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Antileukaemic effect of PI 3 K ‐m TOR inhibitors in acute myeloid leukaemia‐gene expression profiles reveal CDC 25 B expression as determinate of pharmacological effect
Author(s) -
Reikvam Håkon,
Tamburini Jerome,
Skrede Silje,
Holdhus Rita,
Poulain Laury,
Ersvær Elisabeth,
Hatfield Kimberley J.,
Bruserud Øystein
Publication year - 2014
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.12611
Subject(s) - cell cycle , biology , cell growth , myeloid , gene expression , microbiology and biotechnology , cancer research , gene , chemistry , genetics
Summary Acute myeloid leukaemia ( AML ) is a heterogeneous malignancy. Intracellular signalling through the phosphatidylinositol 3‐kinase ( PI 3 K )‐ A kt‐mammalian target of rapamycin (m TOR ) pathway is important for regulation of cellular growth and metabolism, and inhibitors of this pathway is considered for AML treatment. Primary human AML cells, derived from 96 consecutive adult patients, were examined. The effects of two m TOR inhibitors (rapamycin, temsirolimus) and two PI 3 K inhibitors ( GDC ‐0941, 3‐methyladenine) were studied, and we investigated cytokine‐dependent proliferation, regulation of apoptosis and global gene expression profiles. Only a subset of patients demonstrated strong antiproliferative effects of PI 3 K ‐m TOR inhibitors. Unsupervised hierarchical clustering analysis identified two main clusters of patients; one subset showing weak or absent antiproliferative effects (59%) and another group showing a strong growth inhibition for all drugs and concentrations examined (41%). Global gene expression analyses showed that patients with AML cell resistance against PI 3 K ‐m TOR inhibitors showed increased m RNA expression of the CDC 25 B gene that encodes the cell cycle regulator Cell Division Cycle 25 B . The antileukaemic effect of PI 3 K ‐ A kt‐m TOR inhibition varies between patients, and resistance to these inhibitors is associated with the expression of the cell cycle regulator CDC 25 B , which is known to crosstalk with the PI 3 K ‐ A kt‐m TOR pathway and mediate rapamycin resistance in experimental models.