The metabolic reprogramming in acute myeloid leukemia patients depends on their genotype and is a prognostic marker

Abstract Leukemic cells display some alterations in metabolic pathways, which play a role in leukemogenesis and in patients’ prognosis. To evaluate the characteristics and the impact of this metabolic reprogramming, we explore the bone marrow samples from 54 de novo acute myeloid leukemia (AML) patients, using an untargeted metabolomics approach based on proton high-resolution magic angle spinning-nuclear magnetic resonance. The spectra obtained were subjected to multivariate statistical analysis to find specific metabolome alterations and biomarkers correlated to clinical features. We found that patients display a large diversity of metabolic profiles, according to the different AML cytologic subtypes and molecular statuses. The link between metabolism and molecular status was particularly strong for the oncometabolite 2-hydroxyglutarate (2-HG), whose intracellular production is directly linked to the presence of isocitrate dehydrogenase mutations. Moreover, patients’ prognosis was strongly impacted by several metabolites, such as 2-HG that appeared as a good prognostic biomarker in our cohort. Conversely, deregulations in phospholipid metabolism had a negative impact on prognosis through 2 main metabolites (phosphocholine and phosphoethanolamine), which could be potential aggressiveness biomarkers. Finally, we highlighted an overexpression of glutathione and alanine in chemoresistant patients. Overall, our results demonstrate that different metabolic pathways could be activated in leukemic cells according to their phenotype and maturation levels. This confirms that metabolic reprogramming strongly influences prognosis of patients and underscores a particular role of certain metabolites and associated pathways in AML prognosis, suggesting common mechanisms developed by leukemic cells to maintain their aggressiveness even after well-conducted induction chemotherapy.

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Stable Isotope Labeling Highlights Enhanced Fatty Acid and Lipid Metabolism in Human Acute Myeloid Leukemia

International Journal of Molecular Sciences ◽

10.3390/ijms19113325 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3325 ◽

Cited By ~ 16

Author(s):

Lucille Stuani ◽

Fabien Riols ◽

Pierre Millard ◽

Marie Sabatier ◽

Aurélie Batut ◽

...

Keyword(s):

Fatty Acids ◽

Acute Myeloid Leukemia ◽

Fatty Acid ◽

Lipid Metabolism ◽

Myeloid Leukemia ◽

Metabolic Reprogramming ◽

Frequent Relapses ◽

The Impact ◽

Mutant Cells ◽

Acute Myeloid

Background: In Acute Myeloid Leukemia (AML), a complete response to chemotherapy is usually obtained after conventional chemotherapy but overall patient survival is poor due to highly frequent relapses. As opposed to chronic myeloid leukemia, B lymphoma or multiple myeloma, AML is one of the rare malignant hemopathies the therapy of which has not significantly improved during the past 30 years despite intense research efforts. One promising approach is to determine metabolic dependencies in AML cells. Moreover, two key metabolic enzymes, isocitrate dehydrogenases (IDH1/2), are mutated in more than 15% of AML patient, reinforcing the interest in studying metabolic reprogramming, in particular in this subgroup of patients. Methods: Using a multi-omics approach combining proteomics, lipidomics, and isotopic profiling of [U-13C] glucose and [U-13C] glutamine cultures with more classical biochemical analyses, we studied the impact of the IDH1 R132H mutation in AML cells on lipid biosynthesis. Results: Global proteomic and lipidomic approaches showed a dysregulation of lipid metabolism, especially an increase of phosphatidylinositol, sphingolipids (especially few species of ceramide, sphingosine, and sphinganine), free cholesterol and monounsaturated fatty acids in IDH1 mutant cells. Isotopic profiling of fatty acids revealed that higher lipid anabolism in IDH1 mutant cells corroborated with an increase in lipogenesis fluxes. Conclusions: This integrative approach was efficient to gain insight into metabolism and dynamics of lipid species in leukemic cells. Therefore, we have determined that lipid anabolism is strongly reprogrammed in IDH1 mutant AML cells with a crucial dysregulation of fatty acid metabolism and fluxes, both being mediated by 2-HG (2-Hydroxyglutarate) production.

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Pan-RAF Inhibition Shows Anti-Leukemic Activity in RAS-Mutant Acute Myeloid Leukemia Cells and Potentiates the Effect of Sorafenib in Cells with FLT3 Mutation

Cancers ◽

10.3390/cancers12123511 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3511

Author(s):

Joseph D. Khoury ◽

Mehrnoosh Tashakori ◽

Hong Yang ◽

Sanam Loghavi ◽

Ying Wang ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Cell Signaling ◽

Myeloid Leukemia ◽

Critical Role ◽

Cyclin B1 ◽

Leukemic Cells ◽

Phase Array ◽

Flt3 Mutations ◽

The Impact ◽

Acute Myeloid

RAF molecules play a critical role in cell signaling through their integral impact on the RAS/RAF/MEK/ERK signaling pathway, which is constitutively activated in a sizeable subset of acute myeloid leukemia (AML) patients. We evaluated the impact of pan-RAF inhibition using LY3009120 in AML cells harboring mutations upstream and downstream of RAF. LY3009120 had anti-proliferative and pro-apoptotic effects and suppressed pERK1/2 levels in leukemic cells with RAS and FLT3 mutations. Using reverse protein phase array analysis, we identified reductions in the expression/activation of cell signaling components downstream of RAF (activated p38) and cell cycle regulators (Wee1/cyclin B1, Cdc2/Cdk1, activated Rb, etc.). Notably, LY3009120 potentiated the effect of Ara-C on AML cells and overcame bone marrow mesenchymal stromal cell-mediated chemoresistance, with RAS-mutated cells showing a notable reduction in pAKT (Ser473). Furthermore, the combination of LY3009120 and sorafenib resulted in significantly higher levels of apoptosis in AML cells with heterozygous and hemizygous FLT3 mutations. In conclusion, pan-RAF inhibition in AML using LY3009120 results in anti-leukemic activity, and combination with Ara-C or sorafenib potentiates its effect.

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The impact of therapy-related acute myeloid leukemia (AML) on outcome in 2853 adult patients with newly diagnosed AML

Blood ◽

10.1182/blood-2010-08-301713 ◽

2011 ◽

Vol 117 (7) ◽

pp. 2137-2145 ◽

Cited By ~ 216

Author(s):

Sabine Kayser ◽

Konstanze Döhner ◽

Jürgen Krauter ◽

Claus-Henning Köhne ◽

Heinz A. Horst ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Complete Remission ◽

Myeloid Leukemia ◽

Topoisomerase Ii ◽

De Novo ◽

Negative Impact ◽

Primary Malignancy ◽

De Novo Aml ◽

The Impact ◽

Acute Myeloid

Abstract To study the characteristics and clinical impact of therapy-related acute myeloid leukemia (t-AML). 200 patients (7.0%) had t-AML and 2653 de novo AML (93%). Patients with t-AML were older (P < .0001) and they had lower white blood counts (P = .003) compared with de novo AML patients; t-AML patients had abnormal cytogenetics more frequently, with overrepresentation of 11q23 translocations as well as adverse cytogenetics, including complex and monosomal karyotypes, and with underrepresentation of intermediate-risk karyotypes (P < .0001); t-AML patients had NPM1 mutations (P < .0001) and FLT3 internal tandem duplications (P = .0005) less frequently. Younger age at diagnosis of primary malignancy and treatment with intercalating agents as well as topoisomerase II inhibitors were associated with shorter latency periods to the occurrence of t-AML. In multivariable analyses, t-AML was an adverse prognostic factor for death in complete remission but not relapse in younger intensively treated patients (P < .0001 and P = .39, respectively), relapse but not death in complete remission in older, less intensively treated patients (P = .02 and P = .22, respectively) and overall survival in younger intensively treated patients (P = .01). In more intensively treated younger adults, treatment-related toxicity had a major negative impact on outcome, possibly reflecting cumulative toxicity of cancer treatment.

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Metabolic Reprogramming of Human Mitochondrial NAD(P)+-Dependent-Malic Enzyme 2 in Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2019-123339 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5168-5168

Author(s):

Ching-Tien Peng

Keyword(s):

Acute Myeloid Leukemia ◽

Malic Enzyme ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Conflicts Of Interest ◽

Metabolic Reprogramming ◽

Leukemic Cells ◽

Internal Tandem Duplication ◽

Blast Cells ◽

Acute Myeloid

Yu-Nan Huang1, Kang-Hsi Wu4, Te-fu Weng4, Su-Ching Liu4, Hui-Chih Hung1*, Ching-Tien Peng4,5* FLT3 internal tandem duplication (FLT3-ITD) mutations in patients with acute myeloid leukemia (AML) are usually associated with other mutations resulting in unfavorable outcome. Tyrosine kinase inhibitors (TKI) have shown promising responses, however, these responses are almost transient in therapy-resistant AML. Here, we show that human mitochondrial NAD(P)+-dependent-malic enzyme 2 (ME2) have significantly increased in CD34+ cell of patients with AML. To determine how ME2 establish metabolic reprogramming of leukemogenesis, we performed a comprehensive analysis of metabolism in CRISPR-mediated ME2 knockout leukemic cells (THP-1 and MV4-11) and purified leukemic blast cells (CD34+) derived from patients with AML. We demonstrate that disrupting ME2 signaling exerts potent activities against proliferation, reduced oxidative metabolism and lactate metabolism. We also show that genetic inhibition of RUNX1/FLT3/ME2 markedly repressed AML cell leukemogenesis. In conclusion, our findings provide a rationale for clinical development of this strategy for treating RUNX1 and FLT3-mutated leukemic patients. Disclosures No relevant conflicts of interest to declare.

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Inhibitor of Multi-cyclin-dependent Kinases (AT7519) Reduced Survival of U937 Leukemic Cells and Enhanced Anti-leukemic Effect of Vincristine: A Highlight to CDK Inhibition Efficacy in Acute Leukemia

International Journal of Cancer Management ◽

10.5812/ijcm.101366 ◽

2021 ◽

Vol In Press (In Press) ◽

Author(s):

Fateme Moradi Moraddahande ◽

Mona Shameli Houjghan ◽

Amir-Mohammad Yousefi ◽

Ava Safaroghli-Azar ◽

Atieh Pourbagheri-Sigaroodi ◽

...

Keyword(s):

Cell Cycle ◽

Acute Myeloid Leukemia ◽

Acute Leukemia ◽

Myeloid Leukemia ◽

Leukemic Cells ◽

Mrna Levels ◽

U937 Cells ◽

Cyclin Dependent Kinases ◽

The Impact ◽

Acute Myeloid

Background: The conservative character of the cell cycle outlined that any dysregulation in the regulatory components of this process in normal cells opens a gate toward neoplastic transformation. Objectives: Given the critical role of cyclin-dependent kinases (CDKs) in cancer pathogenesis and based on their frequent aberrancy in human leukemia, the present study aimed at evaluating the suppressive effect of a multi-CDK inhibitor AT7519 on acute myeloid leukemia-derived U937 cells. Methods: To assess the anti-leukemic effects of the inhibitor on acute myeloid leukemia (AML) cells, we used MTT and trypan blue assays. Flow cytometric analysis and q-RT-PCR were also applied to evaluate the impact of AT7519 on cell cycle and apoptosis. Results: The results suggested that suppression of CDK in U937 cells hampered the proliferation of leukemic cells through a G2/M arrest mediated by p21 gene. Additionally, the anti-survival impact of AT7519 on these cells was shown to be along with the apoptosis initiation not only through the increment of pro-apoptotic gene expression but also through diminishing the mRNA levels of both Pin1 and Survivin. Notably, the potent anti-leukemic property of this agent has become more prominent when we found that the blockage of CDKs in AML cells could synergize with the cytotoxic effect of vincristine (VCR). To the best of our knowledge, little is known about the molecular mechanisms of resistance to AT7519 and we proposed that the effectiveness of this agent was partially attenuated through either c-Myc or autophagy activation in U937 cells. Conclusions: This study suggests that the pharmacological targeting of CDKs could probably unwind the complexity of therapeutic obstacles on the way of acute leukemia, either in the context of mono- or combined-modal strategy.

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Lineage tracing of acute myeloid leukemia reveals the impact of hypomethylating agents on chemoresistance selection

Nature Communications ◽

10.1038/s41467-019-12983-z ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 6

Author(s):

Francisco Caiado ◽

Diogo Maia-Silva ◽

Carolina Jardim ◽

Nina Schmolka ◽

Tânia Carvalho ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Dna Methyltransferase ◽

Cancer Recurrence ◽

Lineage Tracing ◽

Leukemic Cells ◽

The Impact ◽

Acute Myeloid

Abstract Chemotherapy-resistant cancer recurrence is a major cause of mortality. In acute myeloid leukemia (AML), chemorefractory relapses result from the complex interplay between altered genetic, epigenetic and transcriptional states in leukemic cells. Here, we develop an experimental model system using in vitro lineage tracing coupled with exome, transcriptome and in vivo functional readouts to assess the AML population dynamics and associated molecular determinants underpinning chemoresistance development. We find that combining standard chemotherapeutic regimens with low doses of DNA methyltransferase inhibitors (DNMTi, hypomethylating drugs) prevents chemoresistant relapses. Mechanistically, DNMTi suppresses the outgrowth of a pre-determined set of chemoresistant AML clones with stemness properties, instead favoring the expansion of rarer and unfit chemosensitive clones. Importantly, we confirm the capacity of DNMTi combination to suppress stemness-dependent chemoresistance development in xenotransplantation models and primary AML patient samples. Together, these results support the potential of DNMTi combination treatment to circumvent the development of chemorefractory AML relapses.

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The HLA-B −21 dimorphism impacts on NK cell education and clinical outcome of immunotherapy in acute myeloid leukemia

Blood ◽

10.1182/blood-2018-09-874990 ◽

2019 ◽

Vol 133 (13) ◽

pp. 1479-1488 ◽

Cited By ~ 14

Author(s):

Alexander Hallner ◽

Elin Bernson ◽

Brwa Ali Hussein ◽

Frida Ewald Sander ◽

Mats Brune ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Nk Cells ◽

Myeloid Leukemia ◽

Nk Cell ◽

Gene Segment ◽

Leukemic Cells ◽

Leader Peptide ◽

Target Cells ◽

The Impact ◽

Acute Myeloid

Abstract Natural killer (NK) cell function is regulated by inhibitory receptors, such as the family of killer immunoglobulin-like receptors (KIRs) and the NKG2A/CD94 heterodimer. These receptors recognize cognate HLA class I molecules on potential target cells, and recent studies imply that an HLA-B dimorphism at position −21 in the gene segment encoding the leader peptide dictates whether NK cell regulation primarily relies on the KIRs or the NKG2A/CD94 receptor. The impact of this HLA-B dimorphism on NK cell–mediated destruction of leukemic cells or on the course of leukemia is largely unknown. In a first part of this study, we compared functions of NK cells in subjects carrying HLA-B −21M or 21T using interleukin-2 (IL-2)–activated NK cells and leukemic cells from patients with acute myeloid leukemia (AML). Subjects carrying HLA-B −21M harbored better-educated NKG2A+ NK cells and displayed superior capacity to degranulate lytic granules against KIR ligand-matched primary leukemic blasts. Second, we aimed to define the potential impact of HLA-B −21 variation on the course of AML in a phase 4 trial in which patients received IL-2–based immunotherapy. In keeping with the hypothesis that 21M may be associated with improved NK cell functionality, we observed superior leukemia-free survival and overall survival in −21M patients than in −21T patients during IL-2–based immunotherapy. We propose that genetic variation at HLA-B −21 may determine the antileukemic efficacy of activated NK cells and the clinical benefit of NK cell–activating immunotherapy.

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Favorable Impact of the t(9;11) in Childhood Acute Myeloid Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2002.08.023 ◽

2002 ◽

Vol 20 (9) ◽

pp. 2302-2309 ◽

Cited By ~ 76

Author(s):

Jeffrey E. Rubnitz ◽

Susana C. Raimondi ◽

Xin Tong ◽

Deo Kumar Srivastava ◽

Bassem I. Razzouk ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Relative Risk ◽

Confidence Interval ◽

Myeloid Leukemia ◽

Cox Proportional Hazards Model ◽

The Other ◽

Leukemic Cells ◽

The Impact ◽

Risk Of Relapse ◽

Acute Myeloid

PURPOSE: To determine the impact of MLL rearrangements on the outcome of children with acute myeloid leukemia (AML). PATIENTS AND METHODS: We analyzed the clinical and biologic features of 298 infants and children with primary AML treated on four consecutive institutional clinical trials. The Kaplan-Meier method was used in survival analysis and the Cox proportional-hazards model was used to analyze the effect of potential prognostic factors on event-free survival (± 1 SE). RESULTS: Molecular studies of 152 cases detected 42 with MLL rearrangements. The karyotypes of these 42 revealed the t(9;11) (15 cases), abnormalities of chromosomes 10 and 11 (nine cases), the t(11;19) (four cases), other abnormalities of 11q23 (seven cases), and miscellaneous rearrangements (seven cases). Among these 42 patients, the 15 whose leukemic cells carried the t(9;11) had a better outcome (66% ± 15%) than the other 27 (25.9% ± 11.2%; P = .004). Cases with the t(9;11) were also characterized by M5 AML morphology (21 of 23 cases). Of the 63 patients with M5 AML, the 21 whose leukemic cells demonstrated the t(9;11) had a better outcome (71.1% ± 11%) than the other 42 (25.8% ± 7.9%; P = .0004). The only independent factors indicating a favorable prognosis were presenting leukocyte count less than 50 × 109/L (relative risk of relapse, 0.73; 95% confidence interval, 0.55 to 0.97; P = .03) and the t(9;11) (relative risk of relapse, 0.32; 95% confidence interval, 0.16 to 0.64; P = .002). CONCLUSION: We conclude that the t(9;11) is the most favorable genetic factor for patients with AML treated at our institution.

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AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations

Blood ◽

10.1182/blood-2009-05-223784 ◽

2009 ◽

Vol 114 (26) ◽

pp. 5352-5361 ◽

Cited By ~ 211

Author(s):

Jih-Luh Tang ◽

Hsin-An Hou ◽

Chien-Yuan Chen ◽

Chieh-Yu Liu ◽

Wen-Chien Chou ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

De Novo ◽

Remission Rate ◽

Adult Patients ◽

Poor Prognostic Factor ◽

The Impact ◽

Runx1 Mutation ◽

Acute Myeloid

AbstractSomatic mutation of the AML1/RUNX1(RUNX1) gene is seen in acute myeloid leukemia (AML) M0 subtype and in AML transformed from myelodysplastic syndrome, but the impact of this gene mutation on survival in AML patients remains unclear. In this study, we sought to determine the clinical implications of RUNX1 mutations in 470 adult patients with de novo non-M3 AML. Sixty-three distinct RUNX1 mutations were identified in 62 persons (13.2%); 32 were in N-terminal and 31, C-terminal. The RUNX1 mutation was closely associated with male sex, older age, lower lactic dehydrogenase value, French-American-British M0/M1 subtypes, and expression of HLA-DR and CD34, but inversely correlated with CD33, CD15, CD19, and CD56 expression. Furthermore, the mutation was positively associated with MLL/PTD but negatively associated with CEBPA and NPM1 mutations. AML patients with RUNX1 mutations had a significantly lower complete remission rate and shorter disease-free and overall survival than those without the mutation. Multivariate analysis demonstrated that RUNX1 mutation was an independent poor prognostic factor for overall survival. Sequential analysis in 133 patients revealed that none acquired novel RUNX1 mutations during clinical courses. Our findings provide evidence that RUNX1 mutations are associated with distinct biologic and clinical characteristics and poor prognosis in patients with de novo AML.

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Acute myeloid leukemia with leukemic pleural effusion and high levels of pleural adenosine deaminase: A case report and review of literature

Open Medicine ◽

10.1515/med-2021-0243 ◽

2021 ◽

Vol 16 (1) ◽

pp. 387-396

Author(s):

Sing-Ting Wang ◽

Chieh-Lung Chen ◽

Shih-Hsin Liang ◽

Shih-Peng Yeh ◽

Wen-Chien Cheng

Keyword(s):

Acute Myeloid Leukemia ◽

Pleural Effusion ◽

Adenosine Deaminase ◽

Myeloid Leukemia ◽

Diagnostic Yield ◽

Leukemic Cells ◽

Pleural Effusions ◽

Diagnostic Dilemma ◽

True Incidence ◽

Acute Myeloid

Abstract Pleural effusions are rarely observed in association with acute myeloid leukemia (AML), and their true incidence remains unknown. Given the low diagnostic yield from cytopathologic analysis of malignant pleural effusions and the fact that patients with leukemia are often thrombocytopenic and unable to tolerate invasive procedures, the incidence of leukemic effusions may be underestimated. Here, we report a rare case of pleural effusion in a patient with newly diagnosed AML. Initial analysis revealed an exudative, lymphocyte-predominant effusion. High levels of adenosine deaminase (ADA) were detected in pleural fluid, consistent with a diagnosis of tuberculosis. However, the analysis of pleural cytology revealed leukemic cells, permitting the diagnosis of leukemic effusion to be made. The patient underwent induction chemotherapy and pleural effusion resolved without recurrence. This case emphasizes the diagnostic dilemma presented by high levels of ADA in a leukemic pleural effusion, as this association has not been previously considered in the literature.

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