Adult Acute Myeloid Leukemia Long-Term Survivors

Cheng, Maojie; Hourigan, Christopher S.; Smith, Thomas J.

doi:10.4172/2329-6917.1000135

Cited by 13 publications

(12 citation statements)

References 82 publications

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“…Acute myeloid leukemia (AML) is characterized by clonal expansion of undifferentiated myeloid precursors (Cheng et al 2014 ; Papaemmanuil et al 2016 ). Although classical chemotherapy can achieve complete remission (CR) in the majority of AML patients, the relapse rate within 3 years of diagnosis is 50–70% and the 5-year overall survival in adult AML patients is only 5–55% (Al-Hussaini and DiPersio 2014 ; Byrd et al 2002 ; Cheng et al 2014 ). Novel therapeutic agents are desperately needed for AML to overcome continued poor outcomes.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic potential of GSK-J4, a histone demethylase KDM6B/JMJD3 inhibitor, for acute myeloid leukemia

Zhang

Sheng

et al. 2018

J Cancer Res Clin Oncol

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PurposeAcute myeloid leukemia (AML) is a heterogeneous disease with poor outcomes. Despite increased evidence shows that dysregulation of histone modification contributes to AML, specific drugs targeting key histone modulators are not applied in the clinical treatment of AML. Here, we investigated whether targeting KDM6B, the demethylase of tri-methylated histone H3 lysine 27 (H3K27me3), has a therapeutic potential for AML.MethodsA KDM6B-specific inhibitor, GSK-J4, was applied to treat the primary cells from AML patients and AML cell lines in vitro and in vivo. RNA-sequencing was performed to reveal the underlying mechanisms of inhibiting KDM6B for the treatment of AML.ResultsHere we observed that the mRNA expression of KDM6B was up-regulated in AML and positively correlated with poor survival. Treatment with GSK-J4 increased the global level of H3K27me3 and reduced the proliferation and colony-forming ability of primary AML cells and AML cell lines. GSK-J4 treatment significantly induced cell apoptosis and cell-cycle arrest in Kasumi-1 cells, and displayed a synergistic effect with cytosine arabinoside. Notably, injection of GSK-J4 attenuated the disease progression in a human AML xenograft mouse model in vivo. Treatment with GSK-J4 predominantly resulted in down-regulation of DNA replication and cell-cycle-related pathways, as well as abrogated the expression of critical cancer-promoting HOX genes. ChIP-qPCR validated an increased enrichment of H3K27me3 in the transcription start sites of these HOX genes.ConclusionsIn summary, our findings suggest that targeting KDM6B with GSK-J4 has a therapeutic potential for the treatment of AML.Electronic supplementary materialThe online version of this article (10.1007/s00432-018-2631-7) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Therapeutic potential of GSK-J4, a histone demethylase KDM6B/JMJD3 inhibitor, for acute myeloid leukemia

Zhang

Sheng

et al. 2018

J Cancer Res Clin Oncol

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“…It has been estimated that of those patients who will achieve initial remission, approximately 50-70% of them will relapse within three years. Nevertheless, a lower percentage of adult AML patients survive to five years [37] while some infrequent cases with survival over ten years have also been reported [38]. In general, across several cancer types, there are rare cases of patients who manage to remain progression-free for atypically long durations of time, while in some rare cases patients never relapse [20,39].…”

Section: Inferring Favorable Prognostic Markers From the Transcriptomic Profiles Of Long-term Survivors Of Amlmentioning

confidence: 99%

In Silico Methods for the Identification of Diagnostic and Favorable Prognostic Markers in Acute Myeloid Leukemia

Yilmaz

Toy

Marquardt

et al. 2021

IJMS

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Acute myeloid leukemia (AML), the most common type of acute leukemia in adults, is mainly asymptomatic at early stages and progresses/recurs rapidly and frequently. These attributes necessitate the identification of biomarkers for timely diagnosis and accurate prognosis. In this study, differential gene expression analysis was performed on large-scale transcriptomics data of AML patients versus corresponding normal tissue. Weighted gene co-expression network analysis was conducted to construct networks of co-expressed genes, and detect gene modules. Finally, hub genes were identified from selected modules by applying network-based methods. This robust and integrative bioinformatics approach revealed a set of twenty-four genes, mainly related to cell cycle and immune response, the diagnostic significance of which was subsequently compared against two independent gene expression datasets. Furthermore, based on a recent notion suggesting that molecular characteristics of a few, unusual patients with exceptionally favorable survival can provide insights for improving the outcome of individuals with more typical disease trajectories, we defined groups of long-term survivors in AML patient cohorts and compared their transcriptomes versus the general population to infer favorable prognostic signatures. These findings could have potential applications in the clinical setting, in particular, in diagnosis and prognosis of AML.

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“…The consistent inclusion of MRD in AML in a setting like the one described will ultimately result in a smoother and more evidence-based methodology for following these patients. The impact of such an individualized monitoring strategy on patient anxiety and post-treatment health-related quality of life (HRQOL) should be studied [97]. …”

Section: What Are the Constraints That Impact Aml Mrd And Its Adoptiomentioning

confidence: 99%

Advancing the Minimal Residual Disease Concept in Acute Myeloid Leukemia

Hokland

Ommen

Mulè

et al. 2015

Seminars in Hematology

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The criteria to evaluate response to treatment in acute myeloid leukemia (AML) have changed little in the past sixty years. It is now possible to use higher sensitivity tools to measure residual disease burden in AML. Such minimal or measurable residual disease (MRD) measurements provide a deeper understanding of current patient status and allow stratification for risk of subsequent clinical relapse. Despite these obvious advantages, and after over a decade of laboratory investigation and pre-clinical validation, MRD measurements are not currently routinely used for clinical decision-making or drug development in non-APL AML. We review here some potential constraints that may have delayed adoption including a natural hesitancy of end users, economic impact concerns, misperceptions regarding the meaning of and need for assay sensitivity, the lack of one single MRD solution for all AML patients and finally the need to involve patients in decision making based on such correlates. It is our opinion that none of these issues represent insurmountable barriers and our hope is that by providing potential solutions we can help map a path forward to a future where our patients will be offered personalized treatment plans based on the amount of AML they have left remaining to treat.

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Adult Acute Myeloid Leukemia Long-Term Survivors

Cited by 13 publications

References 82 publications

Therapeutic potential of GSK-J4, a histone demethylase KDM6B/JMJD3 inhibitor, for acute myeloid leukemia

Therapeutic potential of GSK-J4, a histone demethylase KDM6B/JMJD3 inhibitor, for acute myeloid leukemia

In Silico Methods for the Identification of Diagnostic and Favorable Prognostic Markers in Acute Myeloid Leukemia

Advancing the Minimal Residual Disease Concept in Acute Myeloid Leukemia

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