bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2021‒08‒15
eight papers selected by
Camila Kehl Dias
Federal University of Rio Grande do Sul

  1. Cancer Discov. 2020 Feb;10(2): 172
      HBO1 is required for maintenance of leukemia stem cells (LSC) in acute myeloid leukemia (AML).
  2. Cancer Sci. 2021 Aug 07.
      Evi1 is a transcription factor essential for the development as well as progression of acute myeloid leukemia (AML) and high Evi1 AML is associated with extremely poor clinical outcome. Since targeting metabolic vulnerability is the emerging therapeutic strategy of cancer, we herein investigated a novel therapeutic target of Evi1 by analyzing transcriptomic, epigenetic and metabolomic profiling of mouse high Evi1 leukemia cells. We revealed that Evi1 overexpression and Evi1-driven leukemic transformation upregulate transcription of gluconeogenesis enzyme Fbp1 and other pentose phosphate enzymes with interaction between Evi1 and enhancer region of these genes. Metabolome analysis using Evi1-overexpressing leukemia cells uncovered pentose phosphate pathway upregulation by Evi1 overexpression. Suppression of Fbp1 as well as pentose phosphate pathway enzymes by shRNA mediated knockdown selectively decreased Evi1-driven leukemogenesis in vitro. Moreover, pharmacological or shRNA-mediated Fbp1 inhibition in secondarily transplanted Evi1-overexpressing leukemia mouse significantly decreased leukemia cell burden. Collectively, targeting FBP1 is a promising therapeutic strategy of high Evi1 AML.
    Keywords:  Acute Myeloid Leukemia; Gluconeogenesis; Oncogene; Pentose phosphate pathway; Transcription Factors
  3. Leukemia. 2021 Aug 11.
      Regulatory T cells (Tregs) could maintain the characteristics of stem cells and inhibit the differentiation of normal hematopoietic stem/progenitor cells. Recent studies have shown that Tregs, as an important component of acute myeloid leukemia (AML) microenvironments, can help AML cells to evade immune surveillance. However, their function in directly regulating the stemness of AML cells remains elusive. In this study, the increased stemness of AML cells promoted by Tregs was verified in vitro and in vivo. The cytokines released by Tregs were explored, the highly expressed anti-inflammatory cytokine IL10 was found, which could promote the stemness of AML cells through the activation of PI3K/AKT signal pathway. Moreover, disrupting the IL10/IL10R/PI3K/AKT signal in AML/ETO c-kitmut (A/Ec) leukemia mice could prolong the mice survival and reduce the stemness of A/Ec leukemia cells. Finally, it was confirmed in patient samples that the proportion of Tregs to leukemia stem cells (LSCs) was positively correlated, and in CD34+ primary AML cells, the activation of PI3K/AKT was stronger in patients with high Tregs' infiltration. After rhIL10 treatment, primary AML cells showed increased activation of PI3K/AKT signaling. Therefore, blocking the interaction between Tregs and AML cells may be a new approach to target LSCs in AML treatment.
  4. Cancer Discov. 2020 Oct;10(10): 1438
      Residual acute myeloid leukemia (AML) cells required bone marrow stromal cell-derived aspartate.
  5. Front Oncol. 2021 ;11 696532
      Forkhead box protein M1 (FOXM1) is a crucial regulator of cancer development and chemoresistance. It is often overexpressed in acute myeloid leukemia (AML) and is associated with poor survival and reduced efficacy of cytarabine therapy. Molecular mechanisms underlying high FOXM1 expression levels in malignant cells are still unclear. Here we demonstrate that AKT and FOXM1 constitute a positive autoregulatory loop in AML cells that sustains high activity of both pro-oncogenic regulators. Inactivation of either AKT or FOXM1 signaling results in disruption of whole loop, coordinated suppression of FOXM1 or AKT, respectively, and similar transcriptomic changes. AML cells with inhibited AKT activity or stable FOXM1 knockdown display increase in HOXA genes expression and BCL2L1 suppression that are associated with prominent sensitization to treatment with Bcl-2 inhibitor venetoclax. Taken together, our data indicate that AKT and FOXM1 in AML cells should not be evaluated as single independent regulators but as two parts of a common FOXM1-AKT positive feedback circuit. We also report for the first time that FOXM1 inactivation can overcome AML venetoclax resistance. Thus, targeting FOXM1-AKT loop may open new possibilities in overcoming AML drug resistance and improving outcomes for AML patients.
    Keywords:  AKT pathway; FOXM1; HOXA gene family; acute myeloid leukemia; drug resistance; positive feedback loop; venetoclax
  6. Cancer Discov. 2020 Dec;10(12): OF10
      Mitochondrial oxidative phosphorylation (OXPHOS) defects increased intestinal cancer growth in vivo.
  7. Cell Metab. 2021 Aug 03. pii: S1550-4131(21)00332-6. [Epub ahead of print]
      Cancer cells are metabolically similar to their corresponding normal tissues. Differences between cancers and normal tissues may reflect reprogramming during transformation or maintenance of the metabolism of the specific normal cell type that originated the cancer. Here, we compare glucose metabolism in hematopoiesis and leukemia. Thymus T cell progenitors were glucose avid and oxidized more glucose in the tricarboxylic acid cycle through pyruvate dehydrogenase (PDH) as compared with other hematopoietic cells. PDH deletion decreased double-positive T cell progenitor cells but had no effect on hematopoietic stem cells, myeloid progenitors, or other hematopoietic cells. PDH deletion blocked the development of Pten-deficient T cell leukemia, but not the development of a Pten-deficient myeloid neoplasm. Therefore, the requirement for PDH in leukemia reflected the metabolism of the normal cell of origin independently of the driver genetic lesion. PDH was required to prevent pyruvate accumulation and maintain glutathione levels and redox homeostasis.
    Keywords:  T cell leukemia; double-positive thymocytes; glycolysis; hematopoietic stem cells; metabolism; pyruvate dehydrogenase; thymus
  8. World J Stem Cells. 2021 Jul 26. 13(7): 934-943
      The classical cancer stem cell (CSCs) theory proposed the existence of a rare but constant subpopulation of CSCs. In this model cancer cells are organized hierarchically and are responsible for tumor resistance and tumor relapse. Thus, eliminating CSCs will eventually lead to cure of cancer. This simplistic model has been challenged by experimental data. In 2010 we proposed a novel and controversial alternative model of CSC biology (the Stemness Phenotype Model, SPM). The SPM proposed a non-hierarchical model of cancer biology in which there is no specific subpopulation of CSCs in tumors. Instead, cancer cells are highly plastic in term of stemness and CSCs and non-CSCs can interconvert into each other depending on the microenvironment. This model predicts the existence of cancer cells ranging from a pure CSC phenotype to pure non-CSC phenotype and that survival of a single cell can originate a new tumor. During the past 10 years, a plethora of experimental evidence in a variety of cancer types has shown that cancer cells are indeed extremely plastic and able to interconvert into cells with different stemness phenotype. In this review we will (1) briefly describe the cumulative evidence from our laboratory and others supporting the SPM; (2) the implications of the SPM in translational oncology; and (3) discuss potential strategies to develop more effective therapeutic regimens for cancer treatment.
    Keywords:  Cancer; Chemotherapy; Interconversion; Plasticity; Stem cells; Stemness