Stromal control of chronic lymphocytic leukemia cells

Paul Faustin Seke Etet,¹ Armel Herve Nwabo Kamdje,² Jeremie Mbo Amvene,² Yousef Aldebasi,³ Mohammed Farahna,¹ Lorella Vecchio<sup>4

1</sup>Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia; ²Department of Medicine, University of Ngaoundere, Ngaoundere, Cameroon; ³Department of Optometry, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia; ⁴Laboratory of Cytometry, Institute of Molecular Genetics, CNR, University of Pavia, Pavia, Italy

Abstract: In the ongoing efforts to develop therapies against chronic lymphocytic leukemia (CLL), stromal factors allowing malignant cells to escape spontaneous and chemotherapy-mediated apoptosis, giving way to relapses, have been abundantly investigated. Bone marrow adherent cell types, collectively referred to as stromal cells, appear to be key players in such escape, mainly because CLL malignant cells, which rapidly undergo spontaneous apoptosis when cultured in vitro, survive, migrate, and resist cytotoxic agents in co-culture with bone marrow stromal cells. CLL displays variable clinical courses according to well-defined prognostic factors induced on malignant B-cells (CLL cells) or expressed by the transformed bone marrow stromal microenvironment. Particularly, a critical pathogenic role is played by proinflammatory factors, adhesion molecules, and signaling molecules involved in cell fate and stemness, such as Notch, Wnt, sonic Hedgehog, phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), and the B-cell CLL/lymphoma 2 (Bcl-2) family of regulator proteins. As herein discussed, these molecules probably form a complex network favoring CLL cell survival, proliferation, and chemoresistance to anticancer therapy. Characterizing the sets of signaling pathways involved in the interactions between stromal cells and CLL cells may provide new tools for CLL clinical phenotyping and for re-sensitizing chemotherapy resistant cells.

Keywords: chronic lymphoblastic leukemia, CLL, signaling pathways, cancer, stromal cells