Recent Publication
Mechanism of Initial Favorable Response to Decitabine in TP53-Mutated MDS/AML and Potential Mechanisms of Subsequent Relapse
Clin Cancer Res (2025) 31 (14): 3048–3061
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.
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. 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. 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. 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.
Photo selected as cover page
The cover shows a patient’s trephine biopsy on day 28 after a 10-day decitabine treatment. The biopsy shows interstitial lymphocytic aggregates comprising small lymphocytes; blasts were not increased. For details, see the article by Ng and colleagues on page 3048 of this issue.
Inhibition of PLK4 remodels histone methylation and activates immune response via cGAS-STING pathway in TP53 mutated AML
Blood (2023) 142 (23): 2002–2015
Man CH, Lam W, Dang CC, Zeng XY, Zheng LC, Chan NN, Ng NKL, Chan KC, Kwok TH, Ng TC, Leung WY, Huen M, Wong CC, So CWE, Dou Z, Goyama S, Bray MR, Mak TW, Leung AYH.
Acute myeloid leukemia (AML) with TP53 mutation is one of the most lethal cancers and portends an extremely poor prognosis. Based on in silico analyses of druggable genes and differential gene expression in TP53 mutated AML, we identified polo-like kinase 4 (PLK4) as a novel therapeutic target and examined its expression, regulation, pathogenetic mechanisms and therapeutic potential in TP53 mutated AML. PLK4 expression was suppressed by activated p53 signaling in TP53 wildtype AML and was increased in TP53 mutated AML cell lines and primary samples. Short-term PLK4 inhibition induced DNA damage and apoptosis in TP53 wildtype AML. Prolonged PLK4 inhibition suppressed the growth of TP53 mutated AML and was associated with DNA damage, apoptosis, senescence, polyploidy and defective cytokinesis. A hitherto undescribed PLK4/PRMT5/EZH2/H3K27me3 axis was demonstrated in both TP53 wildtype and mutated AML, resulting in histone modification through PLK4 induced PRMT5 phosphorylation. In TP53 mutated AML, combined effects of histone modification and polyploidy activated the cGAS-STING pathway, leading to secretion of cytokines and chemokines and activation of macrophages and T cells upon co-culture with AML cells. In vivo, PLK4 inhibition also induced cytokine and chemokine expression in mouse recipients and its combination with anti-CD47 antibody, which inhibited the "don't-eat-me" signal in macrophages, synergistically reduced leukemic burden and prolonged animal survival. The study shed important light on the pathogenetic role of PLK4 and might lead to novel therapeutic strategies in TP53 mutated AML.​
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Wang, D., Zheng, L., Cheng, B. Y. L., Sin, C. F., Li, R., Tsui, S. P., Yi, X., Ma, A. C. H., He, B. L., Leung, A. Y. H. & Sun, X.
Isocitrate dehydrogenase 2 (IDH2) mutations occur in more than 15% of cytogenetically normal acute myeloid leukemia (CN-AML) but comparative studies of their roles in leukemogenesis have been scarce. We generated zebrafish models of IDH2R172K and IDH2R140Q AML and reported their pathologic, functional and transcriptomic features and therapeutic responses to target therapies. Transgenic embryos co-expressing FLT3ITD and IDH2 mutations showed accentuation of myelopoiesis. As these embryos were raised to adulthood, full-blown leukemia ensued with multi-lineage dysplasia, increase in myeloblasts and marrow cellularity and splenomegaly. The leukemia cells were transplantable into primary and secondary recipients and resulted in more aggressive disease. Tg(Runx1:FLT3ITDIDH2R172K) but not Tg(Runx1:FLT3ITDIDH2R140Q) zebrafish showed an increase in T-cell development at embryonic and adult stages. Single-cell transcriptomic analysis revealed increased myeloid skewing, differentiation blockade and enrichment of leukemia-associated gene signatures in both zebrafish models. Tg(Runx1:FLT3ITDIDH2R172K) but not Tg(Runx1:FLT3ITDIDH2R140Q) zebrafish showed an increase in interferon signals at the adult stage. Leukemic phenotypes in both zebrafish could be ameliorated by quizartinib and enasidenib. In conclusion, the zebrafish models of IDH2 mutated AML recapitulated the morphologic, clinical, functional and transcriptomic characteristics of human diseases, and provided the prototype for developing zebrafish leukemia models of other genotypes that would become a platform for high throughput drug screening.
