Mechanism of Initial Favorable Response to Decitabine in TP53-Mutated MDS/AML and Potential Mechanisms of Subsequent Relapse

Nelson K.L. Ng; Stephen S.Y. Lam; Lichuan Zheng; Xingliang Liu; Mingxuan Liang; Lam Ng; Koon C. Chan; Chun X. Zhang; Rachel L.S. Tse; Arthur K.L. Cheung; Ho-Wan Ip; Chun H. Au; Edmond S.K. Ma; Chi T. Ng; Ying Ni; Run S. Li; Guang S. Ling; Suet Y. Leung; Asif Javed; Anskar Y.H. Leung

doi:10.1158/1078-0432.CCR-24-3192

Mechanism of Initial Favorable Response to Decitabine in TP53-Mutated MDS/AML and Potential Mechanisms of Subsequent Relapse

Nelson K.L. Ng (Co-first Author)
, Stephen S.Y. Lam (Co-first Author)
, Lichuan Zheng (Co-first Author)
, Xingliang Liu (Co-first Author)
, Mingxuan Liang
, Lam Ng
, Koon C. Chan
, Chun X. Zhang
, Rachel L.S. Tse
, Arthur K.L. Cheung
, Ho-Wan Ip
, Chun H. Au
, Edmond S.K. Ma
, Chi T. Ng
, Ying Ni
, Run S. Li
, Guang S. Ling
, Suet Y. Leung
, Asif Javed^*
, Anskar Y.H. Leung^*

^*Corresponding author for this work

Department of Infectious Diseases and Public Health

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

1 Citation (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	3048-3061
Journal	Clinical Cancer Research
Volume	31
Issue number	14
Online published	21 May 2025
DOIs	https://doi.org/10.1158/1078-0432.CCR-24-3192
Publication status	Published - 15 Jul 2025

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SDG 3 Good Health and Well-being

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Ng, N. K. L., Lam, S. S. Y., Zheng, L., Liu, X., Liang, M., Ng, L., Chan, K. C., Zhang, C. X., Tse, R. L. S., Cheung, A. K. L., Ip, H.-W., Au, C. H., Ma, E. S. K., Ng, C. T., Ni, Y., Li, R. S., Ling, G. S., Leung, S. Y., Javed, A., & Leung, A. Y. H. (2025). Mechanism of Initial Favorable Response to Decitabine in TP53-Mutated MDS/AML and Potential Mechanisms of Subsequent Relapse. Clinical Cancer Research, 31(14), 3048-3061. https://doi.org/10.1158/1078-0432.CCR-24-3192

@article{a8d14a3f17e64a7b9c568fb1b4e8867b,

title = "Mechanism of Initial Favorable Response to Decitabine in TP53-Mutated MDS/AML and Potential Mechanisms of Subsequent Relapse",

abstract = "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. {\textcopyright}2025 American Association for Cancer Research.",

author = "Ng, \{Nelson K.L.\} and Lam, \{Stephen S.Y.\} and Lichuan Zheng and Xingliang Liu and Mingxuan Liang and Lam Ng and Chan, \{Koon C.\} and Zhang, \{Chun X.\} and Tse, \{Rachel L.S.\} and Cheung, \{Arthur K.L.\} and Ho-Wan Ip and Au, \{Chun H.\} and Ma, \{Edmond S.K.\} and Ng, \{Chi T.\} and Ying Ni and Li, \{Run S.\} and Ling, \{Guang S.\} and Leung, \{Suet Y.\} and Asif Javed and Leung, \{Anskar Y.H.\}",

note = "{\textcopyright}2025 American Association for Cancer Research.",

year = "2025",

month = jul,

day = "15",

doi = "10.1158/1078-0432.CCR-24-3192",

language = "English",

volume = "31",

pages = "3048--3061",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research",

number = "14",

}

Ng, NKL, Lam, SSY, Zheng, L, Liu, X, Liang, M, Ng, L, Chan, KC, Zhang, CX, Tse, RLS, Cheung, AKL, Ip, H-W, Au, CH, Ma, ESK, Ng, CT, Ni, Y , Li, RS, Ling, GS, Leung, SY, Javed, A & Leung, AYH 2025, 'Mechanism of Initial Favorable Response to Decitabine in TP53-Mutated MDS/AML and Potential Mechanisms of Subsequent Relapse', Clinical Cancer Research, vol. 31, no. 14, pp. 3048-3061. https://doi.org/10.1158/1078-0432.CCR-24-3192

Mechanism of Initial Favorable Response to Decitabine in TP53-Mutated MDS/AML and Potential Mechanisms of Subsequent Relapse. / Ng, Nelson K.L. (Co-first Author); Lam, Stephen S.Y. (Co-first Author); Zheng, Lichuan (Co-first Author) et al.
In: Clinical Cancer Research, Vol. 31, No. 14, 15.07.2025, p. 3048-3061.

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

TY - JOUR

T1 - Mechanism of Initial Favorable Response to Decitabine in TP53-Mutated MDS/AML and Potential Mechanisms of Subsequent Relapse

AU - Ng, Nelson K.L.

AU - Lam, Stephen S.Y.

AU - Zheng, Lichuan

AU - Liu, Xingliang

AU - Liang, Mingxuan

AU - Ng, Lam

AU - Chan, Koon C.

AU - Zhang, Chun X.

AU - Tse, Rachel L.S.

AU - Cheung, Arthur K.L.

AU - Ip, Ho-Wan

AU - Au, Chun H.

AU - Ma, Edmond S.K.

AU - Ng, Chi T.

AU - Ni, Ying

AU - Li, Run S.

AU - Ling, Guang S.

AU - Leung, Suet Y.

AU - Javed, Asif

AU - Leung, Anskar Y.H.

PY - 2025/7/15

Y1 - 2025/7/15

N2 - 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. ©2025 American Association for Cancer Research.

AB - 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. ©2025 American Association for Cancer Research.

U2 - 10.1158/1078-0432.CCR-24-3192

DO - 10.1158/1078-0432.CCR-24-3192

M3 - RGC 21 - Publication in refereed journal

C2 - 40397797

SN - 1078-0432

VL - 31

SP - 3048

EP - 3061

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 14

ER -

Mechanism of Initial Favorable Response to Decitabine in TP53-Mutated MDS/AML and Potential Mechanisms of Subsequent Relapse

Abstract

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