Clinical cancer research : an official journal of the American Association for Cancer Research · 2025
Mechanism of Initial Favorable Response to Decitabine in TP53-Mutated MDS/AML and Potential Mechanisms of Subsequent Relapse.
СтатьяКлиническое исследование II фазыНазвание и аннотация: Перевод в очереди
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Ng Nelson K L, Lam Stephen S Y, Zheng Lichuan, Liu Xingliang, Liang Mingxuan, Ng Lam, Chan Koon C, Zhang Chun X, Tse Rachel L S, Cheung Arthur K L, Ip Ho-Wan, Au Chun H, Ma Edmond S K, Ng Chi T, Ni Ying, Li Run S, Ling Guang S, Leung Suet Y, Javed Asif, Leung Anskar Y H
Аннотация
PURPOSE: Myelodysplastic syndrome and acute myeloid leukemia with complex and monosomy karyotypes show a high prevalence of TP53 mutations (TP53m), poor response to induction chemotherapy, and adverse outcomes. These diseases may respond to decitabine, but the mechanisms are presently unclear.
EXPERIMENTAL DESIGN: Patients with myelodysplastic syndrome and acute myeloid leukemia were treated with decitabine for 10 days in a phase II clinical study. In this study, we collected serial samples from patients before and at the completion of decitabine treatment, morphologic remission, and relapse. The samples were interrogated with targeted myeloid panel sequencing, nanopore DNA cytosine methylation sequencing, and single-cell transcriptomics to investigate potential interactions between leukemic and immune populations.
RESULTS: The integrative analysis allowed for the characterization of shifting dynamics within leukemic and immune cell populations in individual patients. Single-cell transcriptomic analyses confirmed immune activation in TP53m responders after decitabine treatment. At relapse, leukemic populations showed upregulation of MYC signaling and heat shock response, whereas T cells showed an exhaustion signature.
CONCLUSIONS: Our work highlighted the complex interplay between leukemic and immune populations in TP53m patients upon decitabine treatment that might account for clinical responses and subsequent relapses.
EXPERIMENTAL DESIGN: Patients with myelodysplastic syndrome and acute myeloid leukemia were treated with decitabine for 10 days in a phase II clinical study. In this study, we collected serial samples from patients before and at the completion of decitabine treatment, morphologic remission, and relapse. The samples were interrogated with targeted myeloid panel sequencing, nanopore DNA cytosine methylation sequencing, and single-cell transcriptomics to investigate potential interactions between leukemic and immune populations.
RESULTS: The integrative analysis allowed for the characterization of shifting dynamics within leukemic and immune cell populations in individual patients. Single-cell transcriptomic analyses confirmed immune activation in TP53m responders after decitabine treatment. At relapse, leukemic populations showed upregulation of MYC signaling and heat shock response, whereas T cells showed an exhaustion signature.
CONCLUSIONS: Our work highlighted the complex interplay between leukemic and immune populations in TP53m patients upon decitabine treatment that might account for clinical responses and subsequent relapses.