Constitutive Activation of the DNA Damage Signaling Pathway in Acute Myeloid Leukemia with Complex Karyotype: Potential Importance for Checkpoint Targeting Therapy

Christine Didier,Cindy Cavelier,Bernard Ducommun,Stéphane Manenti,Cécile Demur,Véronique Mansat-De Mas,Christian Recher,Naïs Prade

doi:10.1158/0008-5472.can-09-0939

Abstract

Genomic instability in solid tumors participates in the oncogenetic process and is associated with the activation of the DNA damage response pathway. Here, we report the activation of the constitutive DNA damage and checkpoint pathway associated with complex karyotypes in samples from patients with acute myeloid leukemia (AML). We show that antagonizing CHK1 kinase with a small inhibitory compound or by RNA interference strongly reduces the clonogenic properties of high-DNA damage level AML samples, particularly those with complex karyotypes. Moreover, we observe a beneficial effect of CHK1 inhibition in high-DNA damage level AML samples treated with 1-beta-d-arabinofuranosylcytosine. In contrast, CHK1 inhibition has no effect on the clonogenic properties of normal hematopoietic progenitors. All together, our results indicate that CHK1 inhibition may represent an attractive therapeutic opportunity in AML with complex karyotype.

Highlights

Acute myeloid leukemia (AML), the most frequent acute leukemia in adults, is a clonal disorder characterized by the accumulation of malignant hematopoietic progenitor cells (HPC) with an impaired differentiation program
We first examined the existence of detectable constitutive DNA damage in samples of blasts from AML patient, using flow cytometry to quantify H2AX phosphorylation [30]
Phospho-H2AX labeling of cells was only detected in a fresh AML blast sample, whereas fresh normal CD34+ HPC were unlabeled. These results indicate that AML blast cells from patients exhibit variable levels of constitutive DNA damage that are in the range of the physiologic response to DNA injury; they show that samples from complex karyotype patients express a relatively higher level of constitutive DNA damage

Summary

Introduction

Acute myeloid leukemia (AML), the most frequent acute leukemia in adults, is a clonal disorder characterized by the accumulation of malignant hematopoietic progenitor cells (HPC) with an impaired differentiation program. Despite considerable progress in the therapy of AML and a high rate of complete remission after induction chemotherapy, most patients relapse and succumb to the disease [1]. This clinical observation highlights the difficulties involved in eradicating the leukemic stem cells that are responsible for the emergence of new leukemic progenitor cells leading to relapse. AML is a heterogeneous disease and patients differ strongly in their response to therapy, in the occurrence of relapse and in overall survival, according to prognosis factors such as age and presence of molecular and/ or cytogenetic abnormalities. Complex karyotype AML, Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/)

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