bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2021‒01‒03
twenty-six papers selected by
Camila Kehl Dias
Federal University of Rio Grande do Sul

  1. Leuk Lymphoma. 2020 Dec 30. 1-9
      Widely-used response criteria, conditional upon count recovery, were developed for acute myeloid leukemia (AML) in the context of intensive chemotherapy (IC). Extending these definitions to continuously-administered venetoclax-based therapies might underestimate responses. Best practices for venetoclax-based therapies mandate interruption after an end-of-cycle 1 bone marrow biopsy shows morphologic remission with cytopenias. We analyzed 435 patients with newly-diagnosed AML and follow-up response assessments. Of the 101 who responded to venetoclax + azacitidine, overall survival for patients whose response was upgraded due to count recovery during a 14-day post-disease assessment period, from complete remission (CR) with incomplete recovery of blood counts to CR, was not different compared to patients who did not need the 14-day period for count recovery. These results were distinct from 138 IC patients. Although sample sizes for the comparison groups were small, and conclusions are exploratory and must be verified, these findings support consideration of new response criteria for venetoclax-based regimens.
    Keywords:  AML; ELN; response; upgrade; venetoclax
  2. Mitochondrion. 2020 Dec 28. pii: S1567-7249(20)30230-0. [Epub ahead of print]
      Optic atrophy-1 (OPA1) is a dynamin-like GTPase localized to the mitochondrial inner membrane, playing key roles in inner membrane fusion and cristae maintenance. OPA1 is regulated by the mitochondrial transmembrane potential (Δψm): when Δψm is intact, long OPA1 isoforms (L-OPA1) carry out inner membrane fusion. Upon loss of Δψm, L-OPA1 isoforms are proteolytically cleaved to short (S-OPA1) isoforms by the stress-inducible OMA1 metalloprotease, causing collapse of the mitochondrial network and promoting apoptosis. Here, we show that L-OPA1 isoforms of H9c2 cardiomyoblasts are retained under loss of Δψm, despite the presence of OMA1. However, when H9c2s are differentiated to a more cardiac-like phenotype via treatment with retinoic acid (RA) in low serum media, loss of Δ ψm induces robust, and reversible, cleavage of L-OPA1 and subsequent OMA1 degradation. These findings indicate that a potent developmental switch regulates Δ ψm-sensitive OPA1 cleavage, suggesting novel developmental and regulatory mechanisms for OPA1 homeostasis.
    Keywords:  Mitochondria; OMA1; OPA1; cardiac; cultured cell; differentiation
  3. Immunity. 2020 Dec 15. pii: S1074-7613(20)30508-2. [Epub ahead of print]
      The interleukin-6 (IL-6) membrane receptor and its circulating soluble form, sIL-6R, can be targeted by antibody therapy to reduce deleterious immune signaling caused by chronic overexpression of the pro-inflammatory cytokine IL-6. This strategy may also hold promise for treating acute hyperinflammation, such as observed in coronavirus disease 2019 (COVID-19), highlighting a need to define regulators of IL-6 homeostasis. We found that conventional dendritic cells (cDCs), defined in mice via expression of the transcription factor Zbtb46, were a major source of circulating sIL-6R and, thus, systemically regulated IL-6 signaling. This was uncovered through identification of a cDC-dependent but T cell-independent modality that naturally adjuvants plasma cell differentiation and antibody responses to protein antigens. This pathway was then revealed as part of a broader biological buffer system in which cDC-derived sIL-6R set the in-solution persistence of IL-6. This control axis may further inform the development of therapeutic agents to modulate pro-inflammatory immune reactions.
    Keywords:  antibody response; immune defense; inflammation; regulation; signaling
  4. Int J Mol Sci. 2020 Dec 18. pii: E9660. [Epub ahead of print]21(24):
      Lipid catabolism represents an Achilles heel in prostate cancer (PCa) that can be exploited for therapy. CPT1A regulates the entry of fatty acids into the mitochondria for beta-oxidation and its inhibition has been shown to decrease PCa growth. In this study, we examined the pharmacological blockade of lipid oxidation with ranolazine in TRAMPC1 PCa models. Oral administration of ranolazine (100 mg/Kg for 21 days) resulted in decreased tumor CD8+ T-cells Tim3 content, increased macrophages, and decreased blood myeloid immunosuppressive monocytes. Using multispectral staining, drug treatments increased infiltration of CD8+ T-cells and dendritic cells compared to vehicle. Functional studies with spleen cells of drug-treated tumors co-cultured with TRAMPC1 cells showed increased ex vivo T-cell cytotoxic activity, suggesting an anti-tumoral response. Lastly, a decrease in CD4+ and CD8+ T-cells expressing PD1 was observed when exhausted spleen cells were incubated with TRAMPC1 Cpt1a-KD compared to the control cells. These data indicated that genetically blocking the ability of the tumor cells to oxidize lipid can change the activation status of the neighboring T-cells. This study provides new knowledge of the role of lipid catabolism in the intercommunication of tumor and immune cells, which can be extrapolated to other cancers with high CPT1A expression.
    Keywords:  CD8 T-cells; CPT1A; acyl-carnitines; dendritic cells; lipid metabolism; prostate cancer; ranolazine
  5. PLoS One. 2020 ;15(12): e0244499
      The synthesis of a mitochondria-targeted derivative of the classical mitochondrial uncoupler carbonyl cyanide-m-chlorophenylhydrazone (CCCP) by alkoxy substitution of CCCP with n-decyl(triphenyl)phosphonium cation yielded mitoCCCP, which was able to inhibit the uncoupling action of CCCP, tyrphostin A9 and niclosamide on rat liver mitochondria, but not that of 2,4-dinitrophenol, at a concentration of 1-2 μM. MitoCCCP did not uncouple mitochondria by itself at these concentrations, although it exhibited uncoupling action at tens of micromolar concentrations. Thus, mitoCCCP appeared to be a more effective mitochondrial recoupler than 6-ketocholestanol. Both mitoCCCP and 6-ketocholestanol did not inhibit the protonophoric activity of CCCP in artificial bilayer lipid membranes, which might compromise the simple proton-shuttling mechanism of the uncoupling activity on mitochondria.
  6. Cancer. 2020 Dec 30.
    Keywords:  IL-6; androgen deprivation therapy; fatigue; immune checkpoint blockade; immunotherapy; inflammation; prostate cancer; quality of life
  7. Ann Thorac Surg. 2020 Dec 19. pii: S0003-4975(20)32144-5. [Epub ahead of print]
      BACKGROUND: Tumor response and lymph node involvement are the most important prognosticators in resected patients with esophageal adenocarcinoma after neoadjuvant chemoradiation (nCRT). We hypothesise that lymph node response (LNR) is also a valuable prognosticator in these patients, potentially revealing the added effect of nCRT.METHODS: Hematoxylin-eosin slides of 193 esophageal adenocarcinoma patients with clinical suspicion of lymph node involvement (cN+) and treated with nCRT between 2008 and 2015 were assessed. Lymph nodes containing viable tumor cells were considered ypN+ and those negative for viable tumor were ypN0. LNR was also described according to an earlier defined method. Three groups were obtained: ypN0/LNR-, ypN0/LNR+ and ypN+. They were compared to 188 cN+ patients being pN0 (n=45) or pN+ (n=143) after upfront esophageal resection.
    RESULTS: 44 patients were ypN0/LNR-, 55 ypN0/LNR+ and 94 ypN+. Median overall survival was respectively 96.4, 31.2 and 20.6 months and was significantly different between ypN0/LNR- and ypN0/LNR+ groups (p=0.020). Survival was comparable between ypN0/LNR- and pN0 (104.2 months) groups (p=0.519) and between ypN+ and pN+ (21,6 months) groups (p=0,966). In ypN0 patients, risk of death in LNR+ patients was tripled compared to LNR- patients.
    CONCLUSIONS: In cN+ esophageal adenocarcinoma patients treated with nCRT with postoperative final pathology being ypN0, median overall survival is tripled when no signs of LNR were found and comparable to cN+/pN0 upfront esophagectomy patients, suggesting that 23% of patients treated with nCRT were in fact true N0 and overtreated by nCRT. ypN+ patients have no survival benefit compared to pN+ patients.
  8. Cancers (Basel). 2020 Dec 23. pii: E19. [Epub ahead of print]13(1):
      Glioblastoma (GBM) is the most aggressive intrinsic brain tumor in adults. Despite maximal therapy consisting of surgery and radio/chemotherapy, GBM remains largely incurable with a median survival of less than 15 months. GBM has a strong immunosuppressive nature with a multitude of tumor and microenvironment (TME) derived factors that prohibit an effective immune response. To date, all clinical trials failed to provide lasting clinical efficacy, despite the relatively high success rates of preclinical studies to show effectivity of immunotherapy. Various factors may explain this discrepancy, including the inability of a single mouse model to fully recapitulate the complexity and heterogeneity of GBM. It is therefore critical to understand the features and limitations of each model, which should probably be combined to grab the full spectrum of the disease. In this review, we summarize the available knowledge concerning immune composition, stem cell characteristics and response to standard-of-care and immunotherapeutics for the most commonly available immunocompetent mouse models of GBM.
    Keywords:  animal model; glioblastoma; immune response; immunotherapy; model; murine; preclinical
  9. Mol Cell. 2020 Dec 22. pii: S1097-2765(20)30904-7. [Epub ahead of print]
      Aerobic glycolysis, or preferential fermentation of glucose-derived pyruvate to lactate despite available oxygen, is associated with proliferation across many organisms and conditions. To better understand that association, we examined the metabolic consequence of activating the pyruvate dehydrogenase complex (PDH) to increase pyruvate oxidation at the expense of fermentation. We find that increasing PDH activity impairs cell proliferation by reducing the NAD+/NADH ratio. This change in NAD+/NADH is caused by increased mitochondrial membrane potential that impairs mitochondrial electron transport and NAD+ regeneration. Uncoupling respiration from ATP synthesis or increasing ATP hydrolysis restores NAD+/NADH homeostasis and proliferation even when glucose oxidation is increased. These data suggest that when demand for NAD+ to support oxidation reactions exceeds the rate of ATP turnover in cells, NAD+ regeneration by mitochondrial respiration becomes constrained, promoting fermentation, despite available oxygen. This argues that cells engage in aerobic glycolysis when the demand for NAD+ is in excess of the demand for ATP.
    Keywords:  Aerobic Glycolysis; Cell Metabolism; Fermentation; NAD+; PDK; Warburg Effect
  10. STAR Protoc. 2020 Dec 18. 1(3): 100161
      We describe a protocol for a long-term co-culture assay to study the contribution of mesenchymal stromal cells (MSCs) in regulating hematopoietic stem/progenitor cell (HSPC) activity. In addition, we describe the use of a clonogenic assay to determine myelo-erythroid differentiation. This long-term culture-initiating cell assay can be used for qualitative analysis of MSCs capable of supporting hematopoiesis and may also be used as a proxy readout to study HSPC repopulation. For complete details on the use and execution of this protocol, please refer to Sinha et al. (2020).
    Keywords:  Cell Biology; Stem Cells
  11. Asian Pac J Cancer Prev. 2020 Dec 01. pii: 89382. [Epub ahead of print]21(12): 3587-3593
      BACKGROUND: Receptor status in breast cancer is known to be related to survival. However, the relationship between breast cancer subtype, preferential sites of metastasis, and overall survival is not clear.METHODS: A total of 414,528 patients from the National Cancer Database (2010-2013) were examined. All patients received surgery and systemic treatments. Breast cancer was subtyped based on hormonal receptor (HR) and HER2 status.
    RESULTS: HR-/HER2+ breast cancer patients had the highest overall rate of metastasis while HR+/HER2- had the lowest. HR+/HER2+ cancer had the most frequent metastasis to the bone, and HR-/HER2+ to brain, liver, lung and multiple sites. Generally, patients with brain or multiple metastasis had the worst overall survival (OS) across different subtypes.  Patients with bone oligometastasis tend to have better OS than patients with metastasis to other site but significantly worse OS than patients without any metastasis.
    CONCLUSIONS: This large study exhibits how breast cancer subtype plays a role in the rate and site of metastasis as well as in overall survival.  Surveillance and treatment strategies should be tailored on the risk and potential site of metastases based upon receptor subtype.
    Keywords:  bone metastasis; brain metastasis; breast cancer; liver metastasis; lung metastasis
  12. Cell Rep Med. 2020 Dec 22. 1(9): 100156
      Mode of delivery strongly influences the early infant gut microbiome. Children born by cesarean section (C-section) lack Bacteroides species until 6-18 months of age. One hypothesis is that these differences stem from lack of exposure to the maternal vaginal microbiome. Here, we re-evaluate this hypothesis by comparing the microbial profiles of 75 infants born vaginally or by planned versus emergent C-section. Multiple children born by C-section have a high abundance of Bacteroides in their first few days of life, but at 2 weeks, both C-section groups lack Bacteroides (primarily according to 16S sequencing), despite their difference in exposure to the birth canal. Finally, a comparison of microbial strain profiles between infants and maternal vaginal or rectal samples finds evidence for mother-to-child transmission of rectal rather than vaginal strains. These results suggest differences in colonization stability as an important factor in infant gut microbiome composition rather than birth canal exposure.
    Keywords:  infant gut microbiota, caesarean delivery, Bacteroides, delivery mode, transmission of maternal strains
  13. Hematol Oncol Stem Cell Ther. 2020 Dec 21. pii: S1658-3876(20)30179-5. [Epub ahead of print]
  14. Front Oncol. 2020 ;10 581107
      For many pediatric sarcoma patients, multi-modal therapy including chemotherapy, radiation, and surgery is sufficient to cure their disease. However, event-free and overall survival rates for patients with more advanced disease are grim, necessitating the development of novel therapeutic approaches. Within many pediatric sarcomas, the normal immune response, including recognition and destruction of cancer cells, is lost due to the highly immune suppressive tumor microenvironment (TME). In this setting, tumor cells evade immune detection and capitalize on the immune suppressed microenvironment, leading to unchecked proliferation and metastasis. Recent preclinical and clinical approaches are aimed at understanding this immune suppressive microenvironment and employing cancer immunotherapy in an attempt to overcome this, by renewing the ability of the immune system to recognize and destroy cancer cells. While there are several factors that drive the attenuation of immune responses in the sarcoma TME, one of the most remarkable are tumor associated macrophage (TAMs). TAMs suppress immune cytolytic function, promote tumor growth and metastases, and are generally associated with a poor prognosis in most pediatric sarcoma subtypes. In this review, we summarize the mechanisms underlying TAM-facilitated immune evasion and tumorigenesis and discuss the potential therapeutic application of TAM-focused drugs in the treatment of pediatric sarcomas.
    Keywords:  efferocytosis; immunotherapy; pediatric sarcoma; tumor microenvironment; tumor-associated macrophage
  15. Cell Immunol. 2020 Dec 14. pii: S0008-8749(20)30420-2. [Epub ahead of print]360 104260
      The majority of human colorectal cancer remains resistant to immune checkpoint inhibitor (ICI) immunotherapy, but the underlying mechanism is incompletely understood. We report here that MS4A1, the gene encoding B cell surface marker CD20, is significantly downregulated in human colorectal carcinoma. Furthermore, MS4A1 expression level in colorectal carcinoma is positively correlated with patient survival. Analysis of scRNA-Seq dataset from public database revealed that MS4A1 is also expressed in subsets of T cells. A CD8+CD20+ subset of T cells exists in the neighboring non-neoplastic colon but disappears in tumor in human colorectal carcinoma. Furthermore, analysis of a published nivolumab treatment dataset indicated that nivolumab-bound T cells from human patients during anti-PD-1 immunotherapy exhibit significantly higher MS4A1 expression. Our findings indicate that CD8+CD20+ T subset functions in host cancer immunosurveillance and tumor microenvironment suppresses this T subset through a PD-L1-dependent mechanism.
    Keywords:  CD20; Colon carcinoma; Immune checkpoint; Immune suppression; MS4A1; PD-L1; T cells
  16. Front Pediatr. 2020 ;8 618426
    Keywords:  acute leukemia biology; new drugs; pediatric acute lymphoblastic leukemia; pediatric acute myeloid leukemia; pediatric leukemia; targeted therapies
  17. Haematologica. 2020 Dec 23. Online ahead of print
      MCL-1 and BCL-2 are both frequently overexpressed in acute myeloid leukemia and critical for the survival of acute myeloid leukemia cells and acute myeloid leukemia stem cells. MCL-1 is a key factor in venetoclax resistance. Using genetic and pharmacological approaches, we discovered that MCL-1 regulates leukemia cell bioenergetics and carbohydrate metabolisms, including the TCA cycle, glycolysis and pentose phosphate pathway and modulates cell adhesion proteins and leukemia-stromal interactions. Inhibition of MCL-1 sensitizes to BCL-2 inhibition in acute myeloid leukemia cells and acute myeloid leukemia stem/progenitor cells, including those with intrinsic and acquired resistance to venetoclax through cooperative release of pro-apoptotic BIM, BAX, and BAK from binding to anti-apoptotic BCL-2 proteins and inhibition of cell metabolism and key stromal microenvironmental mechanisms. The combined inhibition of MCL-1 by MCL-1 inhibitor AZD5991 or CDK9 inhibitor AZD4573 and BCL-2 by venetoclax greatly extended survival of mice bearing patient-derived xenografts established from an acute myeloid leukemia patient who acquired resistance to venetoclax/decitabine. These results demonstrate that co-targeting MCL-1 and BCL-2 improves the efficacy of and overcomes preexisting and acquired resistance to BCL-2 inhibition. Activation of metabolomic pathways and leukemia-stroma interactions are newly discovered functions of MCL-1 in acute myeloid leukemia, which are independent from canonical regulation of apoptosis by MCL-1. Our data provide new mechanisms of synergy and rationale for co-targeting MCL-1 and BCL-2 clinically in patients with acute myeloid leukemia and potentially other cancers.
  18. Cancer Biol Ther. 2020 Dec 27. 1-13
      The prognosis of AML is generally poor, with 5-year survival rate of 25%. There has been substantial progress in identification of new therapeutic targets, along with approval of at least three targeted therapies for AML in recent years. Nevertheless, treatment has largely remained unchanged over couple of decades, with ~40% patients not achieving remission. AML is a highly heterogenous disease and there is a need for a preclinical platform to understand the heterogeneity and tumor microenvironment that can guide therapy selection. In this study, we employed an ex vivo tumor explant model to study tumor microenvironment and to select a treatment course for AML patients. Our data reveal dysregulation of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) in a subset of AML patients. Based on this observation, epigenetic modulators azacitidine and panobinostat alone and in combination, were evaluated as treatment regimens in cytarabine refractory tumors. More than 50% of the treated samples showed response to the combination therapy. In order to explore alternate treatment modalities for tumors refractory to these epigenetic modulators, TCGA data analysis was done which revealed increased expression and hypomethylation of IFNGR1/2, suggesting activation of JAK/STAT pathway in AML. This was further interrogated ex vivo, with p-STAT3 expression in patients' samples. Fedratinib, a JAK/STAT inhibitor was evaluated and 78% tumor efficacy response was achieved. Taken together, our data indicate that ex vivo platform derived from patient samples is capable in guiding optimal therapy selection for various classes of drugs including identification of novel targeted therapies.
    Keywords:  AML; epigenetic modulators; ex vivo explant; fedratinib
  19. Int J Oncol. 2020 Nov 09.
      Indoline‑2,3‑dione or indole‑1H‑2,3‑dione, commonly known as isatin, is found in plants of genus Isatin and in Couropita guianancis aubl, and inhibits tumor cell proliferation through its antioxidant effects. The present study analyzed the effect of isatin on the malignant phenotype of neuroblastoma cells, and reported that isatin significantly inhibited neuroblastoma cell proliferation, invasion and migration in vitro in a dose‑dependent manner, and distant metastasis in tumor‑bearing mice. Mechanistically, isatin inhibited lysine‑specific histone demethylase (LSD)1 and reversed the blockade on p53, thereby activating the apoptotic pathway. The inhibitory effect of isatin on LSD1 may be mediated via direct binding and molecular docking or indirectly through the TGFβ/ERK/NF‑κB signaling pathway. Isatin also alleviated the renal and hepatic toxicity of cyclophosphamide in the tumor‑bearing mice, indicating its potential as a candidate drug as well as an adjuvant for treating metastatic neuroblastoma.
  20. Haematologica. 2020 Dec 30. Online ahead of print
      Drug resistance impedes the long-term effect of targeted therapies in acute myeloid leukemia (AML), necessitating the identification of mechanisms underlying resistance. Approximately 25% of AML patients carry FLT3 mutations and develop post-treatment insensitivity to FLT3 inhibitors, including sorafenib. Using a genome-wide CRISPR screen, we identified LZTR1, NF1, TSC1 or TSC2, negative regulators of the MAPK and MTOR pathways, as mediators of sorafenib resistance. Analyses of ex vivo drug sensitivity assays in FLT3-ITD AML patient samples revealed lower expression of LZTR1, NF1, and TSC2 correlated with sorafenib sensitivity. Importantly, MAPK and/or MTOR complex1 (MTORC1) activity were upregulated in AML cells made resistant to several FLT3 inhibitors, including crenolanib, quizartinib, or sorafenib. These cells were sensitive to MEK inhibitors, and the combination of FLT3 and MEK inhibitors showed enhanced efficacy, suggesting its effectiveness in AML patients with FLT3 mutations and those with resistance to FLT3 inhibitors.