bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2022–07–17
twelve papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Targeting stem cells in myelodysplastic syndromes and acute myeloid leukemia.
  2. Targeting mitochondrial metabolism for precision medicine in cancer.
  3. Leukemic Stem Cell: A Mini-Review on Clinical Perspectives.
  4. Historical perspective of tumor glycolysis: A century with Otto Warburg.
  5. The Molecular Mechanisms of Resistance to IDH Inhibitors in Acute Myeloid Leukemia.
  6. KDM4 inhibitor SD49-7 attenuates leukemia stem cell via KDM4A/MDM2/p21CIP1 axis.
  7. 'Warburg effect' controls tumor growth, bacterial, viral infections and immunity - Genetic deconstruction and therapeutic perspectives.
  8. IKZF1::CIITA, a novel fusion transcript in a case of relapsed B-cell acute lymphoblastic leukemia.
  9. The Role and Therapeutic Perspectives of Sirtuin 3 in Cancer Metabolism Reprogramming, Metastasis, and Chemoresistance.
  10. B-cell acute lymphoblastic leukemia promotes an immune suppressive microenvironment that can be overcome by IL-12.
  11. Improved outcomes with 7+3 induction chemotherapy for acute myeloid leukemia over the past four decades: analysis of SWOG trial data.
  12. IL-10 and TNFα are associated with decreased survival in low-risk pediatric acute myeloid leukemia; a children's oncology group report.
  1. J Intern Med. 2022 Jul 13.
    Targeting stem cells in myelodysplastic syndromes and acute myeloid leukemia.
    Petter S Woll, Tetsuichi Yoshizato, Eva Hellström-Lindberg, Thoas Fioretos, Benjamin L Ebert, Sten Eirik W Jacobsen.
      The genetic architecture of cancer has been delineated through advances in high-throughput next-generation sequencing, where the sequential acquisition of recurrent driver mutations initially targeted towards normal cells ultimately leads to malignant transformation. Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are hematologic malignancies frequently initiated by mutations in the normal hematopoietic stem cell compartment leading to the establishment of leukemic stem cells. Although the genetic characterization of MDS and AML has led to identification of new therapeutic targets and development of new promising therapeutic strategies, disease progression, relapse, and treatment-related mortality remain a major challenge in MDS and AML. The selective persistence of rare leukemic stem cells following therapy-induced remission implies unique resistance mechanisms of leukemic stem cells towards conventional therapeutic strategies and that leukemic stem cells represent the cellular origin of relapse. Therefore, targeted surveillance of leukemic stem cells following therapy should, in the future, allow better prediction of relapse and disease progression, but is currently challenged by our restricted ability to distinguish leukemic stem cells from other leukemic cells and residual normal cells. To advance current and new clinical strategies for the treatment of MDS and AML, there is a need to improve our understanding and characterization of MDS and AML stem cells at the cellular, molecular, and genetic levels. Such work has already led to the identification of promising new candidate leukemic stem cell molecular targets that can now be exploited in preclinical and clinical therapeutic strategies, towards more efficient and specific elimination of leukemic stem cells.
    Keywords:  acute myeloid leukemia; clonal evolution; hematopoietic stem cells; leukemic stem cells; myelodysplastic syndromes; therapeutic targets
    DOI:  https://doi.org/10.1111/joim.13535
  2. Cell Death Differ. 2022 Jul;29(7): 1304-1317
    Targeting mitochondrial metabolism for precision medicine in cancer.
    Lourdes Sainero-Alcolado, Judit Liaño-Pons, María Victoria Ruiz-Pérez, Marie Arsenian-Henriksson.
      During decades, the research field of cancer metabolism was based on the Warburg effect, described almost one century ago. Lately, the key role of mitochondria in cancer development has been demonstrated. Many mitochondrial pathways including oxidative phosphorylation, fatty acid, glutamine, and one carbon metabolism are altered in tumors, due to mutations in oncogenes and tumor suppressor genes, as well as in metabolic enzymes. This results in metabolic reprogramming that sustains rapid cell proliferation and can lead to an increase in reactive oxygen species used by cancer cells to maintain pro-tumorigenic signaling pathways while avoiding cellular death. The knowledge acquired on the importance of mitochondrial cancer metabolism is now being translated into clinical practice. Detailed genomic, transcriptomic, and metabolomic analysis of tumors are necessary to develop more precise treatments. The successful use of drugs targeting metabolic mitochondrial enzymes has highlighted the potential for their use in precision medicine and many therapeutic candidates are in clinical trials. However, development of efficient personalized drugs has proved challenging and the combination with other strategies such as chemocytotoxic drugs, immunotherapy, and ketogenic or calorie restriction diets is likely necessary to boost their potential. In this review, we summarize the main mitochondrial features, metabolic pathways, and their alterations in different cancer types. We also present an overview of current inhibitors, highlight enzymes that are attractive targets, and discuss challenges with translation of these approaches into clinical practice. The role of mitochondria in cancer is indisputable and presents several attractive targets for both tailored and personalized cancer therapy.
    DOI:  https://doi.org/10.1038/s41418-022-01022-y
  3. Front Oncol. 2022 ;12 931050
    Leukemic Stem Cell: A Mini-Review on Clinical Perspectives.
    Igor Valentim Barreto, Flávia Melo Cunha de Pinho Pessoa, Caio Bezerra Machado, Laudreísa da Costa Pantoja, Rodrigo Monteiro Ribeiro, Germison Silva Lopes, Maria Elisabete Amaral de Moraes, Manoel Odorico de Moraes Filho, Lucas Eduardo Botelho de Souza, Rommel Mário Rodriguez Burbano, André Salim Khayat, Caroline Aquino Moreira-Nunes.
      Hematopoietic stem cells (HSCs) are known for their ability to proliferate and self-renew, thus being responsible for sustaining the hematopoietic system and residing in the bone marrow (BM). Leukemic stem cells (LSCs) are recognized by their stemness features such as drug resistance, self-renewal, and undifferentiated state. LSCs are also present in BM, being found in only 0.1%, approximately. This makes their identification and even their differentiation difficult since, despite the mutations, they are cells that still have many similarities with HSCs. Although the common characteristics, LSCs are heterogeneous cells and have different phenotypic characteristics, genetic mutations, and metabolic alterations. This whole set of alterations enables the cell to initiate the process of carcinogenesis, in addition to conferring drug resistance and providing relapses. The study of LSCs has been evolving and its application can help patients, where through its count as a biomarker, it can indicate a prognostic factor and reveal treatment results. The selection of a target to LSC therapy is fundamental. Ideally, the target chosen should be highly expressed by LSCs, highly selective, absence of expression on other cells, in particular HSC, and preferentially expressed by high numbers of patients. In view of the large number of similarities between LSCs and HSCs, it is not surprising that current treatment approaches are limited. In this mini review we seek to describe the immunophenotypic characteristics and mechanisms of resistance presented by LSCs, also approaching possible alternatives for the treatment of patients.
    Keywords:  clinical relapse; drug resistance; hematopoietic stem cells; leukemia stem cell; molecular biomarkers
    DOI:  https://doi.org/10.3389/fonc.2022.931050
  4. Semin Cancer Biol. 2022 Jul 06. pii: S1044-579X(22)00162-6. [Epub ahead of print]
    Historical perspective of tumor glycolysis: A century with Otto Warburg.
    Giulia Bononi, Samuele Masoni, Valeria Di Bussolo, Tiziano Tuccinardi, Carlotta Granchi, Filippo Minutolo.
      Tumors have long been known to rewire their metabolism to endorse their proliferation, growth, survival, and invasiveness. One of the common characteristics of these alterations is the enhanced glucose uptake and its subsequent transformation into lactic acid by means of glycolysis, regardless the availability of oxygen or the mitochondria effectiveness. This phenomenon is called the "Warburg effect", which has turned into a century of age now, since its first disclosure by German physiologist Otto Heinrich Warburg. Since then, this peculiar metabolic switch in tumors has been addressed by extensive studies covering several areas of research. In this historical perspective, we aim at illustrating the evolution of these studies over time and their implication in various fields of science.
    Keywords:  Aerobic glycolysis; Historical perspective; Reverse Warburg effect; Tumor metabolism; Warburg effect
    DOI:  https://doi.org/10.1016/j.semcancer.2022.07.003
  5. Front Oncol. 2022 ;12 931462
    The Molecular Mechanisms of Resistance to IDH Inhibitors in Acute Myeloid Leukemia.
    Xiaomei Zhuang, Han Zhong Pei, Tianwen Li, Junbin Huang, Yao Guo, Yuming Zhao, Ming Yang, Dengyang Zhang, Zhiguang Chang, Qi Zhang, Liuting Yu, Chunxiao He, Liqing Zhang, Yihang Pan, Chun Chen, Yun Chen.
      Gain-of-function mutations of isocitrate dehydrogenases 1/2 (IDH1/2) play crucial roles in the development and progression of acute myeloid leukemia (AML), which provide promising therapeutic targets. Two small molecular inhibitors, ivosidenib and enasidenib have been approved for the treatment of IDH1- and IDH2-mutant AML, respectively. Although these inhibitors benefit patients with AML clinically, drug resistance still occurs and have become a major problem for targeted therapies of IDH-mutant AML. A number of up-to-date studies have demonstrated molecular mechanisms of resistance, providing rationales of novel therapeutic strategies targeting mutant IDH1/2. In this review, we discuss mechanisms of resistance to ivosidenib and enasidenib in patients with AML.
    Keywords:  IDH1; IDH2; acute myeloid leukemia; cancer metabolism; drug resistance
    DOI:  https://doi.org/10.3389/fonc.2022.931462
  6. Theranostics. 2022 ;12(11): 4922-4934
    KDM4 inhibitor SD49-7 attenuates leukemia stem cell via KDM4A/MDM2/p21CIP1 axis.
    Yinghui Li, Chaoqun Wang, Huier Gao, Jiali Gu, Yiran Zhang, Yingyi Zhang, Min Xie, Xuelian Cheng, Ming Yang, Wenshan Zhang, Yafang Li, Mei He, Hui Xu, Hexiao Zhang, Qing Ji, Tianhua Ma, Sheng Ding, Yu Zhao, Yingdai Gao.
      Rationale: Traditional treatments for leukemia fail to address stem cell drug resistance characterized by epigenetic mediators such as histone lysine-specific demethylase 4 (KDM4). The KDM4 family, which acts as epigenetic regulators inducing histone demethylation during the development and progression of leukemia, lacks specific molecular inhibitors. Methods: The KDM4 inhibitor, SD49-7, was synthesized and purified based on acyl hydrazone Schiff base. The interaction between SD49-7 and KDM4s was monitored in vitro by surface plasma resonance (SPR). In vitro and in vivo biological function experiments were performed to analyze apoptosis, colony-formation, proliferation, differentiation, and cell cycle in cell sub-lines and mice. Molecular mechanisms were demonstrated by RNA-seq, ChIP-seq, RT-qPCR and Western blotting. Results: We found significantly high KDM4A expression levels in several human leukemia subtypes. The knockdown of KDM4s inhibited leukemogenesis in the MLL-AF9 leukemia mouse model but did not affect the survival of normal human hematopoietic cells. We identified SD49-7 as a selective KDM4 inhibitor that impaired the progression of leukemia stem cells (LSCs) in vitro. SD49-7 suppressed leukemia development in the mouse model and patient-derived xenograft model of leukemia. Depletion of KDM4s activated the apoptosis signaling pathway by suppressing MDM2 expression via modulating H3K9me3 levels on the MDM2 promoter region. Conclusion: Our study demonstrates a unique KDM4 inhibitor for LSCs to overcome the resistance to traditional treatment and offers KDM4 inhibition as a promising strategy for resistant leukemia therapy.
    Keywords:  Leukemia stem cells; Lysine-specific demethylase 4; Small molecular compounds
    DOI:  https://doi.org/10.7150/thno.71460
  7. Semin Cancer Biol. 2022 Jul 09. pii: S1044-579X(22)00175-4. [Epub ahead of print]
    'Warburg effect' controls tumor growth, bacterial, viral infections and immunity - Genetic deconstruction and therapeutic perspectives.
    J Pouysségur, Marchiq, S K Parks, J Durivault, M Ždralević, M Vucetic.
      The evolutionary pressure for life transitioning from extended periods of hypoxia to an increasingly oxygenated atmosphere initiated drastic selections for a variety of biochemical pathways supporting the robust life currently present on the planet. First, we discuss how fermentative glycolysis, a primitive metabolic pathway present at the emergence of life, is instrumental for the rapid growth of cancer, regenerating tissues, immune cells but also bacteria and viruses during infections. The 'Warburg effect', activated via Myc and HIF-1 in response to growth factors and hypoxia, is an essential metabolic and energetic pathway which satisfies nutritional and energetic demands required for rapid genome replication. Second, we present the key role of lactic acid, the end-product of fermentative glycolysis able to move across cell membranes in both directions via monocarboxylate transporting proteins (i.e. MCT1/4) contributing to cell-pH homeostasis but also to the complex immune response via acidosis of the tumour microenvironment. Importantly lactate is recycled in multiple organs as a major metabolic precursor of gluconeogenesis and energy source protecting cells and animals from harsh nutritional or oxygen restrictions. Third, we revisit the Warburg effect via CRISPR-Cas9 disruption of glucose-6-phosphate isomerase (GPI-KO) or lactate dehydrogenases (LDHA/B-DKO) in two aggressive tumours (melanoma B16-F10, human adenocarcinoma LS174T). Full suppression of lactic acid production reduces but does not suppress tumour growth due to reactivation of OXPHOS. In contrast, disruption of the lactic acid transporters MCT1/4 suppressed glycolysis, mTORC1, and tumour growth as a result of intracellular acidosis. Finally, we briefly discuss the current clinical developments of an MCT1 specific drug AZ3965, and the recent progress for a specific in vivo MCT4 inhibitor, two drugs of very high potential for future cancer clinical applications.
    Keywords:  BASIGIN; CRISPR-cas9; GPI; LDHA; LDHB; MCT1; MCT4; OXPHOS; Warburg effect; acidosis; bacteria; cancer; fermentative glycolysis; glycogen; immune evasion; immunity; lactate; pathogens; viruses
    DOI:  https://doi.org/10.1016/j.semcancer.2022.07.004
  8. Pediatr Blood Cancer. 2022 Jul 11. e29872
    IKZF1::CIITA, a novel fusion transcript in a case of relapsed B-cell acute lymphoblastic leukemia.
    Preity Sharma, Sanjeev Kumar Gupta, Gadha K Leons, Sameer Bakhshi, Ritu Gupta, Lata Rani, Smeeta Gajendra, Anita Roy, Deepam Pushpam.
      
    DOI:  https://doi.org/10.1002/pbc.29872
  9. Front Oncol. 2022 ;12 910963
    The Role and Therapeutic Perspectives of Sirtuin 3 in Cancer Metabolism Reprogramming, Metastasis, and Chemoresistance.
    QingYi Zhao, Jing Zhou, Feng Li, Sen Guo, Liang Zhang, Jing Li, Qin Qi, Yin Shi.
      Sirtuin 3 (SIRT3), the nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, acts as a metabolic modulator mainly located in mitochondria via regulating the process of the relevant biochemical processes by targeting crucial mediators. Recently, owing to its dual role in cancer, SIRT3 has attracted extensive attention. Cancer cells have different metabolic patterns from normal cells, and SIRT3-mediated metabolism reprogramming could be critical in the cancer context, which is closely related to the mechanism of metabolism reprogramming, metastasis, and chemoresistance in tumor cells. Therefore, it is crucial to elucidate the relevant pathological mechanisms and take appropriate countermeasures for the progression of clinical strategies to inhibit the development of cancer. In this review, existing available data on the regulation of cancer metabolism reprogramming, metastasis, and chemoresistance progression of SIRT3 are detailed, as well as the status quo of SIRT3 small molecule modulators is updated in the application of cancer therapy, aiming to highlight strategies directly targeting SIRT3-mediated tumor-suppressing and tumor-promoting, and provide new approaches for therapy application. Furthermore, we offer an effective evidence-based basis for the evolvement of potential personalized therapy management strategies for SIRT3 in cancer settings.
    Keywords:  activator; cancer; chemoresistance; inhibitor; metabolism reprogramming; metastasis; sirtuin 3; therapy
    DOI:  https://doi.org/10.3389/fonc.2022.910963
  10. Sci Rep. 2022 Jul 13. 12(1): 11870
    B-cell acute lymphoblastic leukemia promotes an immune suppressive microenvironment that can be overcome by IL-12.
    Rae Hunter, Kathleen J Imbach, Chengjing Zhou, Jodi Dougan, Jamie A G Hamilton, Kevin Z Chen, Priscilla Do, Ashley Townsel, Greg Gibson, Erik C Dreaden, Edmund K Waller, Karmella A Haynes, Curtis J Henry, Christopher C Porter.
      Immunotherapies have revolutionized the treatment of B-cell acute lymphoblastic leukemia (B-ALL), but the duration of responses is still sub-optimal. We sought to identify mechanisms of immune suppression in B-ALL and strategies to overcome them. Plasma collected from children with B-ALL with measurable residual disease after induction chemotherapy showed differential cytokine expression, particularly IL-7, while single-cell RNA-sequencing revealed the expression of genes associated with immune exhaustion in immune cell subsets. We also found that the supernatant of leukemia cells suppressed T-cell function ex vivo. Modeling B-ALL in mice, we observed an altered tumor immune microenvironment, including compromised activation of T-cells and dendritic cells (DC). However, recombinant IL-12 (rIL-12) treatment of mice with B-ALL restored the levels of several pro-inflammatory cytokines and chemokines in the bone marrow and increased the number of splenic and bone marrow resident T-cells and DCs. RNA-sequencing of T-cells isolated from vehicle and rIL-12 treated mice with B-ALL revealed that the leukemia-induced increase in genes associated with exhaustion, including Lag3, Tigit, and Il10, was abrogated with rIL-12 treatment. In addition, the cytolytic capacity of T-cells co-cultured with B-ALL cells was enhanced when IL-12 and blinatumomab treatments were combined. Overall, these results demonstrate that the leukemia immune suppressive microenvironment can be restored with rIL-12 treatment which has direct therapeutic implications.
    DOI:  https://doi.org/10.1038/s41598-022-16152-z
  11. Haematologica. 2022 Jul 14.
    Improved outcomes with 7+3 induction chemotherapy for acute myeloid leukemia over the past four decades: analysis of SWOG trial data.
    Megan Othus, Guillermo Garcia-Manero, John E Godwin, James K Weick, Frederick R Appelbaum, Harry P Erba, Elihu H Estey.
      We have previously shown that complete response (CR) rates and overall survival (OS) of patients with acute myeloid leukemia (AML) have improved since the 1980s. However, we have not previously evaluated how the length of first CR (CR1) has changed over this time period. To address this, we analyzed 1,247 patients age 65 or younger randomized to 7+3 arms from 5 SWOG studies: S8600 (n=530), S9031 (n=98), S9333 (n=57), S0106 (n=301), S1203 (n=261). We evaluated length of CR1 and survival after relapse from CR1 over the 4 decades these studies represent. Both length of CR1 and survival after relapse from CR1 have improved over the last four decades. The relative benefit associated with CR1 and the relative detriment associated with relapse have decreased over this period; while achieving CR1 and relapse from CR1 still have strong prognostic associations with outcomes, the magnitude of the association has decreased over time. Possible explanations for these patterns include higher CR rates with salvage therapies after relapse, more frequent use of hematopoietic cell transplant, and better supportive care.
    DOI:  https://doi.org/10.3324/haematol.2022.280765
  12. Pediatr Hematol Oncol. 2022 Jul 15. 1-12
    IL-10 and TNFα are associated with decreased survival in low-risk pediatric acute myeloid leukemia; a children's oncology group report.
    Alexandra M Stevens, Terzah M Horton, Chana L Glasser, Robert B Gerbing, Richard Aplenc, Todd A Alonzo, Michele S Redell.
      Pediatric acute myeloid leukemia (AML) is a devastating disease with a high risk of relapse. Current risk classification designates patients as high or low risk (LR) based on molecular features and therapy response. However, 30% of LR patients still suffer relapse, indicating a need for improvement in risk stratification. Cytokine levels, such as IL-6 and IL-10, have been shown to be prognostic in adult AML but have not been well studied in children. Previously, we reported elevated IL-6 levels in pediatric AML bone marrow to be associated with inferior prognosis. Here, we expanded our investigation to assess cytokine levels in diagnostic peripheral blood plasma (PBP) of pediatric AML patients and determined correlation with outcome. Diagnostic PBP was obtained from 80 patients with LR AML enrolled on the Children's Oncology Group AAML1031 study and normal PBP from 11 controls. Cytokine levels were measured and correlation with clinical outcome was assessed. IL-6, TNFα, MIP-3a, and IL-1β were significantly higher in AML patients versus controls when corrected by the Bonferroni method. Furthermore, elevated TNFα and IL-10 were significantly associated with inferior outcomes. Our data demonstrate that in diagnostic PBP of LR pediatric AML patients, certain cytokine levels are elevated as compared to healthy controls and that elevated TNFα and IL-10 are associated with inferior outcomes, supporting the idea that an abnormal inflammatory state may predict poor outcomes. Studies are needed to determine the mechanisms by which these cytokines impact survival, and to further evaluate their use as prognostic biomarkers in pediatric AML.
    Keywords:  Interluekin 6; cytokine; microenvironment; risk stratification; soluble factor
    DOI:  https://doi.org/10.1080/08880018.2022.2089790
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