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

¹ Université de Toulouse, LBCMCP, ² Centre National de la Recherche Scientifique, LBCMCP-UMR5088, ³ Institut National de la Sante et de la Recherche Medicale, Centre de Physiopathologie Toulouse Purpan-U563, and ⁴ Laboratoire d'Hématologie-CHU Toulouse-Purpan, TSA 40031, Toulouse, France

Requests for reprints: Bernard Ducommun and Cécile Demur, 118 Route de Narbonne, 31062 Toulouse Cedex, France. Phone: 33-5-61-55-62-10; Fax: 33-5-61-55-81-09; E-mail: ducommun{at}cict.fr.

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-β-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. [Cancer Res 2009;69(22):8652–61]

Key Words: AML • DNA damage • Checkpoint