Genetic regulation of the RUNX transcription factor family has antitumor effects

Morita, Ken; Suzuki, K.; Maeda, Shuichi; Matsuo, Akihiko; Mitsuda, Yoshihide; Tokushige, Chieko; Kashiwazaki, Gengo; Taniguchi, Jun; Maeda, Rina; Noura, Mina; Hirata, Masahiro; Kataoka, Tatsuki R.; Yano, Ayaka; Yamada, Yoshimi; Kiyose, Hiroki; Tokumasu, Mayu; Matsuo, Hidemasa; Tanaka, Sunao; Okuno, Yasushi; Muto, Manabu; Naka, Kazuhito; Ito, Kosei; Kitamura, Toshio; Kaneda, Yasufumi; Liu, Paul P.; Bando, Toshikazu; Adachi, Souichi; Sugiyama, Hiroshi; Kamikubo, Yasuhiko

doi:10.1172/jci91788

Cited by 104 publications

(201 citation statements)

References 51 publications

(53 reference statements)

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“…Recently, we have reported that RUNX cluster regulation is a promising therapeutic strategy against various types of cancers, including AML. 6 Although our previous work validated the antitumor potential of RUNX1-inhibiton strategy, the precise mechanisms of how RUNX1 engages in tumorigenesis remain elusive. While assessing the significance of RUNX1 expressions in the prognosis of de novo AML patients, we have coincidentally found that the RUNX1-intermediately-expressing cohort exhibit the worst outcomes among them.…”

Section: Discussionmentioning

confidence: 90%

“…[3][4][5] We have also discovered the requirement of RUNX family proteins in the maintenance of leukemia cells as well as of tumors derived from various origins and first shed light on the oncogenic property of RUNX family proteins in the initiation and maintenance of malignant tumors in general. 6 Although we have revealed the functional redundancy of RUNX family members in leukemogenesis and the significance of total amount of RUNX family (RUNX1 1 RUNX2 1 RUNX3) expressions in the maintenance of AML cells in the previous report, the impact of RUNX1 expression levels on the total amount of RUNX expressions or the precise mechanism of RUNX1-derived tumorigenesis remains elusive. 6 Glutathione S-transferase (GST) is a cytosolic and membranebound enzyme handling the detoxification of electrophilic compounds such as chemotherapeutic drugs, environmental toxins, and products of oxidative stress, through conjugating with glutathione.…”

mentioning

confidence: 79%

“…6 Although we have revealed the functional redundancy of RUNX family members in leukemogenesis and the significance of total amount of RUNX family (RUNX1 1 RUNX2 1 RUNX3) expressions in the maintenance of AML cells in the previous report, the impact of RUNX1 expression levels on the total amount of RUNX expressions or the precise mechanism of RUNX1-derived tumorigenesis remains elusive. 6 Glutathione S-transferase (GST) is a cytosolic and membranebound enzyme handling the detoxification of electrophilic compounds such as chemotherapeutic drugs, environmental toxins, and products of oxidative stress, through conjugating with glutathione. At present, 8 distinct classes of the soluble cytoplasmic mammalian glutathione S-transferases have been identified, and the a subtype (GSTA) is the most abundant form among them.…”

mentioning

confidence: 79%

“…Relative luciferase activity Cell number ( X 10 4 cells) RUNX family members such as RUNX2 and RUNX3 upon RUNX1 silencing, because RUNX family members have redundant biological functions in leukemogenesis 6 and this mutual compensation among RUNX family members could possibly take part in the fine-tuning of GSTA2 expressions. Interestingly, the equivalent level of compensatory upregulation of RUNX2 and RUNX3 expressions were observed in sh_Rx1_moderate-transduced and sh_Rx1_profound-transduced AML cells.…”

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confidence: 99%

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Paradoxical enhancement of leukemogenesis in acute myeloid leukemia with moderately attenuated RUNX1 expressions

Morita¹,

Maeda²,

Suzuki³

et al. 2017

Blood Advances

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Key Points• Moderate attenuation of RUNX1 expression upregulates total RUNX expressions and enhances leukemogenesis through RUNX-GSTA2-ROS axis.• Inhibiting GSTA2 function in vivo prolongs the overall survival of AML mice with intermediate RUNX1 expressions.Besides being a classical tumor suppressor, runt-related transcription factor 1 (RUNX1) is now widely recognized for its oncogenic role in the development of acute myeloid leukemia (AML). Here we report that this bidirectional function of RUNX1 possibly arises from the total level of RUNX family expressions. Indeed, analysis of clinical data revealed that intermediatelevel gene expression of RUNX1 marked the poorest-prognostic cohort in relation to AML patients with high-or low-level RUNX1 expressions. Through a series of RUNX1 knockdown experiments with various RUNX1 attenuation potentials, we found that moderate attenuation of RUNX1 contributed to the enhanced propagation of AML cells through accelerated cell-cycle progression, whereas profound RUNX1 depletion led to cell-cycle arrest and apoptosis. In these RUNX1-silenced tumors, amounts of compensative upregulation of RUNX2 and RUNX3 expressions were roughly equivalent and created an absolute elevation of total RUNX (RUNX1 1 RUNX2 1 RUNX3) expression levels in RUNX1 moderately attenuated AML cells. This elevation resulted in enhanced transactivation of glutathione S-transferase a 2 (GSTA2) expression, a vital enzyme handling the catabolization of intracellular reactive oxygen species (ROS) as well as advancing the cell-cycle progressions, and thus ultimately led to the acquisition of proliferative advantage in RUNX1 moderately attenuated AML cells. Besides, treatment with ethacrynic acid, which is known for its GSTA inhibiting property, actually prolonged the survival of AML mice in vivo. Collectively, our findings indicate that moderately attenuated RUNX1 expressions paradoxically enhance leukemogenesis in AML cells through intracellular environmental change via GSTA2, which could be a novel therapeutic target in antileukemia strategy. IntroductionRUNX1, a member of RUNX transcription family proteins (RUNX1, RUNX2, and RUNX3), is an essential transcription factor mediating diverse functions in mammalian cells including cell differentiation, proliferation, cell-cycle regulation, and apoptosis. RUNX1 forms a stable heterodimeric complex with core-binding factor beta on the genome DNA sequence specifically and enhances the transcription of the target genes. Frequent gene alterations including mutations and translocations in RUNX1 provided the basis for classical conception that regards RUNX1 as an oncosuppressor. 1,2 This classical viewpoint has been challenged by our recent findings that wild-type RUNX1 is stringently required for the development of acute myeloid leukemia (AML) with inv (16) The full-text version of this article contains a data supplement. 14408 AUGUST 2017 x VOLUME 1, NUMBER 18fusions. [3][4][5] We have also discovered the requirement of RUNX family proteins in the maintenance of leukemi...

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Section: Discussionmentioning

confidence: 90%

mentioning

confidence: 79%

mentioning

confidence: 79%

mentioning

confidence: 99%

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Paradoxical enhancement of leukemogenesis in acute myeloid leukemia with moderately attenuated RUNX1 expressions

Morita¹,

Maeda²,

Suzuki³

et al. 2017

Blood Advances

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“…While the leukemogenic role of Runt-related (RUNX) transcription factors has been intensively studied and well described in acute myeloid leukemia (AML), [1][2][3][4][5][6] little is known about the effect of RUNX inhibition on the microenvironment surrounding tumor cells in vivo. Leukemic stem cells reside in the distinct regions within this microenvironment called niches.…”

Section: Introductionmentioning

confidence: 99%

RUNX transcription factors potentially control E-selectin expression in the bone marrow vascular niche in mice

Morita¹,

Tokushige²,

Maeda³

et al. 2018

Blood Advances

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Pyrrole–Imidazole Polyamides – A Frontrunner in Nucleic Acid‐Based Small Molecule Drugs

Vaijayanthi

Pandian

Sugiyama

2023

Advanced Therapeutics

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The remarkable success of messenger RNA vaccines against the ongoing coronavirus-2019 (COVID-19) pandemic renews attention toward nucleic acid therapeutics. While nucleic acid therapy using unmodified DNA or RNA is the primary focus in disease treatment, there is growing need to develop nucleic acid-based small molecules owing to their potential clinical benefits as drugs in terms of cost and scalability. While small molecules targeting protein-protein interactions are known to alter the transcriptional status of a cell, they can result in a transient effect and variation of bio-efficacy among patients. Small molecules targeting DNA and/or RNA are in demand in the precision medicine approach as they have consistent bioactivity among patients. This review details the progress of sequence-specific DNA-binding pyrrole-imidazole polyamides (PIPs) in modulating the transcriptional status of target gene(s) without altering the underlying DNA sequence. Here, the different versions of PIPs are listed, and also, how conjugating them with DNA alkylating agents, epigenetic modulators, and other drugs can improve their clinical utility as targeted transcription therapeutics. Owing to their specificity, functional diversity, and limited toxicity, PIP technology holds enormous promise as frontrunner in small-molecule-based nucleic acid drugs to precisely regulate therapeutically important genes on demand and treat intractable diseases.

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Genetic regulation of the RUNX transcription factor family has antitumor effects

Cited by 104 publications

References 51 publications

Paradoxical enhancement of leukemogenesis in acute myeloid leukemia with moderately attenuated RUNX1 expressions

Paradoxical enhancement of leukemogenesis in acute myeloid leukemia with moderately attenuated RUNX1 expressions

RUNX transcription factors potentially control E-selectin expression in the bone marrow vascular niche in mice

Pyrrole–Imidazole Polyamides – A Frontrunner in Nucleic Acid‐Based Small Molecule Drugs

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