Nilotinib interferes with cell cycle, ABC transporters and JAK-STAT signaling pathway in CD34+/lin- cells of patients with chronic phase chronic myeloid leukemia after 12 months of treatment

Alessandra Trojani, Ester Pungolino, Alessandra Dal Molin, Milena Lodola, Giuseppe Rossi, Mariella D’Adda, Alessandra Perego, Chiara Elena, Mauro Turrini, Lorenza Borin, Cristina Bucelli, Simona Malato, Maria Cristina Carraro, Francesco Spina, Maria Luisa Latargia, Salvatore Artale, Pierangelo Spedini, Michela Anghilieri, Barbara Di Camillo, Giacomo Baruzzo & 4 others Gabriella De Canal, Alessandra Iurlo, Enrica Morra, Roberto Cairoli

Research output: Contribution to journalArticle

Abstract

Chronic myeloid leukemia (CML) is characterized by the constitutive tyrosine kinase activity of the oncoprotein BCR-ABL1 in myeloid progenitor cells that activates multiple signal transduction pathways leading to the leukemic phenotype. The tyrosine-kinase inhibitor (TKI) nilotinib inhibits the tyrosine kinase activity of BCR-ABL1 in CML patients. Despite the success of nilotinib treatment in patients with chronic-phase (CP) CML, a population of Philadelphia-positive (Ph+) quiescent stem cells escapes the drug activity and can lead to drug resistance. The molecular mechanism by which these quiescent cells remain insensitive is poorly understood. The aim of this study was to compare the gene expression profiling (GEP) of bone marrow (BM) CD34+/lin- cells from CP-CML patients at diagnosis and after 12 months of nilotinib treatment by microarray, in order to identify gene expression changes and the dysregulation of pathways due to nilotinib action. We selected BM CD34+/lin- cells from 78 CP-CML patients at diagnosis and after 12 months of first-line nilotinib therapy and microarray analysis was performed. GEP bioinformatic analyses identified 2,959 differently expressed probes and functional clustering determined some significantly enriched pathways between diagnosis and 12 months of nilotinib treatment. Among these pathways, we observed the under expression of 26 genes encoding proteins belonging to the cell cycle after 12 months of nilotinib treatment which led to the up-regulation of chromosome replication, cell proliferation, DNA replication, and DNA damage checkpoint at diagnosis. We demonstrated the under expression of the ATP-binding cassette (ABC) transporters ABCC4, ABCC5, and ABCD3 encoding proteins which pumped drugs out of the cells after 12 months of nilotinib. Moreover, GEP data demonstrated the deregulation of genes involved in the JAK-STAT signaling pathway. The down-regulation of JAK2, IL7, STAM, PIK3CA, PTPN11, RAF1, and SOS1 key genes after 12 months of nilotinib could demonstrate the up-regulation of cell cycle, proliferation and differentiation via MAPK and PI3K-AKT signaling pathways at diagnosis.

Original languageEnglish
Article numbere0218444
JournalPLoS One
Volume14
Issue number7
DOIs
Publication statusPublished - Jan 1 2019

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Leukemia, Myeloid, Chronic Phase
myeloid leukemia
ABC transporters
ATP-Binding Cassette Transporters
cell cycle
Cell Cycle
Cells
tyrosine
gene expression
phosphotransferases (kinases)
Gene expression
bone marrow
Gene Expression Profiling
cells
stem cells
Protein-Tyrosine Kinases
Therapeutics
drugs
genes
Microarrays

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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Nilotinib interferes with cell cycle, ABC transporters and JAK-STAT signaling pathway in CD34+/lin- cells of patients with chronic phase chronic myeloid leukemia after 12 months of treatment. / Trojani, Alessandra; Pungolino, Ester; Molin, Alessandra Dal; Lodola, Milena; Rossi, Giuseppe; D’Adda, Mariella; Perego, Alessandra; Elena, Chiara; Turrini, Mauro; Borin, Lorenza; Bucelli, Cristina; Malato, Simona; Carraro, Maria Cristina; Spina, Francesco; Latargia, Maria Luisa; Artale, Salvatore; Spedini, Pierangelo; Anghilieri, Michela; Camillo, Barbara Di; Baruzzo, Giacomo; De Canal, Gabriella; Iurlo, Alessandra; Morra, Enrica; Cairoli, Roberto.

In: PLoS One, Vol. 14, No. 7, e0218444, 01.01.2019.

Research output: Contribution to journalArticle

Trojani, A, Pungolino, E, Molin, AD, Lodola, M, Rossi, G, D’Adda, M, Perego, A, Elena, C, Turrini, M, Borin, L, Bucelli, C, Malato, S, Carraro, MC, Spina, F, Latargia, ML, Artale, S, Spedini, P, Anghilieri, M, Camillo, BD, Baruzzo, G, De Canal, G, Iurlo, A, Morra, E & Cairoli, R 2019, 'Nilotinib interferes with cell cycle, ABC transporters and JAK-STAT signaling pathway in CD34+/lin- cells of patients with chronic phase chronic myeloid leukemia after 12 months of treatment', PLoS One, vol. 14, no. 7, e0218444. https://doi.org/10.1371/journal.pone.0218444
Trojani, Alessandra ; Pungolino, Ester ; Molin, Alessandra Dal ; Lodola, Milena ; Rossi, Giuseppe ; D’Adda, Mariella ; Perego, Alessandra ; Elena, Chiara ; Turrini, Mauro ; Borin, Lorenza ; Bucelli, Cristina ; Malato, Simona ; Carraro, Maria Cristina ; Spina, Francesco ; Latargia, Maria Luisa ; Artale, Salvatore ; Spedini, Pierangelo ; Anghilieri, Michela ; Camillo, Barbara Di ; Baruzzo, Giacomo ; De Canal, Gabriella ; Iurlo, Alessandra ; Morra, Enrica ; Cairoli, Roberto. / Nilotinib interferes with cell cycle, ABC transporters and JAK-STAT signaling pathway in CD34+/lin- cells of patients with chronic phase chronic myeloid leukemia after 12 months of treatment. In: PLoS One. 2019 ; Vol. 14, No. 7.
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abstract = "Chronic myeloid leukemia (CML) is characterized by the constitutive tyrosine kinase activity of the oncoprotein BCR-ABL1 in myeloid progenitor cells that activates multiple signal transduction pathways leading to the leukemic phenotype. The tyrosine-kinase inhibitor (TKI) nilotinib inhibits the tyrosine kinase activity of BCR-ABL1 in CML patients. Despite the success of nilotinib treatment in patients with chronic-phase (CP) CML, a population of Philadelphia-positive (Ph+) quiescent stem cells escapes the drug activity and can lead to drug resistance. The molecular mechanism by which these quiescent cells remain insensitive is poorly understood. The aim of this study was to compare the gene expression profiling (GEP) of bone marrow (BM) CD34+/lin- cells from CP-CML patients at diagnosis and after 12 months of nilotinib treatment by microarray, in order to identify gene expression changes and the dysregulation of pathways due to nilotinib action. We selected BM CD34+/lin- cells from 78 CP-CML patients at diagnosis and after 12 months of first-line nilotinib therapy and microarray analysis was performed. GEP bioinformatic analyses identified 2,959 differently expressed probes and functional clustering determined some significantly enriched pathways between diagnosis and 12 months of nilotinib treatment. Among these pathways, we observed the under expression of 26 genes encoding proteins belonging to the cell cycle after 12 months of nilotinib treatment which led to the up-regulation of chromosome replication, cell proliferation, DNA replication, and DNA damage checkpoint at diagnosis. We demonstrated the under expression of the ATP-binding cassette (ABC) transporters ABCC4, ABCC5, and ABCD3 encoding proteins which pumped drugs out of the cells after 12 months of nilotinib. Moreover, GEP data demonstrated the deregulation of genes involved in the JAK-STAT signaling pathway. The down-regulation of JAK2, IL7, STAM, PIK3CA, PTPN11, RAF1, and SOS1 key genes after 12 months of nilotinib could demonstrate the up-regulation of cell cycle, proliferation and differentiation via MAPK and PI3K-AKT signaling pathways at diagnosis.",
author = "Alessandra Trojani and Ester Pungolino and Molin, {Alessandra Dal} and Milena Lodola and Giuseppe Rossi and Mariella D’Adda and Alessandra Perego and Chiara Elena and Mauro Turrini and Lorenza Borin and Cristina Bucelli and Simona Malato and Carraro, {Maria Cristina} and Francesco Spina and Latargia, {Maria Luisa} and Salvatore Artale and Pierangelo Spedini and Michela Anghilieri and Camillo, {Barbara Di} and Giacomo Baruzzo and {De Canal}, Gabriella and Alessandra Iurlo and Enrica Morra and Roberto Cairoli",
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T1 - Nilotinib interferes with cell cycle, ABC transporters and JAK-STAT signaling pathway in CD34+/lin- cells of patients with chronic phase chronic myeloid leukemia after 12 months of treatment

AU - Trojani, Alessandra

AU - Pungolino, Ester

AU - Molin, Alessandra Dal

AU - Lodola, Milena

AU - Rossi, Giuseppe

AU - D’Adda, Mariella

AU - Perego, Alessandra

AU - Elena, Chiara

AU - Turrini, Mauro

AU - Borin, Lorenza

AU - Bucelli, Cristina

AU - Malato, Simona

AU - Carraro, Maria Cristina

AU - Spina, Francesco

AU - Latargia, Maria Luisa

AU - Artale, Salvatore

AU - Spedini, Pierangelo

AU - Anghilieri, Michela

AU - Camillo, Barbara Di

AU - Baruzzo, Giacomo

AU - De Canal, Gabriella

AU - Iurlo, Alessandra

AU - Morra, Enrica

AU - Cairoli, Roberto

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Chronic myeloid leukemia (CML) is characterized by the constitutive tyrosine kinase activity of the oncoprotein BCR-ABL1 in myeloid progenitor cells that activates multiple signal transduction pathways leading to the leukemic phenotype. The tyrosine-kinase inhibitor (TKI) nilotinib inhibits the tyrosine kinase activity of BCR-ABL1 in CML patients. Despite the success of nilotinib treatment in patients with chronic-phase (CP) CML, a population of Philadelphia-positive (Ph+) quiescent stem cells escapes the drug activity and can lead to drug resistance. The molecular mechanism by which these quiescent cells remain insensitive is poorly understood. The aim of this study was to compare the gene expression profiling (GEP) of bone marrow (BM) CD34+/lin- cells from CP-CML patients at diagnosis and after 12 months of nilotinib treatment by microarray, in order to identify gene expression changes and the dysregulation of pathways due to nilotinib action. We selected BM CD34+/lin- cells from 78 CP-CML patients at diagnosis and after 12 months of first-line nilotinib therapy and microarray analysis was performed. GEP bioinformatic analyses identified 2,959 differently expressed probes and functional clustering determined some significantly enriched pathways between diagnosis and 12 months of nilotinib treatment. Among these pathways, we observed the under expression of 26 genes encoding proteins belonging to the cell cycle after 12 months of nilotinib treatment which led to the up-regulation of chromosome replication, cell proliferation, DNA replication, and DNA damage checkpoint at diagnosis. We demonstrated the under expression of the ATP-binding cassette (ABC) transporters ABCC4, ABCC5, and ABCD3 encoding proteins which pumped drugs out of the cells after 12 months of nilotinib. Moreover, GEP data demonstrated the deregulation of genes involved in the JAK-STAT signaling pathway. The down-regulation of JAK2, IL7, STAM, PIK3CA, PTPN11, RAF1, and SOS1 key genes after 12 months of nilotinib could demonstrate the up-regulation of cell cycle, proliferation and differentiation via MAPK and PI3K-AKT signaling pathways at diagnosis.

AB - Chronic myeloid leukemia (CML) is characterized by the constitutive tyrosine kinase activity of the oncoprotein BCR-ABL1 in myeloid progenitor cells that activates multiple signal transduction pathways leading to the leukemic phenotype. The tyrosine-kinase inhibitor (TKI) nilotinib inhibits the tyrosine kinase activity of BCR-ABL1 in CML patients. Despite the success of nilotinib treatment in patients with chronic-phase (CP) CML, a population of Philadelphia-positive (Ph+) quiescent stem cells escapes the drug activity and can lead to drug resistance. The molecular mechanism by which these quiescent cells remain insensitive is poorly understood. The aim of this study was to compare the gene expression profiling (GEP) of bone marrow (BM) CD34+/lin- cells from CP-CML patients at diagnosis and after 12 months of nilotinib treatment by microarray, in order to identify gene expression changes and the dysregulation of pathways due to nilotinib action. We selected BM CD34+/lin- cells from 78 CP-CML patients at diagnosis and after 12 months of first-line nilotinib therapy and microarray analysis was performed. GEP bioinformatic analyses identified 2,959 differently expressed probes and functional clustering determined some significantly enriched pathways between diagnosis and 12 months of nilotinib treatment. Among these pathways, we observed the under expression of 26 genes encoding proteins belonging to the cell cycle after 12 months of nilotinib treatment which led to the up-regulation of chromosome replication, cell proliferation, DNA replication, and DNA damage checkpoint at diagnosis. We demonstrated the under expression of the ATP-binding cassette (ABC) transporters ABCC4, ABCC5, and ABCD3 encoding proteins which pumped drugs out of the cells after 12 months of nilotinib. Moreover, GEP data demonstrated the deregulation of genes involved in the JAK-STAT signaling pathway. The down-regulation of JAK2, IL7, STAM, PIK3CA, PTPN11, RAF1, and SOS1 key genes after 12 months of nilotinib could demonstrate the up-regulation of cell cycle, proliferation and differentiation via MAPK and PI3K-AKT signaling pathways at diagnosis.

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