Integrated genomic-metabolic classification of acute myeloid leukemia defines a subgroup with NPM1 and cohesin/DNA damage mutations

Simonetti, Giorgia; Mengucci, Carlo; Padella, Antonella; Fonzi, Eugenio; Picone, Gianfranco; Delpino, Claudio; Nanni, Jacopo; Tommaso, Rossella De; Franchini, Eugenia; Papayannidis, Cristina; Marconi, Giovanni; Pazzaglia, Massimiliano; Perricone, Margherita; Scarpi, Emanuela; Fontana, Maria Chiara; Bruno, Samantha; Tebaldi, Michela; Ferrari, Anna; Bochicchio, Maria Teresa; Rorà, Andrea Ghelli Luserna di; Ghetti, Martina; Napolitano, Roberta; Astolfi, Annalisa; Baldazzi, Carmen; Guadagnuolo, Viviana; Ottaviani, Emanuela; Iacobucci, Ilaria; Cavo, Michèle; Castellani, Gastone; Haferlach, Torsten; Remondini, Daniel; Capozzi, Francesco; Martinelli, Giovanni

doi:10.1038/s41375-021-01318-x

Cited by 17 publications

(17 citation statements)

References 56 publications

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“…This data is consistent with previous findings showing 1,25VD3 controls G1-S phase-cycle machinery in human breast cancer cells by repressing the CCND1 gene [ 12 ]. A recent study suggests that numerous metabolic pathways except for gluconeogenesis can be therapeutically exploited to overcome the TKI-resistance [ 13 ], and inhibition of glutaminolysis can achieve a promising treatment effect on AML-FLT3 blasts [ 14 ]. Vitamin D supplementation has been also found to correct the metabolic disturbance caused by a fructose-rich diet [ 15 ].…”

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confidence: 99%

Vitamin D activates FBP1 to block the Warburg effect and modulate blast metabolism in acute myeloid leukemia

Hino

Baylink

et al. 2022

Biomark Res

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Acute myeloid leukemia (AML) has the lowest survival rate among the leukemias. Targeting intracellular metabolism and energy production in leukemic cells can be a promising therapeutic strategy for AML. Recently, we presented the successful use of vitamin D (1,25VD3) gene therapy to treat AML mouse models in vivo. In this study, recognizing the importance of 1,25VD3 as one of only 2 molecules (along with glucose) photosynthesized for energy during the beginning stage of life on this planet, we explored the functional role of 1,25VD3 in AML metabolism.Transcriptome database (RNA-seq) of four different AML cell lines revealed 17,757 genes responding to 1,25VD3-treatment. Moreover, we discovered that fructose-bisphosphatase 1 (FBP1) noticeably stands out as the only gene (out of 17,757 genes) with a 250-fold increase in gene expression, which is known to encode the key rate-limiting gluconeogenic enzyme fructose-1,6-bisphosphatase. The significant increased expression of FBP1 gene and proteins induced by 1,25VD3 was confirmed by qPCR, western blot, flow cytometry, immunocytochemistry and functional lactate assay. Additionally, 1,25VD3 was found to regulate different AML metabolic processes including gluconeogenesis, glycolysis, TCA, de novo nucleotide synthesis, etc. In summary, we provided the first evidence that 1,25 VD3-induced FBP1 overexpression might be a novel therapeutic target to block the “Warburg Effect” to reduce energy production in AML blasts.

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confidence: 99%

Vitamin D activates FBP1 to block the Warburg effect and modulate blast metabolism in acute myeloid leukemia

Hino

Baylink

et al. 2022

Biomark Res

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“…These data provided a pattern of the crosstalk between metabolic and genomicspathways in AML. These results, highlighted as an integrated genomic-metabolic study applied in pathology, could pave the way to personalized medicine [84].…”

Section: Systemic Metabolomic Profiling: the New Era Of Personalized Medicinementioning

confidence: 93%

Revealing the Mysteries of Acute Myeloid Leukemia: From Quantitative PCR through Next-Generation Sequencing and Systemic Metabolomic Profiling

Panuzzo

Jovanovski

Ali

et al. 2022

JCM

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The efforts made in the last decade regarding the molecular landscape of acute myeloid leukemia (AML) have created the possibility of obtaining patients’ personalized treatment. Indeed, the improvement of accurate diagnosis and precise assessment of minimal residual disease (MRD) increased the number of new markers suitable for novel and targeted therapies. This progress was obtained thanks to the development of molecular techniques starting with real-time quantitative PCR (Rt-qPCR) passing through digital droplet PCR (ddPCR) and next-generation sequencing (NGS) up to the new attractive metabolomic approach. The objective of this surge in technological advances is a better delineation of AML clonal heterogeneity, monitoring patients without disease-specific mutation and designing customized post-remission strategies based on MRD assessment. In this context, metabolomics, which pertains to overall small molecules profiling, emerged as relevant access for risk stratification and targeted therapies improvement. In this review, we performed a detailed overview of the most popular modern methods used in hematological laboratories, pointing out their vital importance for MRD monitoring in order to improve overall survival, early detection of possible relapses and treatment efficacy.

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“…According to public genomic data available on acute leukemias on the cBio portal [ 64 ] (TCGA-LAML [ 65 ] and Beat AML [ 66 ] datasets) and our cohort (NGS-PTL [ 67 , 68 ]), there is no evidence of genomic alterations of PARP1 in adult patients and few cases have been reported in pediatric cohorts [ 64 ] (2/295 in TARGET-AML [ 69 ], 0.7%; 8/819 in TARGET-ALL [ 70 ], 1.0%, Fig. 3 A and Table 2 ).…”

Section: Genomic Alterations Of Parps and Ddr Gene...mentioning

confidence: 99%

Targeting PARP proteins in acute leukemia: DNA damage response inhibition and therapeutic strategies

et al. 2022

Self Cite

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The members of the Poly(ADP‐ribose) polymerase (PARP) superfamily are involved in several biological processes and, in particular, in the DNA damage response (DDR). The most studied members, PARP1, PARP2 and PARP3, act as sensors of DNA damages, in order to activate different intracellular repair pathways, including single-strand repair, homologous recombination, conventional and alternative non-homologous end joining. This review recapitulates the functional role of PARPs in the DDR pathways, also in relationship with the cell cycle phases, which drives our knowledge of the mechanisms of action of PARP inhibitors (PARPi), encompassing inhibition of single-strand breaks and base excision repair, PARP trapping and sensitization to antileukemia immune responses. Several studies have demonstrated a preclinical activity of the current available PARPi, olaparib, rucaparib, niraparib, veliparib and talazoparib, as single agent and/or in combination with cytotoxic, hypomethylating or targeted drugs in acute leukemia, thus encouraging the development of clinical trials. We here summarize the most recent preclinical and clinical findings and discuss the synthetic lethal interactions of PARPi in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Despite the low frequency of genomic alterations of PARP and other DDR-related genes in acute leukemia, selective vulnerabilities have been reported in several disease subgroups, along with a “BRCAness phenotype.” AML carrying the RUNX1-RUNX1T1 or PML-RARA fusion genes or mutations in signaling genes (FLT3-ITD in combination with TET2 or TET2 and DNMT3A deficiency), cohesin complex members (STAG2), TP53 and BCOR as co-occurring lesions, IDH1/2 and ALL cases expressing the TCF3-HLF chimera or TET1 was highly sensitive to PARPi in preclinical studies. These data, along with the warning coming from the observation of cases of therapy-related myeloid malignancies among patients receiving PARPi for solid tumors treatment, indicate that PARPi represents a promising strategy in a personalized medicine setting. The characterization of the clonal and subclonal genetic background and of the DDR functionality is crucial to select acute leukemia patients that will likely benefit of PARPi-based therapeutic regimens.

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Integrated genomic-metabolic classification of acute myeloid leukemia defines a subgroup with NPM1 and cohesin/DNA damage mutations

Cited by 17 publications

References 56 publications

Vitamin D activates FBP1 to block the Warburg effect and modulate blast metabolism in acute myeloid leukemia

Vitamin D activates FBP1 to block the Warburg effect and modulate blast metabolism in acute myeloid leukemia

Revealing the Mysteries of Acute Myeloid Leukemia: From Quantitative PCR through Next-Generation Sequencing and Systemic Metabolomic Profiling

Targeting PARP proteins in acute leukemia: DNA damage response inhibition and therapeutic strategies

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