Low-dose lenalidomide plus cytarabine induce complete remission that can be predicted by genetic profiling in elderly acute myeloid leukemia patients

Visani, Giuseppe; Ferrara, Felicetto; Raimondo, Francesco Di; Loscocco, Federica; Sparaventi, Giovanni; Paolini, Stefania; Fuligni, Fabio; Gazzola, Anna; Rossi, Mosè; Laginestra, Maria Antonella; Caraci, Maria Rita; Riccardi, Cira; Rocchi, Marco; Visani, Axel; Pileri, S; Piccaluga, Pier Paolo; Isidori, Alessandro

doi:10.1038/leu.2014.31

Cited by 13 publications

(9 citation statements)

References 14 publications

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“…A, OS curves (Kaplan-Meier method) of AML patients treated with lenalidomide plus AraC classified into two groups [group 1, complete responders (CR), blue line; group 2, nonresponders (NR), red line] based on the expression of the entire NET-related inflammatory signature (support vector machine algorithm). B, Three genes belonging to the NET-related inflammatory signature were found among those differentially expressed according to the clinical response (complete responders vs. nonresponders achievement) in AML patients receiving lenalidomide plus AraC (24). C, OS curves (Kaplan-Meier method) of AML patients treated with lenalidomide plus AraC classified into two groups (group 1, complete responders, blue line; group 2, nonresponders, red line) based on the three genes of the NET-related inflammatory signature (C5AR1, NFKBIA, IRF7; support vector machine algorithm).…”

Section: Discussionmentioning

confidence: 99%

“…We also analyzed 461 AML cases for which gene expression data and information on the NPM1 status (mutated vs. wild type) were available (GEO Access: GSE6891; refs. 22, 23) and 15 AML cases included in a phase II clinical trial testing the combination of lenalidomide and cytarabine (LenAra) and for which our group previously generated GEP (24). Each case was assigned to either group 1 or 2 based on the expression of the NET-related inflammatory signature.…”

Section: In Vitro Cultures Of Linmentioning

confidence: 99%

“…The NET-related inflammatory gene signature predicts response to immunomodulatory drugs To assess the potential clinical impact of NET-related inflammatory features, we applied our signature to a cohort of high-risk AML patients (N ¼ 26; complete responders ¼ 14; nonresponders ¼ 12) treated with the combination of chemotherapy and the immunomodulatory drug lenalidomide (24). The molecular signature associated with complete response (24) significantly overlapped with the NET-related inflammatory signature (c 2 , P ¼ 0.03), being also enriched in genes characteristic of NPM1 mutated AML.…”

Section: Npmc Mutation Affects the Netosis Of Pmn And Net-induced Promentioning

confidence: 99%

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Persistent Immune Stimulation Exacerbates Genetically Driven Myeloproliferative Disorders via Stromal Remodeling

et al. 2017

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Systemic immune stimulation has been associated with increased risk of myeloid malignancies, but the pathogenic link is unknown. We demonstrate in animal models that experimental systemic immune activation alters the bone marrow stromal microenvironment, disarranging extracellular matrix (ECM) microarchitecture, with downregulation of secreted protein acidic and rich in cysteine (SPARC) and collagen-I and induction of complement activation. These changes were accompanied by a decrease in Treg frequency and by an increase in activated effector T cells. Under these conditions, hematopoietic precursors harboring nucleophosmin-1 (NPM1) mutation generated myeloid cells unfit for normal hematopoiesis but prone to immunogenic death, leading to neutrophil extracellular trap (NET) formation. NET fostered the progression of the indolent NPM1-driven myeloproliferation toward an exacerbated and proliferative dysplastic phenotype. Enrichment in NET structures was found in the bone marrow of patients with autoimmune disorders and in NPM1-mutated acute myelogenous leukemia (AML) patients. Genes involved in NET formation in the animal model were used to design a NET-related inflammatory gene signature for human myeloid malignancies. This signature identified two AML subsets with different genetic complexity and different enrichment in NPM1 mutation and predicted the response to immunomodulatory drugs. Our results indicate that stromal/ECM changes and priming of bone marrow NETosis by systemic inflammatory conditions can complement genetic and epigenetic events towards the development and progression of myeloid malignancy.

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Section: Discussionmentioning

confidence: 99%

Section: In Vitro Cultures Of Linmentioning

confidence: 99%

Section: Npmc Mutation Affects the Netosis Of Pmn And Net-induced Promentioning

confidence: 99%

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Persistent Immune Stimulation Exacerbates Genetically Driven Myeloproliferative Disorders via Stromal Remodeling

et al. 2017

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“…However, current AML treatment still relies on allogeneic hematopoietic stem cell transplantation and intensive chemotherapy, which cannot be tolerated by many aged patients [4]. As a consequence, only 10% of AML patients aged over 60 years old can be cured by current available therapeutic approaches [5,6].…”

Section: Introductionmentioning

confidence: 99%

LncRNA SNHG4 regulates miR-10a/PTEN to inhibit the proliferation of acute myeloid leukemia cells

Yuan¹,

Wang

2020

Hematology

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Objectives: Long non-coding RNA (lncRNA) small nucleolar RNA host gene 4 (SNHG4) is a characterized oncogenic lncRNA in osteosarcoma. The analysis of the TCGA dataset suggested the downregulation of SNHG4 in acute myeloid leukemia (AML), indicating its possible involvement in this disease. Therefore, this study was performed to analyze the interaction between SNHG4 and miR-10a in AML. Methods: We included 60 patients with AML and 60 healthy participants. Transient transfections, luciferase activity assay, RT-qPCR, CCK-8, and Western blot were used to carry out the research. Results: In this study, we found that SNHG4 was downregulated in AML patients compared to healthy participants. SNHG4 and miR-10a can interact with each other. However, overexpression of SNHG4 and miR-10a failed to affect the expression of each other. Instead, SNHG4 overexpression led to upregulated PTEN, a downstream target of miR-10a. Cell proliferation analysis showed that SNHG4 and PTEN overexpression led to decreased proliferation rates of AML cells and attenuated the enhancing effects of miR-10a on cell proliferation. Conclusion: In conclusion, SNHG4 may regulate miR-10a/PTEN to inhibit the proliferation of AML cells.

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“…Very recently, our group has shown the prospective use of a GEP-driven therapy in a cohort of hard-to-treat AML patients, unfit for standard therapy, with an extremely poor prognosis [18,19]. 66 unfit AML patients aged >70 years received low-dose lenalidomide plus low dose cytarabine [18,19] By studying the global GEP of AML blasts collected before treatment administration, we were able to identify five genes efficiently discriminating patients who did or did not obtain CR.…”

mentioning

confidence: 99%

Genomic Profiling and Predicting Treatment Response in Acute Myeloid Leukemia

Isidori¹,

Loscocco²,

Curti

et al. 2019

Pharmacogenomics

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Low-dose lenalidomide plus cytarabine induce complete remission that can be predicted by genetic profiling in elderly acute myeloid leukemia patients

Cited by 13 publications

References 14 publications

Persistent Immune Stimulation Exacerbates Genetically Driven Myeloproliferative Disorders via Stromal Remodeling

Persistent Immune Stimulation Exacerbates Genetically Driven Myeloproliferative Disorders via Stromal Remodeling

LncRNA SNHG4 regulates miR-10a/PTEN to inhibit the proliferation of acute myeloid leukemia cells

Genomic Profiling and Predicting Treatment Response in Acute Myeloid Leukemia

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