Expression and function of phosphoinositide 3-kinase delta in mesenchymal stromal cells from normal and leukaemic bone marrow

Ahmed Y Ali; Qingdong Guan; Xun Wu; Sen Hou; Versha Banerji; James B Johnston; Donna Wall; David Szwajcer; Spencer B Gibson; Aaron J Marshall

doi:10.1111/bjh.15865

Expression and function of phosphoinositide 3-kinase delta in mesenchymal stromal cells from normal and leukaemic bone marrow

Br J Haematol. 2019 Jun;185(5):883-887. doi: 10.1111/bjh.15865. Epub 2019 Mar 14.

Authors

Ahmed Y Ali^{1

2}, Qingdong Guan^{3

4

5}, Xun Wu¹, Sen Hou¹, Versha Banerji^{2

4}, James B Johnston^{2

4}, Donna Wall⁶, David Szwajcer^{3

4

5}, Spencer B Gibson^{1

2

7}, Aaron J Marshall^{1

2

7}

Affiliations

¹ Department of Immunology, University of Manitoba, Winnipeg, Canada.
² Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, Canada.
³ Cellular Therapy Laboratory, CancerCare Manitoba, Winnipeg, Canada.
⁴ Department of Internal Medicine, University of Manitoba, Winnipeg, Canada.
⁵ The Manitoba Centre for Advanced Cell and Tissue Therapy, The Health Science Centre, Winnipeg, Canada.
⁶ Department of Paediatrics, Division of Haematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, USA.
⁷ Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada.

PMID: 30873593
DOI: 10.1111/bjh.15865

Abstract

Within lymphoid tissues, chronic lymphocytic leukaemia (CLL) cells interact with mesenchymal stromal cells (MSC). Inhibitors of phosphoinositide 3-kinase delta (PI3Kδ) cause release of CLL cells from lymphoid tissues into blood. PI3Kδ inhibitors are thought to target only CLL and other immune cells because PI3Kδ expression is restricted to haematopoietic cells. We found that PI3Kδ is unexpectedly expressed in primary MSC derived from CLL patients and healthy donors. PI3Kδ inhibition in MSC using idelalisib or duvelisib significantly reduced their ability to support CLL migration and adhesion. These observations provide the first evidence that PI3Kδ is expressed and functional in CLL MSC.

Keywords: cell adhesion; cell signalling; chemotaxis; chronic lymphocytic leukaemia; stromal cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology
Bone Marrow Cells / enzymology*
Bone Marrow Cells / pathology
Case-Control Studies
Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors
Class I Phosphatidylinositol 3-Kinases / biosynthesis
Class I Phosphatidylinositol 3-Kinases / genetics
Class I Phosphatidylinositol 3-Kinases / metabolism*
Enzyme Inhibitors / pharmacology
HEK293 Cells
Humans
Isoquinolines / pharmacology
Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy
Leukemia, Lymphocytic, Chronic, B-Cell / enzymology*
Leukemia, Lymphocytic, Chronic, B-Cell / genetics
Leukemia, Lymphocytic, Chronic, B-Cell / pathology
Mesenchymal Stem Cells / enzymology*
Mesenchymal Stem Cells / pathology
Purines / pharmacology
Quinazolinones / pharmacology

Substances

Antineoplastic Agents
Enzyme Inhibitors
Isoquinolines
Purines
Quinazolinones
duvelisib
Class I Phosphatidylinositol 3-Kinases
PIK3CD protein, human
idelalisib