Skip to main content

Advanced Search

Haematologica
  • Home
  • Current Issue
  • Ahead Of Print
  • Archive
  • Submit a Manuscript
    • Author Guidelines
    • Reviewer Guidelines
    • Submit a Manuscript
    • Track a Manuscript
  • About Us
    • About Haematologica
    • Editorial Board
    • Our Policies
  • More
    • Advertising
    • Rights & Permissions
    • Alerts
    • Feedback
    • Contact
Dissecting molecular mechanisms of resistance to Notch1-targeted therapy in T-cell acute lymphoblastic leukemia xenografts
Valentina Agnusdei, Sonia Minuzzo, Marica Pinazza, Alessandra Gasparini, Laura Pezzè, Adriana Agnese Amaro, Lorenza Pasqualini, Paola Del Bianco, Martina Tognon, Chiara Frasson, Pietro Palumbo, Yari Ciribilli, Ulrich Pfeffer, Massimo Carella, Alberto Amadori, Stefano Indraccolo
Haematologica August 2019 : haematol.2019.217687; doi:10.3324/haematol.2019.217687
Valentina Agnusdei
Istituto Oncologico Veneto IOV - IRCCS, Padova, Italia;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sonia Minuzzo
Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marica Pinazza
Istituto Oncologico Veneto IOV - IRCCS, Padova, Italia;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alessandra Gasparini
Istituto Oncologico Veneto IOV - IRCCS, Padova, Italia;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Laura Pezzè
Laboratory of Molecular Cancer Genetics, CIBIO, University of Trento, Trento, Italy;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Adriana Agnese Amaro
IRCCS Ospedale Policlinico San Martino, Genova, Italy;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lorenza Pasqualini
Istituto Oncologico Veneto IOV - IRCCS, Padova, Italia;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Paola Del Bianco
Istituto Oncologico Veneto IOV - IRCCS, Padova, Italia;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Martina Tognon
Istituto Oncologico Veneto IOV - IRCCS, Padova, Italia;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chiara Frasson
Istituto di Ricerca Pediatrica, Fondazione Citta' della Speranza, 35127 Padova, Italy;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Pietro Palumbo
Medical Genetics Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yari Ciribilli
Laboratory of Molecular Cancer Genetics, CIBIO, University of Trento, Trento, Italy;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ulrich Pfeffer
IRCCS Ospedale Policlinico San Martino, Genova, Italy;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Massimo Carella
Medical Genetics Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alberto Amadori
Istituto Oncologico Veneto IOV - IRCCS, Padova, Italia;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stefano Indraccolo
Istituto Oncologico Veneto IOV - IRCCS, Padova, Italia;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site

Author Affiliations

  1. Valentina Agnusdei1,
  2. Sonia Minuzzo2,
  3. Marica Pinazza1,
  4. Alessandra Gasparini1,
  5. Laura Pezzè3,
  6. Adriana Agnese Amaro4,
  7. Lorenza Pasqualini1,
  8. Paola Del Bianco1,
  9. Martina Tognon1,
  10. Chiara Frasson5,
  11. Pietro Palumbo6,
  12. Yari Ciribilli3,
  13. Ulrich Pfeffer4,
  14. Massimo Carella6,
  15. Alberto Amadori1 and
  16. Stefano Indraccolo1,*
  1. 1 Istituto Oncologico Veneto IOV - IRCCS, Padova, Italia;
  2. 2 Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy;
  3. 3 Laboratory of Molecular Cancer Genetics, CIBIO, University of Trento, Trento, Italy;
  4. 4 IRCCS Ospedale Policlinico San Martino, Genova, Italy;
  5. 5 Istituto di Ricerca Pediatrica, Fondazione Citta' della Speranza, 35127 Padova, Italy;
  6. 6 Medical Genetics Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
  1. ↵* Corresponding author; email: stefano.indraccolo{at}unipd.it
  • Article
  • Info & Metrics
  • PDF
Loading

Abstract

Despite substantial progress in treatment of T-cell acute lymphoblastic leukemia, mortality remains relatively high, mainly due to primary or acquired resistance to chemotherapy. Further improvements in survival demand better understanding of T-cell acute lymphoblastic leukemia biology and development of new therapeutic strategies. The Notch pathway has been involved in the pathogenesis of this disease and various therapeutic strategies are currently under development, including selective targeting of Notch receptors by inhibitory antibodies. We previously demonstrated that the Notch1-specific neutralizing antibody OMP52M51 prolongs survival in T-cell acute lymphoblastic leukemia patient-derived xenografts bearing NOTCH1/FBW7 mutations. However, acquired resistance to OMP52M51 eventually developed and we used patient-derived xenografts models to investigate this phenomenon. Multi-level molecular characterization of T-cell acute lymphoblastic leukemia cells resistant to Notch1 blockade and serial transplantation experiments uncovered heterogeneous types of resistance, not previously reported with other Notch inhibitors. In one model, resistance appeared after 156 days of treatment, it was stable and associated with loss of Notch inhibition, reduced mutational load and acquired Notch1 mutations potentially affecting the stability of the heterodimerization domain. Conversely, in another model resistance developed after only 43 days of treatment despite persistent down-regulation of Notch signaling and it was accompanied by modulation of lipid metabolism and reduced surface expression of Notch1. Our findings shed light on heterogeneous mechanisms adopted by the tumor to evade Notch1 blockade and support clinical implementation of antibody-based target therapy for Notch-addicted tumors.

  • Received February 8, 2019.
  • Accepted August 26, 2019.
  • Copyright © 2019, Ferrata Storti Foundation
PreviousNext
Back to top

Keywords

Pediatric Acute Lymphoblastic Leukemia
NOTCH1
resistance
targeted therapy
Xenografts

Vol 104 Issue 12

Haematologica: 104 (12)
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
Email

Thank you for your interest in spreading the word about Haematologica.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Dissecting molecular mechanisms of resistance to Notch1-targeted therapy in T-cell acute lymphoblastic leukemia xenografts
(Your Name) has forwarded a page to you from Haematologica
(Your Name) thought you would like to see this page from the Haematologica web site.
Citation Tools
Dissecting molecular mechanisms of resistance to Notch1-targeted therapy in T-cell acute lymphoblastic leukemia xenografts
Valentina Agnusdei, Sonia Minuzzo, Marica Pinazza, Alessandra Gasparini, Laura Pezzè, Adriana Agnese Amaro, Lorenza Pasqualini, Paola Del Bianco, Martina Tognon, Chiara Frasson, Pietro Palumbo, Yari Ciribilli, Ulrich Pfeffer, Massimo Carella, Alberto Amadori, Stefano Indraccolo
Haematologica Aug 2019, haematol.2019.217687; DOI: 10.3324/haematol.2019.217687

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Valentina Agnusdei, Sonia Minuzzo, Marica Pinazza, Alessandra Gasparini, Laura Pezzè, Adriana Agnese Amaro, Lorenza Pasqualini, Paola Del Bianco, Martina Tognon, Chiara Frasson, Pietro Palumbo, Yari Ciribilli, Ulrich Pfeffer, Massimo Carella, Alberto Amadori, Stefano Indraccolo
Haematologica Aug 2019, haematol.2019.217687; DOI: 10.3324/haematol.2019.217687
del.icio.us logo Digg logo Reddit logo Technorati logo Twitter logo CiteULike logo Connotea logo Facebook logo Google logo Mendeley logo
Request Permissions
  • Tweet Widget
  • Facebook Like
  • Alert me when this article is cited
  • Alert me if a correction is posted

Jump To

  • Article
  • Info & Metrics
  • PDF

More in this TOC Section

Original Article

  • Thrombin generation in cardiovascular disease and mortality - results from the Gutenberg Health Study
  • Fractures and survival in multiple myeloma: results from a population-based study
  • Functional plasminogen activator inhibitor 1 is retained on the activated platelet membrane following platelet activation
Show more Original Article

Acute Lymphoblastic Leukemia

  • Disrupting the leukemia niche in the central nervous system attenuates leukemia chemoresistance
  • Relapses and treatment-related events contributed equally to poor prognosis in children with ABL-class fusion positive B-cell acute lymphoblastic leukemia treated according to AIEOP-BFM protocols
  • A systematic literature review and meta-analysis of minimal residual disease as a prognostic indicator in adult B-cell acute lymphoblastic leukemia
Show more Acute Lymphoblastic Leukemia

Related Articles

Cited By...

What about you?
Tell us your interests and get all the new contents of Haematologica in advance

 

 

Navigate

  • Home
  • Current issue
  • Ahead of print
  • Archive
  • Info for
    • Authors
    • Reviewers
    • Advertisers
    • Subscribers
  • About us
    • About Haematologica
    • Editorial Board
    • Our policies

For Authors

  • Author guidelines
  • Submit Manuscript
  • Track Manuscript

For Reviewers

  • Reviewer Guidelines
  • Access Your Profile
  • Access Your Tasks
  • 2014 reviewers

For Advertisers

  • Information For Advertising

Education

  • Review Articles
  • Guideline Articles

More

  • Rights & Permissions
  • Advertising
  • Alerts
  • Feedback
  • Contact
  • App

Copyright © 2019 by the Ferrata Storti Foundation

ISSN 0390-6078 print

ISSN 1592-8721 online