Decitabine demonstrates antileukemic activity in B cell precursor acute lymphoblastic leukemia with MLL rearrangements

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.Electronic supplementary materialThe online version of this article (10.1186/s13045-018-0607-3) contains supplementary material, which is available to authorized users.

MLL-Rearranged Acute Leukemia with t(4;11)(q21;q23)—Current Treatment Options. Is There a Role for CAR-T Cell Therapy?

“…An attractive therapeutic target for MLL -r leukemia is the epigenetic dysregulation brought about by MLL fusions, which could be treated by the use of nucleoside analogs hypomethylating agents such as decitabine, azacytidine, and clofarabine (NCT02828358) [69,70]. Decitabine, in particular, was shown to exert anti-proliferative action in cell lines and in patient-derived xenografts bearing t(4;11) [71]. A wide range of potentially targetable epigenetic and chromatin regulators have been identified, many of which have not reached clinical stages as of yet [72,73].…”

Decitabine mildly attenuates MLL‐rearranged acute lymphoblastic leukemia in vivo, and represents a poor chemo‐sensitizer

“…We to eradicate MLL-rearranged ALL cells in vitro [42], as well as with L-asparaginase to enhance cytotoxicity in the pediatric T-ALL [30].…”

Combined Casein Kinase II inhibition and epigenetic modulation in acute B-lymphoblastic leukemia

“…Mononuclear cells from bone marrow (BM) aspirates of newly diagnosed ALL patients (Rostock University Medical Center) were isolated using Biocoll separating solution (Merck Millipore, Darmstadt, Germany) and previously characterized on a molecular level using next-generation sequencing (Cancer hotspot panel, Ion PGM System, Thermo Fisher Scientific, Schwerte, Germany) according to the manufacturer’s protocol [10]. All experiments were performed in accordance to the Declaration of Helsinki and the local ethical committee standards.…”

“…once daily d7-d10. Results were compared to previously published DEC-treated animals [10]. Drug response was analyzed by BLI and peripheral blood (PB) flow cytometry (GFP + or CD19-FITC + /CD45-PE + (Becton Dickinson, Heidelberg, Germany)).…”

“…In B-ALL inactivation of numerous tumor suppressor genes by aberrant methylation is associated with poor prognosis [9]. Recently we demonstrated that HMA induce apoptosis and cell cycle arrest and inhibit proliferation in human B-ALL [10].…”