NOTCH1 Is Aberrantly Activated in Chronic Lymphocytic Leukemia Hematopoietic Stem Cells

Mauro Di Ianni; Stefano Baldoni; Beatrice Del Papa; Patrizia Aureli; Erica Dorillo; Filomena De Falco; Elisa Albi; Emanuela Varasano; Ambra Di Tommaso; Raffaella Giancola; Patrizia Accorsi; Gianluca Rotta; Chiara Rompietti; Estevão Carlos Silva Barcelos; Antonio Francesco Campese; Paolo Di Bartolomeo; Isabella Screpanti; Emanuela Rosati; Franca Falzetti; Paolo Sportoletti

doi:10.3389/fonc.2018.00105

NOTCH1 Is Aberrantly Activated in Chronic Lymphocytic Leukemia Hematopoietic Stem Cells

Front Oncol. 2018 Apr 20:8:105. doi: 10.3389/fonc.2018.00105. eCollection 2018.

Authors

Mauro Di Ianni^{1

2}, Stefano Baldoni³, Beatrice Del Papa⁴, Patrizia Aureli⁴, Erica Dorillo⁴, Filomena De Falco⁴, Elisa Albi⁴, Emanuela Varasano⁴, Ambra Di Tommaso³, Raffaella Giancola², Patrizia Accorsi², Gianluca Rotta⁵, Chiara Rompietti⁴, Estevão Carlos Silva Barcelos^{4

6}, Antonio Francesco Campese⁷, Paolo Di Bartolomeo², Isabella Screpanti⁷, Emanuela Rosati⁸, Franca Falzetti⁴, Paolo Sportoletti⁴

Affiliations

¹ Department of Medicine and Aging Sciences, University of Chieti Pescara, Chieti, Italy.
² Department of Hematology, Transfusion Medicine and Biotechnologies, Ospedale Civile, Pescara, Italy.
³ Department of Life, Health and Environmental Sciences, Hematology Section, University of L'Aquila, L'Aquila, Italy.
⁴ Institute of Hematology-Centro di Ricerche Emato-Oncologiche (CREO), University of Perugia, Perugia, Italy.
⁵ BD Biosciences, San Jose, Italy.
⁶ Universidade Federal do Espírito Santo, Vitória, Brazil.
⁷ Department of Molecular Medicine, Sapienza, University of Rome, Rome, Italy.
⁸ Department of Experimental Medicine, Biosciences and Medical Embriology Section, University of Perugia, Perugia, Italy.

Abstract

To investigate chronic lymphocytic leukemia (CLL)-initiating cells, we assessed NOTCH1 mutation/expression in hematopoietic stem cells (HSCs). In NOTCH1-mutated CLL, we detected subclonal mutations in 57% CD34+/CD38- HSCs. NOTCH1 mutation was present in 66% CD34+/CD38+ progenitor cells displaying an increased mutational burden compared to HSCs. Flow cytometric analysis revealed significantly higher NOTCH1 activation in CD34+/CD38- and CD34+/CD38+ cells from CLL patients, regardless NOTCH1 mutation compared to healthy donors. Activated NOTCH1 resulted in overexpression of the NOTCH1 target c-MYC. We conclude that activated NOTCH1 is an early event in CLL that may contribute to aberrant HSCs in this disease.

Keywords: CD34+ cells; NOTCH1 mutation; chronic lymphocytic leukemia; hematopoietic stem cells; notch signaling.