Expression profile and specific network features of the apoptotic machinery explain relapse of acute myeloid leukemia after chemotherapy

Marco Ragusa, Giuseppe Avola, Rosario Angelica, Davide Barbagallo, Maria R. Guglielmino, Laura R. Duro, Alessandra Majorana, Luisa Statello, Loredana Salito, Carla Consoli, Maria G. Camuglia, Cinzia Di Pietro, Giuseppe Milone, Michele Purrello

Research output: Contribution to journalArticle

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Abstract

Background: According to the different sensitivity of their bone marrow CD34+ cells to in vitro treatment with Etoposide or Mafosfamide, Acute Myeloid Leukaemia (AML) patients in apparent complete remission (CR) after chemotherapy induction may be classified into three groups: (i) normally responsive; (ii) chemoresistant; (iii) highly chemosensitive. This inversely correlates with in vivo CD34+ mobilization and, interestingly, also with the prognosis of the disease: patients showing a good mobilizing activity are resistant to chemotherapy and subject to significantly higher rates of Minimal Residual Disease (MRD) and relapse than the others. Based on its known role in patients' response to chemotherapy, we hypothesized an involvement of the Apoptotic Machinery (AM) in these phenotypic features.Methods: To investigate the molecular bases of the differential chemosensitivity of bone marrow hematopoietic stem cells (HSC) in CR AML patients, and the relationship between chemosensitivity, mobilizing activity and relapse rates, we analyzed their AM expression profile by performing Real Time RT-PCR of 84 AM genes in CD34+ pools from the two extreme classes of patients (i.e., chemoresistant and highly chemosensitive), and compared them with normal controls.Results: The AM expression profiles of patients highlighted features that could satisfactorily explain their in vitro chemoresponsive phenotype: specifically, in chemoresistant patients we detected up regulation of antiapoptotic BIRC genes and down regulation of proapoptotic APAF1, FAS, FASL, TNFRSF25. Interestingly, our analysis of the AM network showed that the dysregulated genes in these patients are characterized by high network centrality (i.e., high values of betweenness, closeness, radiality, stress) and high involvement in drug response.Conclusions: AM genes represent critical nodes for the proper execution of cell death following pharmacological induction in patients. We propose that their dysregulation (either due to inborn or de novo genomic mutations selected by treatment) could cause a relapse in apparent CR AML patients. Based on this, AM profiling before chemotherapy and transplantation could identify patients with a predisposing genotype to MRD and relapse: accordingly, they should undergo a different, specifically tailored, therapeutic regimen and should be carefully checked during the post-treatment period.

Original languageEnglish
Article number377
JournalBMC Cancer
Volume10
DOIs
Publication statusPublished - Jul 19 2010

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Acute Myeloid Leukemia
Recurrence
Drug Therapy
Residual Neoplasm
Genes
Induction Chemotherapy
Etoposide
Therapeutics
Hematopoietic Stem Cells
Bone Marrow Cells
Real-Time Polymerase Chain Reaction
Cell Death
Up-Regulation
Down-Regulation
Transplantation
Bone Marrow
Genotype
Pharmacology
Phenotype
Mutation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Genetics

Cite this

Ragusa, M., Avola, G., Angelica, R., Barbagallo, D., Guglielmino, M. R., Duro, L. R., ... Purrello, M. (2010). Expression profile and specific network features of the apoptotic machinery explain relapse of acute myeloid leukemia after chemotherapy. BMC Cancer, 10, [377]. https://doi.org/10.1186/1471-2407-10-377

Expression profile and specific network features of the apoptotic machinery explain relapse of acute myeloid leukemia after chemotherapy. / Ragusa, Marco; Avola, Giuseppe; Angelica, Rosario; Barbagallo, Davide; Guglielmino, Maria R.; Duro, Laura R.; Majorana, Alessandra; Statello, Luisa; Salito, Loredana; Consoli, Carla; Camuglia, Maria G.; Di Pietro, Cinzia; Milone, Giuseppe; Purrello, Michele.

In: BMC Cancer, Vol. 10, 377, 19.07.2010.

Research output: Contribution to journalArticle

Ragusa, M, Avola, G, Angelica, R, Barbagallo, D, Guglielmino, MR, Duro, LR, Majorana, A, Statello, L, Salito, L, Consoli, C, Camuglia, MG, Di Pietro, C, Milone, G & Purrello, M 2010, 'Expression profile and specific network features of the apoptotic machinery explain relapse of acute myeloid leukemia after chemotherapy', BMC Cancer, vol. 10, 377. https://doi.org/10.1186/1471-2407-10-377
Ragusa, Marco ; Avola, Giuseppe ; Angelica, Rosario ; Barbagallo, Davide ; Guglielmino, Maria R. ; Duro, Laura R. ; Majorana, Alessandra ; Statello, Luisa ; Salito, Loredana ; Consoli, Carla ; Camuglia, Maria G. ; Di Pietro, Cinzia ; Milone, Giuseppe ; Purrello, Michele. / Expression profile and specific network features of the apoptotic machinery explain relapse of acute myeloid leukemia after chemotherapy. In: BMC Cancer. 2010 ; Vol. 10.
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abstract = "Background: According to the different sensitivity of their bone marrow CD34+ cells to in vitro treatment with Etoposide or Mafosfamide, Acute Myeloid Leukaemia (AML) patients in apparent complete remission (CR) after chemotherapy induction may be classified into three groups: (i) normally responsive; (ii) chemoresistant; (iii) highly chemosensitive. This inversely correlates with in vivo CD34+ mobilization and, interestingly, also with the prognosis of the disease: patients showing a good mobilizing activity are resistant to chemotherapy and subject to significantly higher rates of Minimal Residual Disease (MRD) and relapse than the others. Based on its known role in patients' response to chemotherapy, we hypothesized an involvement of the Apoptotic Machinery (AM) in these phenotypic features.Methods: To investigate the molecular bases of the differential chemosensitivity of bone marrow hematopoietic stem cells (HSC) in CR AML patients, and the relationship between chemosensitivity, mobilizing activity and relapse rates, we analyzed their AM expression profile by performing Real Time RT-PCR of 84 AM genes in CD34+ pools from the two extreme classes of patients (i.e., chemoresistant and highly chemosensitive), and compared them with normal controls.Results: The AM expression profiles of patients highlighted features that could satisfactorily explain their in vitro chemoresponsive phenotype: specifically, in chemoresistant patients we detected up regulation of antiapoptotic BIRC genes and down regulation of proapoptotic APAF1, FAS, FASL, TNFRSF25. Interestingly, our analysis of the AM network showed that the dysregulated genes in these patients are characterized by high network centrality (i.e., high values of betweenness, closeness, radiality, stress) and high involvement in drug response.Conclusions: AM genes represent critical nodes for the proper execution of cell death following pharmacological induction in patients. We propose that their dysregulation (either due to inborn or de novo genomic mutations selected by treatment) could cause a relapse in apparent CR AML patients. Based on this, AM profiling before chemotherapy and transplantation could identify patients with a predisposing genotype to MRD and relapse: accordingly, they should undergo a different, specifically tailored, therapeutic regimen and should be carefully checked during the post-treatment period.",
author = "Marco Ragusa and Giuseppe Avola and Rosario Angelica and Davide Barbagallo and Guglielmino, {Maria R.} and Duro, {Laura R.} and Alessandra Majorana and Luisa Statello and Loredana Salito and Carla Consoli and Camuglia, {Maria G.} and {Di Pietro}, Cinzia and Giuseppe Milone and Michele Purrello",
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AU - Ragusa, Marco

AU - Avola, Giuseppe

AU - Angelica, Rosario

AU - Barbagallo, Davide

AU - Guglielmino, Maria R.

AU - Duro, Laura R.

AU - Majorana, Alessandra

AU - Statello, Luisa

AU - Salito, Loredana

AU - Consoli, Carla

AU - Camuglia, Maria G.

AU - Di Pietro, Cinzia

AU - Milone, Giuseppe

AU - Purrello, Michele

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N2 - Background: According to the different sensitivity of their bone marrow CD34+ cells to in vitro treatment with Etoposide or Mafosfamide, Acute Myeloid Leukaemia (AML) patients in apparent complete remission (CR) after chemotherapy induction may be classified into three groups: (i) normally responsive; (ii) chemoresistant; (iii) highly chemosensitive. This inversely correlates with in vivo CD34+ mobilization and, interestingly, also with the prognosis of the disease: patients showing a good mobilizing activity are resistant to chemotherapy and subject to significantly higher rates of Minimal Residual Disease (MRD) and relapse than the others. Based on its known role in patients' response to chemotherapy, we hypothesized an involvement of the Apoptotic Machinery (AM) in these phenotypic features.Methods: To investigate the molecular bases of the differential chemosensitivity of bone marrow hematopoietic stem cells (HSC) in CR AML patients, and the relationship between chemosensitivity, mobilizing activity and relapse rates, we analyzed their AM expression profile by performing Real Time RT-PCR of 84 AM genes in CD34+ pools from the two extreme classes of patients (i.e., chemoresistant and highly chemosensitive), and compared them with normal controls.Results: The AM expression profiles of patients highlighted features that could satisfactorily explain their in vitro chemoresponsive phenotype: specifically, in chemoresistant patients we detected up regulation of antiapoptotic BIRC genes and down regulation of proapoptotic APAF1, FAS, FASL, TNFRSF25. Interestingly, our analysis of the AM network showed that the dysregulated genes in these patients are characterized by high network centrality (i.e., high values of betweenness, closeness, radiality, stress) and high involvement in drug response.Conclusions: AM genes represent critical nodes for the proper execution of cell death following pharmacological induction in patients. We propose that their dysregulation (either due to inborn or de novo genomic mutations selected by treatment) could cause a relapse in apparent CR AML patients. Based on this, AM profiling before chemotherapy and transplantation could identify patients with a predisposing genotype to MRD and relapse: accordingly, they should undergo a different, specifically tailored, therapeutic regimen and should be carefully checked during the post-treatment period.

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