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

Roolf, Catrin; Richter, Anna; Konkolefski, Christoph; Knuebel, Gudrun; Sekora, Anett; Krohn, Saskia; Stenzel, Jan; Krause, Bernd J.; Vollmar, Brigitte; Escobar, Hugo Murua

doi:10.1186/s13045-018-0607-3

Cited by 23 publications

(30 citation statements)

References 54 publications

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“…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].…”

Section: Current Therapy For Mll-r Acute Leukemia Patientsmentioning

confidence: 99%

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

Britten

Ragusa

Tosi

et al. 2019

Cells

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The MLL (mixed-lineage leukemia) gene, located on chromosome 11q23, is involved in chromosomal translocations in a subtype of acute leukemia, which represents approximately 10% of acute lymphoblastic leukemia and 2.8% of acute myeloid leukemia cases. These translocations form fusions with various genes, of which more than 80 partner genes for MLL have been identified. The most recurrent fusion partner in MLL rearrangements (MLL-r) is AF4, mapping at chromosome 4q21, accounting for approximately 36% of MLL-r leukemia and particularly prevalent in MLL-r acute lymphoblastic leukemia (ALL) cases (57%). MLL-r leukemia is associated with a sudden onset, aggressive progression, and notoriously poor prognosis in comparison to non-MLL-r leukemias. Despite modern chemotherapeutic interventions and the use of hematopoietic stem cell transplantations, infants, children, and adults with MLL-r leukemia generally have poor prognosis and response to these treatments. Based on the frequency of patients who relapse, do not achieve complete remission, or have brief event-free survival, there is a clear clinical need for a new effective therapy. In this review, we outline the current therapy options for MLL-r patients and the potential application of CAR-T therapy.

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Section: Current Therapy For Mll-r Acute Leukemia Patientsmentioning

confidence: 99%

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

Britten

Ragusa

Tosi

et al. 2019

Cells

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“…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].…”

Section: Discussionmentioning

confidence: 99%

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

Schneider

Castro

Pinhanços

et al. 2020

eJHaem

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MLL‐rearranged acute lymphoblastic leukemia (ALL) represents a highly aggressive ALL subtype, characterized by aberrant DNA methylation patterns. DNA methyltransferase inhibitors, such as decitabine have previously been demonstrated to be effective in eradicating MLL‐rearranged ALL cells in vitro. Here, we assessed the in vivo anti‐leukemic potential of low‐dose DNA methyltransferase inhibitor decitabine using a xenograft mouse model of human MLL‐rearranged ALL. Furthermore, we explored whether prolonged exposure to low‐dose decitabine could chemo‐sensitize MLL‐rearranged ALL cells toward conventional chemotherapy as well as other known epigenetic‐based and anti‐neoplastic compounds. Our data reveal that decitabine prolonged survival in xenograft mice of MLL‐rearranged ALL by 8.5 days (P = .0181), but eventually was insufficient to prevent leukemia out‐growth, based on the examination of the MLLAF4 cell line SEM. Furthermore, we observe that prolonged pretreatment of low‐dose decitabine mildly sensitized toward the conventional drugs prednisolone, vincristine, daunorubicin, asparaginase, and cytarabine in a panel of MLL‐rearranged cell lines. Additionally, we assessed synergistic effects of decitabine with other epigenetic‐based or anticancer drugs using high‐throughput drug library screens. Validation of the top hits, including histone deacetylase inhibitor panobinostat, BCL2 inhibitor Venetoclax, MEK inhibitor pimasertib, and receptor tyrosine kinase foretinib, revealed additive and moderate synergistic effects for the combination of each drug together with decitabine in a cell line‐dependent manner.

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“…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.…”

Section: Methodsmentioning

confidence: 99%

“…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)).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2019

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Background The tumor suppressor protein phosphatase and tensin homolog (PTEN) is a key regulator of the PI3K/AKT pathway which is frequently altered in a variety of tumors including a subset of acute B-lymphoblastic leukemias (B-ALL). While PTEN mutations and deletions are rare in B-ALL, promoter hypermethylation and posttranslational modifications are the main pathways of PTEN inactivation. Casein Kinase II (CK2) is often upregulated in B-ALL and phosphorylates both PTEN and DNA methyltransferase 3A, resulting in increased PI3K/AKT signaling and offering a potential mechanism for further regulation of tumor-related pathways. Methods Here, we evaluated the effects of CK2 inhibitor CX-4945 alone and in combination with hypomethylating agent decitabine on B-ALL proliferation and PI3K/AKT pathway activation. We further investigated if CX-4945 intensified decitabine-induced hypomethylation and identified aberrantly methylated biological processes after CK2 inhibition. In vivo tumor cell proliferation in cell line and patient derived xenografts was assessed by longitudinal full body bioluminescence imaging and peripheral blood flow cytometry of NSG mice. Results CX-4945 incubation resulted in CK2 inhibition and PI3K pathway downregulation thereby inducing apoptosis and anti-proliferative effects. CX-4945 further affected methylation patterns of tumor-related transcription factors and regulators of cellular metabolism. No overlap with decitabine-affected genes or processes was detected. Decitabine alone revealed only modest anti-proliferative effects on B-ALL cell lines, however, if combined with CX-4945 a synergistic inhibition was observed. In vivo assessment of CX-4945 in B-ALL cell line xenografts resulted in delayed proliferation of B-ALL cells. Combination with DEC further decelerated B-ALL expansion significantly and decreased infiltration in bone marrow and spleen. Effects in patient-derived xenografts all harboring a t(4;11) translocation were heterogeneous. Conclusions We herein demonstrate the anti-leukemic potential of CX-4945 in synergy with decitabine in vitro as well as in vivo identifying CK2 as a potentially targetable kinase in B-ALL. Electronic supplementary material The online version of this article (10.1186/s12885-019-5411-0) contains supplementary material, which is available to authorized users.

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

Cited by 23 publications

References 54 publications

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

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

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

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

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