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. 2018 Jun 27;8:229. doi: 10.3389/fonc.2018.00229

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Copyright © 2018 Rosati, Baldoni, De Falco, Del Papa, Dorillo, Rompietti, Albi, Falzetti, Di Ianni and Sportoletti.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Schematic representation of NOTCH1 involvement during chronic lymphocytic leukemia (CLL) development. NOTCH1 activation and mutation are early oncogenic events acquired within hematopoietic stem cells (HSCs) and maintained in their hematopoietic progeny. As suggested by xenograft models, CLL-HSCs are skewed toward B-cell differentiation giving rise to premalignant B cells that resemble human MBL, the pre-leukemic state of CLL. We hypothesize that NOTCH1 alterations, together with other oncogenic events, contribute to the generation of pre-leukemic mature B cells by favoring the expansion of pro-B cells and by cooperating with pre-BCR signaling during the antigen-driven selection of pre-B cells. In lymphoid tissues, antigenic stimulation of specific stereotyped BCRs, in combination with NOTCH1-related microenvironment interactions and additional genetic lesions, might have a role in the transformation process of pre-leukemic mature B cells into CLL.