Abstract
BackgroundPromotor hypermethylation of CpG islands is common in B cell precursor acute lymphoblastic leukemia (BCP-ALL) with mixed lineage leukemia (MLL) gene rearrangements. Hypomethylating agents (HMA) such as azacitidine (AZA) and decitabine (DEC) reduce DNA hypermethylation by incorporation into DNA and were successfully introduced into the clinic for the treatment of myeloid neoplasias.MethodsHere, we investigated whether HMA induce comparable biological effects in MLL-positive BCP-ALL. Further, efficacy of HMA and concomitant application of cytostatic drugs (cytarabine and doxorubicin) were evaluated on established SEM and RS4;11 cell lines. In addition, promising approaches were studied on BCP-ALL cell line- and patient-derived xenograft models.ResultsIn general, DEC effects were stronger compared to AZA on MLL-positive BCP-ALL cells. DEC significantly reduced proliferation by induction of cell cycle arrest in G0/G1 phase and apoptosis. Most sensitive to HMA were SEM cells which are characterized by a fast cell doubling time. The combination of low-dose HMA and conventional cytostatic agents revealed a heterogeneous response pattern. The strongest antiproliferative effects were observed when ALL cells were simultaneously exposed to HMA and cytostatic drugs. Most potent synergistic effects of HMA were induced with cytarabine. Finally, the therapeutic potential of DEC was evaluated on BCP-ALL xenograft models. DEC significantly delayed leukemic proliferation in xenograft models as demonstrated longitudinally by non-invasive bioluminescence as well as 18F-FDG-PET/CT imaging. Unexpectedly, in vivo concomitant application of DEC and cytarabine did not enhance the antiproliferative effect compared to DEC monotherapy.ConclusionsOur data reveal that DEC is active in MLL-positive BCP-ALL and warrant clinical evaluation.
Highlights
Promotor hypermethylation of CpG islands is common in B cell precursor acute lymphoblastic leukemia (BCP-Acute lymphoblastic leukemia (ALL)) with mixed lineage leukemia (MLL) gene rearrangements
A dose-dependent effect of Hypomethylating agents (HMA) on proliferation and metabolic activity was observed in suspension cultures in Iscove’s MDM (SEM) cells after 72-h drug exposure
Our results indicate that the combination of low-dose HMA with low-dose conventional cytostatic drugs induced in part significantly stronger antiproliferative effects compared to single drug exposure
Summary
Promotor hypermethylation of CpG islands is common in B cell precursor acute lymphoblastic leukemia (BCP-ALL) with mixed lineage leukemia (MLL) gene rearrangements. Hypomethylating agents (HMA) such as azacitidine (AZA) and decitabine (DEC) reduce DNA hypermethylation by incorporation into DNA and were successfully introduced into the clinic for the treatment of myeloid neoplasias. B cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by several molecular and cytogenetic changes. One of the most frequently involved genetic alterations in BCP-ALL is the rearrangement of the mixed lineage leukemia (MLL) gene. MLL-AF4-positive ALL is generally considered as high-risk leukemia associated with poor clinical outcome [2]. In the case of CD20 positivity, antibody-based anti-CD-20 immunotherapy has proved to be beneficial [6]. The exact pathogenesis of MLL-positive ALL has not yet been fully
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