bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2022–04–17
eleven papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Imetelstat Induces Leukemia Stem Cell Death in Pediatric Acute Myeloid Leukemia Patient-Derived Xenografts.
  2. Leukemic stem cell signatures in Acute myeloid leukemia- targeting the Guardians with novel approaches.
  3. Isolation, Maintenance and Expansion of Adult Hematopoietic Stem/Progenitor Cells and Leukemic Stem Cells.
  4. JAK3 mutations and mitochondrial apoptosis resistance in T-cell acute lymphoblastic leukemia.
  5. Abnormal bone marrow microenvironment: the "harbor" of acute lymphoblastic leukemia cells.
  6. 'Reverse Warburg effect' of cancer‑associated fibroblasts (Review).
  7. Mechanisms of Resistance to Targeted Therapies for Relapsed or Refractory Acute Myeloid Leukemia.
  8. One genome, many cell states: epigenetic control of innate immunity.
  9. NADH dehydrogenase subunit 1/4/5 promotes survival of acute myeloid leukemia by mediating specific oxidative phosphorylation.
  10. The impact of venetoclax based regimens in the preemptive of measurable residual disease in acute myeloid leukemia.
  11. Repeated Lineage Switches in an Elderly Case of Refractory B-Cell Acute Lymphoblastic Leukemia With MLL Gene Amplification: A Case Report and Literature Review.
  1. J Clin Med. 2022 Mar 30. pii: 1923. [Epub ahead of print]11(7):
    Imetelstat Induces Leukemia Stem Cell Death in Pediatric Acute Myeloid Leukemia Patient-Derived Xenografts.
    Sonali P Barwe, Fei Huang, Edward Anders Kolb, Anilkumar Gopalakrishnapillai.
      Acute myeloid leukemia (AML) in children remains deadly, despite the use of maximally intensive therapy. Because leukemia stem cells (LSCs) significantly contribute to chemoresistance and relapse, therapies that specifically target the LSCs are likely to be more beneficial in improving outcome. LSCs are known to have high telomerase activity and telomerase activity is negatively correlated with survival in pediatric AML. We evaluated the preclinical efficacy of imetelstat, an oligonucleotide inhibitor of telomerase activity in patient-derived xenograft (PDX) lines of pediatric AML. Imetelstat treatment significantly increased apoptosis/death of the LSC population in a dose-dependent manner in six pediatric AML PDX lines ex vivo, while it had limited activity on the stem cell population in normal bone marrow specimens. These results were validated in vivo in two distinct PDX models wherein imetelstat as single agent or in combination with chemotherapy greatly reduced the LSC percentage and prolonged median survival. Imetelstat combination with DNA hypomethylating agent azacitidine was also beneficial in extending survival. Secondary transplantation experiments showed delayed engraftment and improved survival of mice receiving imetelstat-treated cells, confirming the diminished LSC population. Thus, our data suggest that imetelstat represents an effective therapeutic strategy for pediatric AML.
    Keywords:  imetelstat; leukemia stem cells; patient-derived xenograft models; pediatric acute myeloid leukemia; telomerase
    DOI:  https://doi.org/10.3390/jcm11071923
  2. Stem Cell Rev Rep. 2022 Mar 28.
    Leukemic stem cell signatures in Acute myeloid leukemia- targeting the Guardians with novel approaches.
    Deepshi Thakral, Ritu Gupta, Aafreen Khan.
      Acute myeloid leukemia is an aggressive hematopoietic stem cell malignancy with poor outcomes despite the available treatment options including standard chemotherapy, selective targeted therapy and stem cell transplantation. Approximately ~30-40% of AML patients are refractory to initial therapy or succumb to relapse. Induction failure result from inherent resistance to chemotherapy, which is primarily driven by the chemo-resistant residual leukemic stem cells (LSC) that lead to disease progression and recurrence. The rarity and lack of universal surface markers for the identification and isolation of AML LSC renders a major challenge. Therefore, a perpetual quest for novel markers to characterize LSC and design anti-LSC therapies is ongoing. The evolving technologies from high-throughput bulk cell sequencing to high-dimensional single cell analysis has begun to decode the cellular hierarchies and dysregulated transcriptional networks in AML. These inherent properties of LSC as well as cross-talk with the extrinsic bone marrow microenvironmental milieu induce a conducive environment for leukemogenesis by secretion of various cytokines, chemokines and growth factors that shield LSC against conventional chemotherapy. To overcome these barriers, novel approaches of intratumoural delivery that focus on immune-mediated eradication by inducing microenvironmental changes within the tumour as well as avoid systemic toxicity seem encouraging. Selective targeting of LSC and their protective bone marrow niche holds immense potential as a promising therapeutic strategy for AML. Novel multimodal anti-LSC therapies are being explored that can overcome chemo-resistance and immune escape combined with reduced toxicity and sustained delivery may improve remission and survival rates in AML patients and decrease relapse.
    Keywords:  Acute myeloid leukemia; Bone marrow microenvironment; Gene expression profile; Leukemic stem cells; Nanotechnology; Single cell sequencing; Therapeutic targets
    DOI:  https://doi.org/10.1007/s12015-022-10349-5
  3. Cancers (Basel). 2022 Mar 28. pii: 1723. [Epub ahead of print]14(7):
    Isolation, Maintenance and Expansion of Adult Hematopoietic Stem/Progenitor Cells and Leukemic Stem Cells.
    Isabella Maria Mayer, Andrea Hoelbl-Kovacic, Veronika Sexl, Eszter Doma.
      Hematopoietic stem cells (HSCs) are rare, self-renewing cells that perch on top of the hematopoietic tree. The HSCs ensure the constant supply of mature blood cells in a tightly regulated process producing peripheral blood cells. Intense efforts are ongoing to optimize HSC engraftment as therapeutic strategy to treat patients suffering from hematopoietic diseases. Preclinical research paves the way by developing methods to maintain, manipulate and expand HSCs ex vivo to understand their regulation and molecular make-up. The generation of a sufficient number of transplantable HSCs is the Holy Grail for clinical therapy. Leukemia stem cells (LSCs) are characterized by their acquired stem cell characteristics and are responsible for disease initiation, progression, and relapse. We summarize efforts, that have been undertaken to increase the number of long-term (LT)-HSCs and to prevent differentiation towards committed progenitors in ex vivo culture. We provide an overview and compare methods currently available to isolate, maintain and enrich HSC subsets, progenitors and LSCs and discuss their individual advantages and drawbacks.
    Keywords:  dormancy; ex vivo culture; hematopoietic stem cells; leukemic stem cells; maintenance; self-renewal
    DOI:  https://doi.org/10.3390/cancers14071723
  4. Leukemia. 2022 Apr 11.
    JAK3 mutations and mitochondrial apoptosis resistance in T-cell acute lymphoblastic leukemia.
    Kimberly Bodaar, Natsuko Yamagata, Anais Barthe, Jack Landrigan, Triona Ni Chonghaile, Melissa Burns, Kristen E Stevenson, Meenakshi Devidas, Mignon L Loh, Stephen P Hunger, Brent Wood, Lewis B Silverman, David T Teachey, Jules P Meijerink, Anthony Letai, Alejandro Gutierrez.
      Resistance to mitochondrial apoptosis predicts inferior treatment outcomes in patients with diverse tumor types, including T-cell acute lymphoblastic leukemia (T-ALL). However, the genetic basis for variability in this mitochondrial apoptotic phenotype is poorly understood, preventing its rational therapeutic targeting. Using BH3 profiling and exon sequencing analysis of childhood T-ALL clinical specimens, we found that mitochondrial apoptosis resistance was most strongly associated with activating mutations of JAK3. Mutant JAK3 directly repressed apoptosis in leukemia cells, because its inhibition with mechanistically distinct pharmacologic inhibitors resulted in reversal of mitochondrial apoptotic blockade. Inhibition of JAK3 led to loss of MEK, ERK and BCL2 phosphorylation, and BH3 profiling revealed that JAK3-mutant primary T-ALL patient samples were characterized by a dependence on BCL2. Treatment of JAK3-mutant T-ALL cells with the JAK3 inhibitor tofacitinib in combination with a spectrum of conventional chemotherapeutics revealed synergy with glucocorticoids, in vitro and in vivo. These findings thus provide key insights into the molecular genetics of mitochondrial apoptosis resistance in childhood T-ALL, and a compelling rationale for a clinical trial of JAK3 inhibitors in combination with glucocorticoids for patients with JAK3-mutant T-ALL.
    DOI:  https://doi.org/10.1038/s41375-022-01558-5
  5. Blood Sci. 2021 Apr;3(2): 29-34
    Abnormal bone marrow microenvironment: the "harbor" of acute lymphoblastic leukemia cells.
    Zehui Chen, Yaxin Zheng, Yaling Yang, Junnan Kang, M James You, Chen Tian.
      Bone marrow (BM) microenvironment regulates and supports the production of blood cells which are necessary to maintain homeostasis. In analogy to normal hematopoiesis, leukemogenesis is originated from leukemic stem cells (LSCs) which gives rise to more differentiated malignant cells. Leukemia cells occupy BM niches and reconstruct them to support leukemogenesis. The abnormal BM niches are the main sanctuary of LSCs where they can evade chemotherapy-induced death and acquire drug resistance. In this review, we focus on the protective effects of BM niche cells on acute lymphoblastic leukemia cells.
    Keywords:  acute lymphoblastic leukemia; bone marrow microenvironment; osteoblastic niche; vascular niche
    DOI:  https://doi.org/10.1097/BS9.0000000000000071
  6. Int J Oncol. 2022 Jun;pii: 67. [Epub ahead of print]60(6):
    'Reverse Warburg effect' of cancer‑associated fibroblasts (Review).
    Lin Liang, Wentao Li, Xin Li, Xi Jin, Qianjin Liao, Yanling Li, Yanhong Zhou.
      Metabolic reprogramming is one of the main characteristics of malignant tumors. The metabolic reprogramming of tumors is not only related to the characteristics of cancer cells, but also closely related to the tumor microenvironment (TME). 'Aerobic glycolysis' is considered to be the classic metabolic mode of tumor cells. However, recent experiments have shown that the TME plays a key role in carcinogenesis and epithelial‑mesenchymal transition. Cancer‑associated fibroblasts (CAFs) dominate in the microenvironment and affect the homeostasis of the TME. The interaction between cancer cells and the surrounding CAFs markedly affects the growth, metabolism, metastasis, and progression of cancer. Based on this, a 'dual‑chamber' model, also known as the 'Reverse Warburg effect', is proposed. Specifically, cancer cells secrete hydrogen peroxide into the TME to induce oxidative stress in neighboring stromal cells. CAFs undergo aerobic glycolysis and produce high levels of energy‑rich 'fuels' (such as pyruvate, ketone bodies, fatty acids, and lactic acid). In turn, these energy‑rich 'fuels' then 'feed' cancer cells. The mitochondrial oxidative phosphorylation system produces a large quantity of ATP, such that tumor cells have a higher proliferation ability. The proposed 'Reverse Warburg effect' redefines the tumor cell microenvironment and tumor metabolic reprogramming. Therefore, understanding the 'Reverse Warburg effect' of CAFs and its related mechanisms will help us to understand the association between the microenvironment, the matrix, and cancer cells, and may lead to new treatment strategies and targets.
    Keywords:  Reverse Warburg effect; cancer‑associated fibroblasts; interleukin‑6; reactive oxygen species; signal transduction pathway; transforming growth factor‑β
    DOI:  https://doi.org/10.3892/ijo.2022.5357
  7. Exp Hematol. 2022 Apr 10. pii: S0301-472X(22)00133-3. [Epub ahead of print]
    Mechanisms of Resistance to Targeted Therapies for Relapsed or Refractory Acute Myeloid Leukemia.
    Erin M Kropp, Qing Li.
      Acute myeloid leukemia (AML) is an aggressive disease of clonal hematopoiesis with a high rate of relapse and refractory disease despite intensive therapy. Traditionally, relapsed or refractory AML has increased therapeutic resistance and poor long-term survival. In recent years, advancements in the mechanistic understanding of leukemogenesis has allowed for the development of targeted therapies. These therapies offer novel alternatives to intensive chemotherapy and have prolonged survival in relapsed or refractory AML. Unfortunately, a significant portion of patients do not respond to these therapies and relapse occurs in most patients who initially responded. This review will focus on the mechanisms of resistance to targeted therapies in relapsed or refractory AML.
    DOI:  https://doi.org/10.1016/j.exphem.2022.04.001
  8. Curr Opin Immunol. 2022 Apr 08. pii: S0952-7915(22)00018-8. [Epub ahead of print]75 102173
    One genome, many cell states: epigenetic control of innate immunity.
    Isabella Fraschilla, Hajera Amatullah, Kate L Jeffrey.
      A hallmark of the innate immune system is its ability to rapidly initiate short-lived or sustained transcriptional programs in a cell-specific and pathogen-specific manner that is dependent on dynamic chromatin states. Much of the epigenetic landscape is set during cellular differentiation; however, pathogens and other environmental cues also induce changes in chromatin that can either promote tolerance or 'train' innate immune cells for amplified secondary responses. We review chromatin processes that enable innate immune cell differentiation and functional transcriptional responses in naive or experienced cells, in concert with signal transduction and cellular metabolic shifts. We discuss how immune chromatin mechanisms are maladapted in disease and novel therapeutic approaches for cellular reprogramming.
    DOI:  https://doi.org/10.1016/j.coi.2022.102173
  9. Mol Med Rep. 2022 Jun;pii: 195. [Epub ahead of print]25(6):
    NADH dehydrogenase subunit 1/4/5 promotes survival of acute myeloid leukemia by mediating specific oxidative phosphorylation.
    Ye Kuang, Chuanmei Peng, Yulin Dong, Jia Wang, Fanbin Kong, Xiaoqing Yang, Yang Wang, Hui Gao.
      Acute myeloid leukemia (AML) is a type of hematological malignancy caused by uncontrolled clonal proliferation of hematopoietic stem cells. The special energy metabolism mode of AML relying on oxidative phosphorylation is different from the traditional 'Warburg effect'. However, its mechanism is not clear. In the present study, it was demonstrated that the mRNA expression levels of NADH dehydrogenase subunit 1, 4 and 5 (ND1, ND4 and ND5) were upregulated in AML samples from The Cancer Genome Atlas database using the limma package in the R programming language. Reverse transcription‑quantitative PCR and ELISA were used to verify the upregulation of ND1, ND4 and ND5 in clinical samples. Pan‑cancer analysis revealed that the expression of ND1 was upregulated only in AML, ND2 was upregulated only in AML and thymoma, and ND4 was upregulated only in AML and kidney chromophobe. In the present study, it was demonstrated that silencing of ND1/4/5 could inhibit the proliferation of AML cells in transplanted tumor of nude mice. Additionally, it was found that oxidative phosphorylation and energy metabolism of AML cells were decreased after silencing of ND1/4/5. In conclusion, the present study suggested that ND1/4/5 may be involved in the regulation of oxidative phosphorylation metabolism in AML as a potential cancer‑promoting factor.
    Keywords:  NADH dehydrogenase subunit 1/4/5; acute myeloid leukemia; oxidative phosphorylation; proliferation
    DOI:  https://doi.org/10.3892/mmr.2022.12711
  10. Blood Sci. 2022 Jan;4(1): 44-46
    The impact of venetoclax based regimens in the preemptive of measurable residual disease in acute myeloid leukemia.
    Qiuyun Fang, Xiaoyuan Gong, Yan Li, Benfa Gong, Yuntao Liu, Kaiqi Liu, Guangji Zhang, Shuning Wei, Dong Lin, Bingcheng Liu, Ying Wang, Hui Wei, Yingchang Mi, Jianxiang Wang.
      
    DOI:  https://doi.org/10.1097/BS9.0000000000000101
  11. Front Oncol. 2022 ;12 799982
    Repeated Lineage Switches in an Elderly Case of Refractory B-Cell Acute Lymphoblastic Leukemia With MLL Gene Amplification: A Case Report and Literature Review.
    Reina Takeda, Kazuaki Yokoyama, Tomofusa Fukuyama, Toyotaka Kawamata, Mika Ito, Nozomi Yusa, Rika Kasajima, Eigo Shimizu, Nobuhiro Ohno, Kaoru Uchimaru, Rui Yamaguchi, Seiya Imoto, Satoru Miyano, Arinobu Tojo.
      Lineage switches in acute leukemia occur rarely, and the underlying mechanisms are poorly understood. Herein, we report the case of an elderly patient with leukemia in which the leukemia started as B-cell acute lymphoblastic leukemia (B-ALL) and later changed to B- and T-cell mixed phenotype acute leukemia (MPAL) and acute myeloid leukemia (AML) during consecutive induction chemotherapy treatments. A 65-year-old woman was initially diagnosed with Philadelphia chromosome-negative B-ALL primarily expressing TdT/CD34/HLA-DR; more than 20% of the blasts were positive for CD19/CD20/cytoplasmic CD79a/cytoplasmic CD22/CD13/CD71.The blasts were negative for T-lineage markers and myeloperoxidase (MPO). Induction chemotherapy with the standard regimen for B-ALL resulted in primary induction failure. After the second induction chemotherapy regimen, the blasts were found to be B/T bi-phenotypic with additional expression of cytoplasmic CD3. A single course of clofarabine (the fourth induction chemotherapy regimen) dramatically reduced lymphoid marker levels. However, the myeloid markers (e.g., MPO) eventually showed positivity and the leukemia completely changed its lineage to AML. Despite subsequent intensive chemotherapy regimens designed for AML, the patient's leukemia was uncontrollable and a new monoblastic population emerged. The patient died approximately 8 months after the initial diagnosis without experiencing stable remission. Several cytogenetic and genetic features were commonly identified in the initial diagnostic B-ALL and in the following AML, suggesting that this case should be classified as lineage switching leukemia rather than multiple simultaneous cancers (i.e., de novo B-ALL and de novo AML, or primary B-ALL and therapy-related myeloid neoplasm). A complex karyotype was persistently observed with a hemi-allelic loss of chromosome 17 (the location of the TP53 tumor suppressor gene). As the leukemia progressed, the karyotype became more complex, with the additional abnormalities. Sequential target sequencing revealed an increased variant allele frequency of TP53 mutation. Fluorescent in situ hybridization (FISH) revealed an increased number of mixed-lineage leukemia (MLL) genes, both before and after lineage conversion. In contrast, FISH revealed negativity for MLL rearrangements, which are well-known abnormalities associated with lineage switching leukemia and MPAL. To our best knowledge, this is the first reported case of acute leukemia presenting with lineage ambiguity and MLL gene amplification.
    Keywords:  AML – acute myeloid leukaemia; B-ALL; MLL; MPAL – mixed phenotypic acute leukaemia; TP53; gene amplicaiton; lineage switch; monosomy 17
    DOI:  https://doi.org/10.3389/fonc.2022.799982
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