Decitabine enhances chemosensitivity of early T-cell precursor-acute lymphoblastic leukemia cell lines and patient-derived samples

Lu, Benjamin Y.; Thanawala, Shivani U.; Zochowski, Kelly C.; Burke, Michael J.; Carroll, William L.; Bhatla, Teena

doi:10.3109/10428194.2015.1110747

Cited by 25 publications

(18 citation statements)

References 17 publications

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“…To our knowledge, we investigated for the first time biological effects on MLL-positive BCP-ALL cells in regard to sequence of drug exposure including HMA. In previous studies, it has been shown that HMA influenced chemosensitivity of ALL cells differently [ 36 , 40 ]. Lu et al investigated HMA effects on a panel of T-ALL cells [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…In previous studies, it has been shown that HMA influenced chemosensitivity of ALL cells differently [ 36 , 40 ]. Lu et al investigated HMA effects on a panel of T-ALL cells [ 36 ]. They demonstrated synergistic as well as antagonistic effects when cells were exposed sequentially with DEC followed by application of prednisolone, etoposide, or AraC.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, in the same study, most pronounced effects were observed on RS4;11 cells. Strong synergistic effects were induced after pretreatment of DEC followed by AraC exposure [ 36 ]. Again, drug concentrations might explain differences to our results.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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“…Decitabine has also been studied in preclinical trials of early T-cell precursor ALL (ETP-ALL), where it has been shown to be synergistic to conventional chemotherapy. 140 Decitabine is currently being studied in the post-Allo-SCT setting (NCT02264873) and in combination with clofarabine, idarubicin and cytarabine for relapsed/refractory AML and ALL (NCT01794702).…”

Section: Future Therapiesmentioning

confidence: 99%

Acute lymphoblastic leukemia: a comprehensive review and 2017 update

2017

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Acute lymphoblastic leukemia (ALL) is the second most common acute leukemia in adults, with an incidence of over 6500 cases per year in the United States alone. The hallmark of ALL is chromosomal abnormalities and genetic alterations involved in differentiation and proliferation of lymphoid precursor cells. In adults, 75% of cases develop from precursors of the B-cell lineage, with the remainder of cases consisting of malignant T-cell precursors. Traditionally, risk stratification has been based on clinical factors such age, white blood cell count and response to chemotherapy; however, the identification of recurrent genetic alterations has helped refine individual prognosis and guide management. Despite advances in management, the backbone of therapy remains multi-agent chemotherapy with vincristine, corticosteroids and an anthracycline with allogeneic stem cell transplantation for eligible candidates. Elderly patients are often unable to tolerate such regimens and carry a particularly poor prognosis. Here, we review the major recent advances in the treatment of ALL.

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“…Lu et al [13] tested the role of DNA methyltransferase inhibitor decitabine in pretreating ETP-ALL through the vitro test and suggesting that decitabine could enhance the chemosensitivity in ETP-ALL. [14] Sachiko Kawashima-Goto [15] suggested the Bcl2 inhibitor (ABT-737) can recover the sensitivity to prednisolone in leukemic cells with a high expression of MEF2C. Based on this, inhibition of Bcl2 might become a therapeutic candidate for ETP-ALL patients.…”

Section: Discussionmentioning

confidence: 99%

Clinical and molecular characterization of early T-cell precursor acute lymphoblastic leukemia

Wang

Wu²,

Zhang³

2018

Medicine

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Rationale:Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a small subtype of T-cell acute lymphoblastic leukemia with a typical immune-phenotype: lack of T-lineage cell surface markers CD1a and CD8 expression, weak or absent CD5 expression, at least one of the myeloid or hematopoietic stem cell markers. It is characterized by high rate of induction failure and the effective unified treatment strategies are still indeterminate. We present 2 ETP-ALL cases.Patient concerns:A 42-year-old man presented with abnormal hemogram for 4 months, intermittent fever for 2 months and cough for 1 week. A 27-year-old woman was admitted to the hospital for a fever and headache for that had persisted for 1 week.Diagnosis:The peripheral blood examination, the bone marrow aspiration and flow cytometry for both patients revealed ETP-ALL.Interventions:Both cases accepted chemotherapy including cytarabine.Outcomes:In case one, the patient reached complete hematological remission with negative minimal residual detected by flow cytometry after the first circle of chemotherapy. In case 2, the patient received complete remission after the second circle of chemotherapy with high doses of cytarabine.Lessons:The application of the high-dose cytarabine in induction chemotherapy of ETP-ALL can bring better outcome. ETP-ALL with myeloid features may benefit from therapies used in myeloid malignancies.

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Decitabine enhances chemosensitivity of early T-cell precursor-acute lymphoblastic leukemia cell lines and patient-derived samples

Cited by 25 publications

References 17 publications

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

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

Acute lymphoblastic leukemia: a comprehensive review and 2017 update

Clinical and molecular characterization of early T-cell precursor acute lymphoblastic leukemia

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