The Polycomb BMI1 Protein Is Co-expressed With CD26+ in Leukemic Stem Cells of Chronic Myeloid Leukemia

Sara Galimberti, Susanna Grassi, Claudia Baratè, Francesca Guerrini, Elena Ciabatti, Francesca Perutelli, Federica Ricci, Giada Del Genio, Marina Montali, Serena Barachini, Cecilia Giuliani, Maria Immacolata Ferreri, Angelo Valetto, Elisabetta Abruzzese, Chiara Ippolito, Alessandra Iurlo, Monica Bocchia, Anna Sicuranza, Bruno Martino, Lorenzo IovinoGabriele Buda, Serena Salehzadeh, Mario Petrini, Antonello Di Paolo, Letizia Mattii

Research output: Contribution to journalArticle

Abstract

The Polycomb gene BMI1 expression exerts a negative predictive impact on several hematological malignancies, such as acute and chronic myeloid leukemia (CML), myelofibrosis, and follicular lymphoma. As already demonstrated in CML, BMI1 is responsible for the resistance to the tyrosine kinase inhibitors (TKIs) in a BCR-ABL1-independent way. Even if, it is unknown where BMI1 in CML is expressed (in progenitors or more mature cells). We decided, therefore, to evaluate if and where the BMI1 protein is located, focusing mainly on the CD34+/CD38-/CD26+ CML progenitors. To begin we measured, by flow cytometry, the proportion of CD34+/CD26+ cells in 31 bone marrow samples from 20 CML patients, at diagnosis and during treatment with imatinib. After that the bone marrow blood smears were stained with antibodies anti-CD26, BCR-ABL1, and BMI1. These smears were observed by a confocal laser microscope and a 3D reconstruction was then performed. At diagnosis, CD34+/CD26+ cells median value/μL was 0.48; this number increased from diagnosis to the third month of therapy and then reduced during treatment with imatinib. The number and behavior of the CD26+ progenitors were independent from the BCR-ABL1 expression, but they summed up what previously observed about the BMI1 expression modulation. In this work we demonstrate for the first time that in CML the BMI1 protein is co-expressed with BCR-ABL1 only in the cytoplasm of the CD26+ precursors; on the contrary, in other hematological malignancies where BMI1 is commonly expressed (follicular lymphoma, essential thrombocytemia, acute myeloid leukemia), it was not co-localized with CD26 or, obviously, with BCR-ABL1. Once translated into the clinical context, if BMI1 is a marker of stemness, our results would suggest the combination of the BMI1 inhibitors with TKIs as an interesting object of research, and, probably, as a promising way to overcome resistance in CML patients.

Original languageEnglish
Pages (from-to)555
JournalFrontiers in Oncology
Volume8
DOIs
Publication statusPublished - 2018

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Stem Cells
Proteins
Follicular Lymphoma
Hematologic Neoplasms
Acute Myeloid Leukemia
Protein-Tyrosine Kinases
Bone Marrow
Primary Myelofibrosis
Anti-Idiotypic Antibodies
Flow Cytometry
Cytoplasm
Lasers
Therapeutics
Gene Expression
Research

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Galimberti, S., Grassi, S., Baratè, C., Guerrini, F., Ciabatti, E., Perutelli, F., ... Mattii, L. (2018). The Polycomb BMI1 Protein Is Co-expressed With CD26+ in Leukemic Stem Cells of Chronic Myeloid Leukemia. Frontiers in Oncology, 8, 555. https://doi.org/10.3389/fonc.2018.00555

The Polycomb BMI1 Protein Is Co-expressed With CD26+ in Leukemic Stem Cells of Chronic Myeloid Leukemia. / Galimberti, Sara; Grassi, Susanna; Baratè, Claudia; Guerrini, Francesca; Ciabatti, Elena; Perutelli, Francesca; Ricci, Federica; Del Genio, Giada; Montali, Marina; Barachini, Serena; Giuliani, Cecilia; Ferreri, Maria Immacolata; Valetto, Angelo; Abruzzese, Elisabetta; Ippolito, Chiara; Iurlo, Alessandra; Bocchia, Monica; Sicuranza, Anna; Martino, Bruno; Iovino, Lorenzo; Buda, Gabriele; Salehzadeh, Serena; Petrini, Mario; Di Paolo, Antonello; Mattii, Letizia.

In: Frontiers in Oncology, Vol. 8, 2018, p. 555.

Research output: Contribution to journalArticle

Galimberti, S, Grassi, S, Baratè, C, Guerrini, F, Ciabatti, E, Perutelli, F, Ricci, F, Del Genio, G, Montali, M, Barachini, S, Giuliani, C, Ferreri, MI, Valetto, A, Abruzzese, E, Ippolito, C, Iurlo, A, Bocchia, M, Sicuranza, A, Martino, B, Iovino, L, Buda, G, Salehzadeh, S, Petrini, M, Di Paolo, A & Mattii, L 2018, 'The Polycomb BMI1 Protein Is Co-expressed With CD26+ in Leukemic Stem Cells of Chronic Myeloid Leukemia', Frontiers in Oncology, vol. 8, pp. 555. https://doi.org/10.3389/fonc.2018.00555
Galimberti, Sara ; Grassi, Susanna ; Baratè, Claudia ; Guerrini, Francesca ; Ciabatti, Elena ; Perutelli, Francesca ; Ricci, Federica ; Del Genio, Giada ; Montali, Marina ; Barachini, Serena ; Giuliani, Cecilia ; Ferreri, Maria Immacolata ; Valetto, Angelo ; Abruzzese, Elisabetta ; Ippolito, Chiara ; Iurlo, Alessandra ; Bocchia, Monica ; Sicuranza, Anna ; Martino, Bruno ; Iovino, Lorenzo ; Buda, Gabriele ; Salehzadeh, Serena ; Petrini, Mario ; Di Paolo, Antonello ; Mattii, Letizia. / The Polycomb BMI1 Protein Is Co-expressed With CD26+ in Leukemic Stem Cells of Chronic Myeloid Leukemia. In: Frontiers in Oncology. 2018 ; Vol. 8. pp. 555.
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abstract = "The Polycomb gene BMI1 expression exerts a negative predictive impact on several hematological malignancies, such as acute and chronic myeloid leukemia (CML), myelofibrosis, and follicular lymphoma. As already demonstrated in CML, BMI1 is responsible for the resistance to the tyrosine kinase inhibitors (TKIs) in a BCR-ABL1-independent way. Even if, it is unknown where BMI1 in CML is expressed (in progenitors or more mature cells). We decided, therefore, to evaluate if and where the BMI1 protein is located, focusing mainly on the CD34+/CD38-/CD26+ CML progenitors. To begin we measured, by flow cytometry, the proportion of CD34+/CD26+ cells in 31 bone marrow samples from 20 CML patients, at diagnosis and during treatment with imatinib. After that the bone marrow blood smears were stained with antibodies anti-CD26, BCR-ABL1, and BMI1. These smears were observed by a confocal laser microscope and a 3D reconstruction was then performed. At diagnosis, CD34+/CD26+ cells median value/μL was 0.48; this number increased from diagnosis to the third month of therapy and then reduced during treatment with imatinib. The number and behavior of the CD26+ progenitors were independent from the BCR-ABL1 expression, but they summed up what previously observed about the BMI1 expression modulation. In this work we demonstrate for the first time that in CML the BMI1 protein is co-expressed with BCR-ABL1 only in the cytoplasm of the CD26+ precursors; on the contrary, in other hematological malignancies where BMI1 is commonly expressed (follicular lymphoma, essential thrombocytemia, acute myeloid leukemia), it was not co-localized with CD26 or, obviously, with BCR-ABL1. Once translated into the clinical context, if BMI1 is a marker of stemness, our results would suggest the combination of the BMI1 inhibitors with TKIs as an interesting object of research, and, probably, as a promising way to overcome resistance in CML patients.",
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T1 - The Polycomb BMI1 Protein Is Co-expressed With CD26+ in Leukemic Stem Cells of Chronic Myeloid Leukemia

AU - Galimberti, Sara

AU - Grassi, Susanna

AU - Baratè, Claudia

AU - Guerrini, Francesca

AU - Ciabatti, Elena

AU - Perutelli, Francesca

AU - Ricci, Federica

AU - Del Genio, Giada

AU - Montali, Marina

AU - Barachini, Serena

AU - Giuliani, Cecilia

AU - Ferreri, Maria Immacolata

AU - Valetto, Angelo

AU - Abruzzese, Elisabetta

AU - Ippolito, Chiara

AU - Iurlo, Alessandra

AU - Bocchia, Monica

AU - Sicuranza, Anna

AU - Martino, Bruno

AU - Iovino, Lorenzo

AU - Buda, Gabriele

AU - Salehzadeh, Serena

AU - Petrini, Mario

AU - Di Paolo, Antonello

AU - Mattii, Letizia

PY - 2018

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N2 - The Polycomb gene BMI1 expression exerts a negative predictive impact on several hematological malignancies, such as acute and chronic myeloid leukemia (CML), myelofibrosis, and follicular lymphoma. As already demonstrated in CML, BMI1 is responsible for the resistance to the tyrosine kinase inhibitors (TKIs) in a BCR-ABL1-independent way. Even if, it is unknown where BMI1 in CML is expressed (in progenitors or more mature cells). We decided, therefore, to evaluate if and where the BMI1 protein is located, focusing mainly on the CD34+/CD38-/CD26+ CML progenitors. To begin we measured, by flow cytometry, the proportion of CD34+/CD26+ cells in 31 bone marrow samples from 20 CML patients, at diagnosis and during treatment with imatinib. After that the bone marrow blood smears were stained with antibodies anti-CD26, BCR-ABL1, and BMI1. These smears were observed by a confocal laser microscope and a 3D reconstruction was then performed. At diagnosis, CD34+/CD26+ cells median value/μL was 0.48; this number increased from diagnosis to the third month of therapy and then reduced during treatment with imatinib. The number and behavior of the CD26+ progenitors were independent from the BCR-ABL1 expression, but they summed up what previously observed about the BMI1 expression modulation. In this work we demonstrate for the first time that in CML the BMI1 protein is co-expressed with BCR-ABL1 only in the cytoplasm of the CD26+ precursors; on the contrary, in other hematological malignancies where BMI1 is commonly expressed (follicular lymphoma, essential thrombocytemia, acute myeloid leukemia), it was not co-localized with CD26 or, obviously, with BCR-ABL1. Once translated into the clinical context, if BMI1 is a marker of stemness, our results would suggest the combination of the BMI1 inhibitors with TKIs as an interesting object of research, and, probably, as a promising way to overcome resistance in CML patients.

AB - The Polycomb gene BMI1 expression exerts a negative predictive impact on several hematological malignancies, such as acute and chronic myeloid leukemia (CML), myelofibrosis, and follicular lymphoma. As already demonstrated in CML, BMI1 is responsible for the resistance to the tyrosine kinase inhibitors (TKIs) in a BCR-ABL1-independent way. Even if, it is unknown where BMI1 in CML is expressed (in progenitors or more mature cells). We decided, therefore, to evaluate if and where the BMI1 protein is located, focusing mainly on the CD34+/CD38-/CD26+ CML progenitors. To begin we measured, by flow cytometry, the proportion of CD34+/CD26+ cells in 31 bone marrow samples from 20 CML patients, at diagnosis and during treatment with imatinib. After that the bone marrow blood smears were stained with antibodies anti-CD26, BCR-ABL1, and BMI1. These smears were observed by a confocal laser microscope and a 3D reconstruction was then performed. At diagnosis, CD34+/CD26+ cells median value/μL was 0.48; this number increased from diagnosis to the third month of therapy and then reduced during treatment with imatinib. The number and behavior of the CD26+ progenitors were independent from the BCR-ABL1 expression, but they summed up what previously observed about the BMI1 expression modulation. In this work we demonstrate for the first time that in CML the BMI1 protein is co-expressed with BCR-ABL1 only in the cytoplasm of the CD26+ precursors; on the contrary, in other hematological malignancies where BMI1 is commonly expressed (follicular lymphoma, essential thrombocytemia, acute myeloid leukemia), it was not co-localized with CD26 or, obviously, with BCR-ABL1. Once translated into the clinical context, if BMI1 is a marker of stemness, our results would suggest the combination of the BMI1 inhibitors with TKIs as an interesting object of research, and, probably, as a promising way to overcome resistance in CML patients.

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DO - 10.3389/fonc.2018.00555

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