Mechanisms of myeloid leukemogenesis: Current perspectives and therapeutic objectives

Bouligny, Ian Michael; Maher, Keri Renee; Grant, Steven

doi:10.1016/j.blre.2022.100996

Cited by 22 publications

(24 citation statements)

References 261 publications

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“…Its overexpression in myeloid malignancies correlates with increased methylation of the tumor suppressor p15INK4B and results in poor clinical outcomes. 35 Furthermore, the impact of EZH2 mutations, both gain-of-function and loss-of-function, on the progression of AML has been documented. 36 As a myelodysplasia-related (MDS-related) gene, EZH2 mutation in AML has been classified as adverse-risk group according to the 5th edition of WHO classifications and 2022 ELN risk stratification.…”

Section: Discussionmentioning

confidence: 99%

“…EZH2, as a part of the polycomb repressive complex 2, plays a critical role in gene transcription regulation through chromatin compaction. Its overexpression in myeloid malignancies correlates with increased methylation of the tumor suppressor p15INK4B and results in poor clinical outcomes 35 . Furthermore, the impact of EZH2 mutations, both gain‐of‐function and loss‐of‐function, on the progression of AML has been documented 36 .…”

Section: Discussionmentioning

confidence: 99%

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Clinical characteristics and prognosis of acute myeloid leukemia patients with Runt‐related transcription factor 1 mutation: A single‐center retrospective analysis

Wang,

Li,

Jiang

et al. 2024

Hematological Oncology

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This study aimed to investigate the clinical characteristics and prognosis of Runt‐related transcription factor 1 (RUNX1) mutant acute myeloid leukemia (AML) patients by comparing the features of AML patients with or without RUNX1 mutation. We retrospectively analyzed 180 AML patients including 36 AML patients with mutant RUNX1(AML‐RUNX1mut) and 144 AML patients with wild‐type RUNX1(AML‐RUNX1wt) were selected using the case‐pair method(1:4). Compared to AML‐RUNX1wt, AML‐RUNX1mut showed higher frequency of ASXL1 (p < 0.001), SRSF2 (p < 0.001), BCORL1 (p < 0.001), RAS (p = 0.010) mutations, and absent NPM1 mutations (p = 0.022). The 3‐year overall survival (OS) and disease‐free survival (DFS) of AML‐RUNX1mut and AML‐RUNX1wt were 73.1% versus 68.0% (p = 0.64) and 80.7% versus 71.6% (p = 0.37), respectively. AML‐RUNX1mut receiving allogeneic hematopoietic cell transplantation (allo‐HSCT) showed better survival than those who did not receive allo‐HSCT (3‐year OS, 84.3% vs. 52.7%; p = 0.006). Multivariate analysis showed that EZH2 mutation (p = 0.003), white blood cell (WBC) ≥30 × 109/L (p = 0.036) and age ≥60 years (p = 0.038) were significant independent risk factors for inferior OS of AML‐RUNX1mut; WBC ≥30 × 109/L (p = 0.013) and DNMT3A mutation (p = 0.045) were significant independent risk factors for shorter DFS of AML‐RUNX1mut. In conclusion, AML‐RUNX1mut showed unique clinical characteristics, but the survival between AML‐RUNX1mut and AML‐RUNX1wt were comparable. EZH2 co‐mutation, DNMT3A co‐mutation, old age and high WBC count were associated with inferior survival of AML‐RUNX1mut. Allo‐HSCT can significantly improve the prognosis of AML‐RUNX1mut.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Clinical characteristics and prognosis of acute myeloid leukemia patients with Runt‐related transcription factor 1 mutation: A single‐center retrospective analysis

Wang,

Li,

Jiang

et al. 2024

Hematological Oncology

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“…AML represents a malignancy stemming from aberrant white blood cells, integral components of the immune system [37]. The occurrence of dysregulation or abnormalities in key signaling pathways, such as NPM1, FLT3, and RUNX1, is closely linked to the development of AML [49,50]. These intricate pathways play pivotal roles in the regulation of cell proliferation, and mutations within them can signi cantly contribute to the unbridled proliferation or metastasis characteristic of AML.…”

Section: Discussionmentioning

confidence: 99%

Targeting AML Growth: Vitamins' Influence on FLT3, NPM1, and RUNX1 Interactions

Dasgupta,

Chatterjee,

Mondal

et al. 2023

Preprint

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The call for implementing inhibitory methods in cancer treatment has intensified. Recently, cancer has deeply affected society, with Acute Myeloid Leukemia (AML) being identified as one of the most formidable and lethal adversaries. This research investigates the intricate interactions between vitamins A, B, C, D, E, and K and critical signaling pathways, such as NPM1, FLT3, and RUNX1, uncovering meaningful associations. Employing the precision of molecular docking with Autodock Vina 1.5.7, a thorough exploration of these interactions was carried out. The analysis entailed a detailed examination of hydrophilic and hydrophobic aspects using LigPlot, complemented by additional insights visualized through PyMol. The considerable occurrence of observed hydrophilic interactions, coupled with the noteworthy binding energy, underscores the potential of vitamin-related derivatives as promising contenders for inhibitory cancer treatments. However, the realization of this potential is contingent upon subsequent investigations, including a comprehensive exploration through RT-qPCR studies. While the study has successfully identified significant interactions, the intricate dynamics of gene expression necessitate thorough studies to attain a holistic understanding of both upregulation and downregulation. In conclusion, the revelations from this study not only set the stage for potential inhibitory treatments of AML through the strategic application of vitamin-based derivatives but also underscore the transformative capabilities of these derivatives. In future research endeavors, should vitamin interactions reveal substantial downregulation, these derivatives stand poised to spearhead innovative cancer treatments, marking a transformative era in targeted drug delivery.

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“…Acute myeloid leukemia is a heterogeneous hematologic malignancy characterized by a maturation arrest of hematopoietic precursors [1]. Because AML is primarily a disease of older adults occurring at a median age of 68 years, many are ineligible for intensive chemotherapy [2,3].…”

Section: Introductionmentioning

confidence: 99%

Augmenting Venetoclax Activity Through Signal Transduction in AML

Bouligny

Maher

Grant

2023

Journal of Cellular Signaling

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Venetoclax, a small-molecule B-cell lymphoma 2 (BCL-2) inhibitor, selectively eradicates leukemic stem cells (LSCs). While venetoclax has revolutionized the treatment of acute myeloid leukemia (AML), treatment failure and disease relapse are common. Mechanisms underlying venetoclax resistance are surprisingly heterogeneous. Venetoclax resistance encompasses a spectrum of genetic and epigenetic changes, with numerous pathways contributing to the upregulation of additional anti-apoptotic proteins. In this review, we address the mechanisms of venetoclax resistance in the context of signal transduction. We emphasize how aberrant cell signaling impairs apoptosis and predisposes to venetoclax failure. Commonly activated pathways, such as FLT3, PI3K/AKT/mTOR, and RAS, contribute to upregulated anti-apoptotic mediators and are frequently responsible for refractory disease or disease relapse. We highlight novel combination strategies aimed at disabling constitutively active signal transduction to augment response and overcome venetoclax resistance.

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Mechanisms of myeloid leukemogenesis: Current perspectives and therapeutic objectives

Cited by 22 publications

References 261 publications

Clinical characteristics and prognosis of acute myeloid leukemia patients with Runt‐related transcription factor 1 mutation: A single‐center retrospective analysis

Clinical characteristics and prognosis of acute myeloid leukemia patients with Runt‐related transcription factor 1 mutation: A single‐center retrospective analysis

Targeting AML Growth: Vitamins' Influence on FLT3, NPM1, and RUNX1 Interactions

Augmenting Venetoclax Activity Through Signal Transduction in AML

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