Abstract 3886: Therapeutic potential of CDK inhibitors in MLL leukemias

Abstract

Abstract Chromosomal rearrangements involving the human mixed - lineage leukaemia (MLL) gene at 11q23, are associated with the development of acute leukemias. Abnormalities in the MLL gene can be detected in de novo acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL) as well as in therapy-related AML, particularly after treatment with DNA topoisomerase II inhibitors. Some malignancies, such as infant ALL, are characterised by exceedingly high incidence (∼80%) of MLL gene rearrangements, which is a strong predictor of an adverse outcome. Current therapies fail in >50% of the infant MLL cases, indicating that innovative therapeutic strategies are urgently needed to improve prognosis. Re-arranged MLL interacts with the transcription complex including CDK9. The association of CDK9 results in an increase in RNApol II phosphorylation and hence overexpression of HoxA9 and Meis1, which are normally down regulated during haematopoietic differentiation, resulting in immortalisation and transformation. These suggest a key role of CDK9 activity in this transformation process and the potential of CDK9 inhibitors to stop the uncontrolled myeloblast proliferation. Additionally, the expression of MCL-1, an anti-apoptotic member of BCL-2 family, was shown to increase in infant MLL samples, which correlated with prednisone resistance and poor prognosis. Importantly, MCL-1 also plays an important role in the development of B and T lymphocytes as well as in the survival of haematopoietic stem cell. Therefore, targeting MCL-1 in infant MLL cells may also induce leukemic cell death of the CD34+CD19- chemoresistant leukemic stem cell. The ability of CDK inhibitors, such as seliciclib, flavopiridol, SNS-032, to down regulate MCL-1 and induce apoptosis in B-CLL and MM cells is well recorded. We studied the effect of a purine CDK inhibitor, Cmpd 5, on MLL cell lines in vitro and in vivo. Cmpd 5 is a structural analogue of seliciclib and a potent and selective inhibitor of CDKs 2, 5, and 9. AML cell lines with MLL re-arrangements were exquisitely sensitive to Cmpd 5. Treatment for 5 hours at concentrations <0.5 μM was sufficient to inhibit completely the proliferation of the most sensitive cell lines. The mode of action corresponded to the target inhibition and included rapid induction of apoptosis. Higher concentration and longer treatment were required to achieve similar effect in a WT MLL cell line. The high sensitivity of MLL/AML cell lines was confirmed in vivo. A very potent (97% TGI) and durable effect was observed in a mouse xenograft model after oral administration of Cmpd 5. Our results suggest that MLL rearranged leukemias are very sensitive toward CDK inhibitors, which down regulate transcription, and justifies further exploration of their therapeutic potential for MLL haematological malignancies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3886.