Abstract
Cell division cycle 25 (CDC25) protein phosphatases regulate cell cycle progression through the activation of cyclin-dependent kinases (CDKs), but they are also involved in chromatin modulation and transcriptional regulation. CDC25 inhibition is regarded as a possible therapeutic strategy for the treatment of human malignancies, including acute myeloid leukemia (AML). We investigated the in vitro effects of CDC25 inhibitors on primary human AML cells derived from 79 unselected patients in suspension cultures. Both the previously well-characterized CDC25 inhibitor NSC95397, as well as five other inhibitors (BN82002 and the novel small molecular compounds ALX1, ALX2, ALX3, and ALX4), only exhibited antiproliferative effects for a subset of patients when tested alone. These antiproliferative effects showed associations with differences in genetic abnormalities and/or AML cell differentiation. However, the responders to CDC25 inhibition could be identified by analysis of global gene expression profiles. The differentially expressed genes were associated with the cytoskeleton, microtubules, and cell signaling. The constitutive release of 28 soluble mediators showed a wide variation among patients and this variation was maintained in the presence of CDC25 inhibition. Finally, NSC95397 had no or only minimal effects on AML cell viability. In conclusion, CDC25 inhibition has antiproliferative effects on primary human AML cells for a subset of patients, and these patients can be identified by gene expression profiling.
Highlights
Acute myeloid leukemia (AML) is an aggressive malignancy characterized by the accumulation of immature myeloblasts in the bone marrow
The presence of 10 μM NSC95397 during culture had no significant effect on viability, neither when analyzing the overall results for the 79 patients, nor when comparing various patient subsets that differed with regard to acute myeloid leukemia (AML) cell differentiation, cytogenetic abnormalities, or Flt3/NPM1 mutations
We investigated the effect of six Cell division cycle 25 (CDC25) inhibitors on primary human AML cells; these cells were derived from a large group of unselected patients
Summary
Acute myeloid leukemia (AML) is an aggressive malignancy characterized by the accumulation of immature myeloblasts in the bone marrow. Several new CDC25 inhibitors with effects on human malignant cells have recently been identified [30,33,34,35,36] Taken together, these studies strongly suggest that CDC25 inhibition should be further investigated as a possible strategy for the treatment of human AML, and these studies have to include comparisons of different inhibitors and different patient subsets. Our studies suggest that CDC25 inhibition is effective for a subset of AML patients, and a subset of AML patients, and this subset can be identified from the patients’ gene expression profile.
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