TY - JOUR

T1 - Activation of a subset of evolutionarily young transposable elements and innate immunity are linked to clinical responses to 5-azacytidine

AU - Ohtani, Hitoshi

AU - Ørskov, Andreas D.

AU - Helbo, Alexandra S.

AU - Gillberg, Linn

AU - Liu, Minmin

AU - Zhou, Wanding

AU - Ungerstedt, Johanna

AU - Hellström-Lindberg, Eva

AU - Sun, Weili

AU - Liang, Gangning

AU - Jones, Peter A.

AU - Grønbæk, Kirsten

PY - 2020

Y1 - 2020

N2 - The DNA methyltransferase inhibitors (DNMTi) 5-azacyti-dine and 5-aza-2-deoxycytidine have been approved for the treatment of different types of hematologic malignancies. However, only about 50% of patients respond to treatment. Therefore, a more comprehensive understanding of the molecular changes in patients treated with DNMTi is needed. Here, we examined gene expression profiles in a total of 150 RNA samples from two adult cohorts and one pediatric cohort with hematologic cancers taken before, during, and after treatment with 5-azacytidine (40 patients; 15 nonresponders, 25 responders). Using each patient as their own control, malignant cells showed preferential activation of a subset of evolutionarily young transposable elements (TE), including endogenous retroviral long terminal repeats (LTR), short and long interspersed nuclear elements (SINE and LINE), and the type I IFN pathway in responders, all independent of disease classification. Transfection of eight upregulated LTRs into recipient human cells in culture showed robust and heterogenous activation of six genes in the type I IFN pathway. These results, obtained in diverse hematologic disease entities, show that common targets (TE) activated by the same drug (5-azacy-tidine) elicit an immune response, which may be important for patient's responses to DNMTi.

AB - The DNA methyltransferase inhibitors (DNMTi) 5-azacyti-dine and 5-aza-2-deoxycytidine have been approved for the treatment of different types of hematologic malignancies. However, only about 50% of patients respond to treatment. Therefore, a more comprehensive understanding of the molecular changes in patients treated with DNMTi is needed. Here, we examined gene expression profiles in a total of 150 RNA samples from two adult cohorts and one pediatric cohort with hematologic cancers taken before, during, and after treatment with 5-azacytidine (40 patients; 15 nonresponders, 25 responders). Using each patient as their own control, malignant cells showed preferential activation of a subset of evolutionarily young transposable elements (TE), including endogenous retroviral long terminal repeats (LTR), short and long interspersed nuclear elements (SINE and LINE), and the type I IFN pathway in responders, all independent of disease classification. Transfection of eight upregulated LTRs into recipient human cells in culture showed robust and heterogenous activation of six genes in the type I IFN pathway. These results, obtained in diverse hematologic disease entities, show that common targets (TE) activated by the same drug (5-azacy-tidine) elicit an immune response, which may be important for patient's responses to DNMTi.

U2 - 10.1158/0008-5472.CAN-19-1696

DO - 10.1158/0008-5472.CAN-19-1696

M3 - Journal article

C2 - 32245794

AN - SCOPUS:85086497441

VL - 80

SP - 2441

EP - 2450

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 12

ER -