi.org/10.1200/JCO.20.03736
  5. J Exp Med. 2021 Jul 05. pii: e20210223. [Epub ahead of print]218(7):
    Aged hematopoietic stem cells are refractory to bloodborne systemic rejuvenation interventions.
    Theodore T Ho, Paul V Dellorusso, Evgenia V Verovskaya, Sietske T Bakker, Johanna Flach, Lucas K Smith, Patrick B Ventura, Olivia M Lansinger, Aurélie Hérault, Si Yi Zhang, Yoon-A Kang, Carl A Mitchell, Saul A Villeda, Emmanuelle Passegué.
      While young blood can restore many aged tissues, its effects on the aged blood system itself and old hematopoietic stem cells (HSCs) have not been determined. Here, we used transplantation, parabiosis, plasma transfer, exercise, calorie restriction, and aging mutant mice to understand the effects of age-regulated systemic factors on HSCs and their bone marrow (BM) niche. We found that neither exposure to young blood, nor long-term residence in young niches after parabiont separation, nor direct heterochronic transplantation had any observable rejuvenating effects on old HSCs. Likewise, exercise and calorie restriction did not improve old HSC function, nor old BM niches. Conversely, young HSCs were not affected by systemic pro-aging conditions, and HSC function was not impacted by mutations influencing organismal aging in established long-lived or progeroid genetic models. Therefore, the blood system that carries factors with either rejuvenating or pro-aging properties for many other tissues is itself refractory to those factors.
    DOI:  https://doi.org/10.1084/jem.20210223
  6. Nat Commun. 2021 May 28. 12(1): 3208
    Restoration of energy homeostasis by SIRT6 extends healthy lifespan.
    A Roichman, S Elhanati, M A Aon, I Abramovich, A Di Francesco, Y Shahar, M Y Avivi, M Shurgi, A Rubinstein, Y Wiesner, A Shuchami, Z Petrover, I Lebenthal-Loinger, O Yaron, A Lyashkov, C Ubaida-Mohien, Y Kanfi, B Lerrer, P J Fernández-Marcos, M Serrano, E Gottlieb, R de Cabo, H Y Cohen.
      Aging leads to a gradual decline in physical activity and disrupted energy homeostasis. The NAD+-dependent SIRT6 deacylase regulates aging and metabolism through mechanisms that largely remain unknown. Here, we show that SIRT6 overexpression leads to a reduction in frailty and lifespan extension in both male and female B6 mice. A combination of physiological assays, in vivo multi-omics analyses and 13C lactate tracing identified an age-dependent decline in glucose homeostasis and hepatic glucose output in wild type mice. In contrast, aged SIRT6-transgenic mice preserve hepatic glucose output and glucose homeostasis through an improvement in the utilization of two major gluconeogenic precursors, lactate and glycerol. To mediate these changes, mechanistically, SIRT6 increases hepatic gluconeogenic gene expression, de novo NAD+ synthesis, and systemically enhances glycerol release from adipose tissue. These findings show that SIRT6 optimizes energy homeostasis in old age to delay frailty and preserve healthy aging.
    DOI:  https://doi.org/10.1038/s41467-021-23545-7
  7. Eur J Nutr. 2021 May 23.
    Mediterranean diet enriched in extra-virgin olive oil or nuts modulates circulating exosomal non-coding RNAs.
    Diana C Mantilla-Escalante, María-Carmen López de Las Hazas, M Carmen Crespo, Roberto Martín-Hernández, Joao Tomé-Carneiro, Lorena Del Pozo-Acebo, Jordi Salas-Salvadó, Mónica Bulló, Alberto Dávalos.
       PURPOSE: Exosomes are extracellular vesicles secreted by cells, which can transport different molecules, including nucleic acids. Dietary habits may induce gene regulation through the modulation of exosomal RNAs. We aimed at characterizing exosomal lncRNAs, mRNA and miRNAs modulation after a 1-year adherence to a low-fat diet (LFD) or to Mediterranean-based diets enriched in extra-virgin olive oil (MedDiet + EVOO) or in a mixture of nuts (MedDiet + Nuts).
    METHODS: Plasma samples were collected, at baseline and after 1 year of dietary interventions, from 150 participants included in the PREDIMED study (Reus Center). LncRNAs, mRNAs and miRNAs were isolated from plasma exosomes and screened. RT-qPCR validation was performed for miRNAs.
    RESULTS: Compared with LFD, 413 lncRNAs and 188 mRNAs, and 476 lncRNAs and 235 mRNAs were differentially modulated in response to the MedDiet + EVOO and MedDiet + Nuts interventions, respectively. In addition, after 1 year of dietary interventions, 26 circulating miRNAs were identified as differentially expressed between groups. After 1 year of intervention, 11 miRNAs significantly changed in LFD group, while 8 and 21 were modulated in response to the MedDiet enriched with EVOO or nuts, respectively. Bioinformatic analyses of differentially expressed miRNAs and their validated target genes suggest certain metabolic pathways are modulated by LFD (PI3K-Akt and AMPK), MedDiet + EVOO (PI3K-Akt, NF-kappa B, HIF-1, and insulin resistance), and MedDiet-Nuts (FoxO, PI3K-Akt, AMPK, p53 and HIF-1) interventions.
    CONCLUSION: Results show that 1-year MedDiet + Nuts and MedDiet + EVOO dietary interventions modulate exosomal RNA content, with the former affecting a higher number of miRNAs. The modulation of exosomal RNAs could help explain how the adherence to a Mediterranean diet may lead to beneficial effects and deserves further investigation.
    Keywords:  Diet; Exosomes; Long non-coding RNAs; MicroRNAs; Nuts; Olive oil
    DOI:  https://doi.org/10.1007/s00394-021-02594-0
  8. Clin Chest Med. 2021 Jun;pii: S0272-5231(21)00039-3. [Epub ahead of print]42(2): 365-373
    Regenerative Medicine and the Hope for a Cure.
    Mareike Lehmann, Melanie Königshoff.
      Current therapeutic strategies have succeeded in slowing down the progression of idiopathic pulmonary fibrosis (IPF). Emerging evidence highlights IPF as a disease of aging and impaired regeneration. Novel antiaging and regenerative medicine approaches hold promise to be able to reverse disease and might present hope for a cure. Research focusing on a deeper understanding of lung stem cell populations and how these are regulated and altered in fibrotic disease continues to drive the field, and accompanied by earlier diagnosis, the adaptation of clinically relevant models and readouts for regeneration of diseased lung, ultimately paves the way for translation into clinics.
    Keywords:  Aging; Cellular senescence; Developmental pathways; ILD; IPF; Regeneration; Translation
    DOI:  https://doi.org/10.1016/j.ccm.2021.03.012
  9. JCI Insight. 2021 May 25. pii: 144913. [Epub ahead of print]
    MMP2 and TLRs modulate immune responses in the tumor microenvironment.
    Luciana R Muniz-Bongers, Christopher B McClain, Mansi Saxena, Gerold Bongers, Miriam Merad, Nina Bhardwaj.
      The presence of an immunosuppressive tumor microenvironment is a major obstacle in the success of cancer immunotherapies. Because extracellular matrix components can shape the microenvironment, we investigated the role of matrix metalloproteinase 2 (MMP2) in melanoma tumorigenesis. Significantly, we found that MMP2 signals pro-inflammatory pathways on antigen presenting cells which requires both toll-like receptor (TLR) 2 and TLR4. B16 melanoma cells that express MMP2 at baseline have slower kinetics in Tlr2-/-Tlr4-/- mice, implicating MMP2 in promoting tumor growth. Indeed, Mmp2 overexpression in B16 cells potentiated rapid tumor growth which was accompanied by reduced intra-tumoral cytolytic cells and increased M2 macrophages. In contrast, knockdown of Mmp2 slowed tumor growth, and enhanced T cell proliferation and NK cell recruitment. Finally we found that these effects of MMP2 are mediated through dysfunctional dendritic cell (DC) - T cell cross-talk as they are lost in Batf3-/- and Rag2-/- mice, respectively. These findings provide insights into the detrimental role of endogenous alarmins like MMP2 in modulating immune responses in the tumor microenvironment.
    Keywords:  Antigen-presenting cells; Immunology; Melanoma; Oncology; T cells
    DOI:  https://doi.org/10.1172/jci.insight.144913
  10. Eur J Clin Invest. 2021 May 27. e13594
    Statin use and incident cardiovascular events in renal transplant recipients.
    Josephine L C Anderson, Markus van der Giet, Antonio W Gomes Neto, Stephan J L Bakker, Uwe J F Tietge.
       BACKGROUND: Statins achieve potent LDL lowering in the general population leading to a significant cardiovascular (CV) risk reduction. In renal transplant recipients (RTR) statins are included in treatment guidelines, however, conclusive evidence of improved cardiovascular outcomes has not been uniformly provided and concerns have been raised about simultaneous use of statins and the immunosuppressant cyclosporine. This study aimed to elucidate the effect of statins on a compound CV endpoint, comprised of ischaemic CV events and CV mortality in RTR, with subgroup analysis focussing on cyclosporine users.
    METHOD: 622 included RTR (follow-up 5.4 years) were matched based on propensity scores and dichotomized by statin use. Survival analysis was conducted.
    RESULTS: Cox regression showed that statin use was not significantly associated with the compound CV endpoint in a fully adjusted model (HR = 0.81, 95% CI = 0.53-1.24, P = .33). Subgroup analyses in RTR using cyclosporine revealed a strong positive association of statin use with the CV compound outcome in a fully adjusted model (HR = 6.60, 95% CI 1.75-24.9, P = .005). Furthermore, statin use was positively correlated with cyclosporine trough levels (correlation coefficient 0.11, P = .04).
    CONCLUSION: In conclusion, statin use does not significantly decrease incident CV events in an overall RTR cohort, but is independently associated with CV-specific mortality and events in cyclosporine using RTR, possibly due to a bilateral pharmacological interaction.
    Keywords:  cardiovascular disease; cyclosporine; pharmacological interaction; renal transplantation; statins
    DOI:  https://doi.org/10.1111/eci.13594
  11. Cancer Cell. 2021 May 12. pii: S1535-6108(21)00225-7. [Epub ahead of print]
    N6-Methyladenosine on mRNA facilitates a phase-separated nuclear body that suppresses myeloid leukemic differentiation.
    Yuanming Cheng, Wei Xie, Brian F Pickering, Karen L Chu, Angela M Savino, Xuejing Yang, Hanzhi Luo, Diu Tt Nguyen, Shanlan Mo, Ersilia Barin, Anthony Velleca, Thomas M Rohwetter, Dinshaw J Patel, Samie R Jaffrey, Michael G Kharas.
      N6-Methyladenosine (m6A) on mRNAs mediates different biological processes and its dysregulation contributes to tumorigenesis. How m6A dictates its diverse molecular and cellular effects in leukemias remains unknown. We found that YTHDC1 is the essential m6A reader in myeloid leukemia from a genome-wide CRISPR screen and that m6A is required for YTHDC1 to undergo liquid-liquid phase separation and form nuclear YTHDC1-m6A condensates (nYACs). The number of nYACs increases in acute myeloid leukemia (AML) cells compared with normal hematopoietic stem and progenitor cells. AML cells require the nYACs to maintain cell survival and the undifferentiated state that is critical for leukemia maintenance. Furthermore, nYACs enable YTHDC1 to protect m6A-mRNAs from the PAXT complex and exosome-associated RNA degradation. Collectively, m6A is required for the formation of a nuclear body mediated by phase separation that maintains mRNA stability and control cancer cell survival and differentiation.
    Keywords:  RNA methylation; RNA-binding proteins; differentiation; myeloid leukemia; phase separation
    DOI:  https://doi.org/10.1016/j.ccell.2021.04.017
  12. Cell Death Dis. 2021 May 26. 12(6): 548
    Roles of tRNA metabolism in aging and lifespan.
    Zheng Zhou, Bao Sun, Dongsheng Yu, Meng Bian.
      Transfer RNAs (tRNAs) mainly function as adapter molecules that decode messenger RNAs (mRNAs) during protein translation by delivering amino acids to the ribosome. Traditionally, tRNAs are considered as housekeepers without additional functions. Nevertheless, it has become apparent from biological research that tRNAs are involved in various physiological and pathological processes. Aging is a form of gradual decline in physiological function that ultimately leads to increased vulnerability to multiple chronic diseases and death. Interestingly, tRNA metabolism is closely associated with aging and lifespan. In this review, we summarize the emerging roles of tRNA-associated metabolism, such as tRNA transcription, tRNA molecules, tRNA modifications, tRNA aminoacylation, and tRNA derivatives, in aging and lifespan, aiming to provide new ideas for developing therapeutics and ultimately extending lifespan in humans.
    DOI:  https://doi.org/10.1038/s41419-021-03838-x
  13. Diabetes Obes Metab. 2021 May 25.
    SGLT-2 inhibitors and protection from cardiovascular death: is it all about heart failure?
    Irene Caruso, Angelo Cignarelli, Luigi Laviola, Francesco Giorgino.
      
    DOI:  https://doi.org/10.1111/dom.14444
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