Skip to main content

Research Repository

Advanced Search

Targeting of CD34+CD38- cells using Gemtuzumab ozogamicin (Mylotarg) in combination with tipifarnib (Zarnestra) in acute Myeloid Leukaemia

Jawad, Mays; Yu, Ning; Seedhouse, Claire; Tandon, Karuna; Russell, Nigel H; Pallis, Monica

Targeting of CD34+CD38- cells using Gemtuzumab ozogamicin (Mylotarg) in combination with tipifarnib (Zarnestra) in acute Myeloid Leukaemia Thumbnail


Authors

Mays Jawad

Ning Yu

Karuna Tandon

Nigel H Russell

Monica Pallis



Abstract

Background
The CD34+CD38- subset of AML cells is enriched for resistance to current chemotherapeutic agents and considered to contribute to disease progression and relapse in Acute Myeloid Leukaemia (AML) patients following initial treatment.

Methods
Chemosensitivity in phenotypically defined subsets from 34 primary AML samples was measured by flow cytometry following 48 hr in vitro treatment with gemtuzumab ozogamicin (GO, Mylotarg) and the farnesyltransferase inhibitor tipifarnib/zarnestra. The DNA damage response was measured using flow cytometry, immunofluorescence and immunohistochemistry.

Results
Using a previously validated in vitro minimal residual disease model, we now show that the combination of GO (10 ng/ml) and tipifarnib (5 μM) targets the CD34+CD38- subset resulting in 65% median cell loss compared to 28% and 13% CD34+CD38- cell loss in GO-treated and tipifarnib-treated cells, respectively. Using phosphokinome profiling and immunofluorescence in the TF-1a cell line, we demonstrate that the drug combination is characterised by the activation of a DNA damage response (induction of γH2A.X and thr68 phosphorylation of chk2). Higher induction of γH2AX was found in CD34+CD38- than in CD34+CD38+ patient cells. In a model system, we show that dormancy impairs damage resolution, allowing accumulation of γH2AX foci.

Conclusions
The chemosensitivity of the CD34+CD38- subset, combined with enhanced damage indicators, suggest that this subset is primed to favour programmed cell death as opposed to repairing damage. This interaction between tipifarnib and GO suggests a potential role in the treatment of AML.

Citation

Jawad, M., Yu, N., Seedhouse, C., Tandon, K., Russell, N. H., & Pallis, M. (2012). Targeting of CD34+CD38- cells using Gemtuzumab ozogamicin (Mylotarg) in combination with tipifarnib (Zarnestra) in acute Myeloid Leukaemia. BMC Cancer, https://doi.org/10.1186/1471-2407-12-431

Journal Article Type Article
Acceptance Date Sep 21, 2012
Online Publication Date Sep 26, 2012
Publication Date 2012
Deposit Date Apr 5, 2024
Publicly Available Date May 3, 2024
Journal BMC Cancer
Electronic ISSN 1471-2407
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
DOI https://doi.org/10.1186/1471-2407-12-431
Public URL https://nottingham-repository.worktribe.com/output/32755012
Publisher URL https://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-12-431

Files





You might also like



Downloadable Citations