Targeting nuclear β-catenin as therapy for post-myeloproliferative neoplasm secondary AML

Saenz, Dyana T.; Fiskus, Warren; Manshouri, Taghi; Mill, Christopher; Qian, Yimin; Raina, Kanak; Rajapakshe, Kimal; Coarfa, Cristian; Soldi, Raffaella; Bose, Prithviraj; Borthakur, Gautam; Kadia, Tapan M.; Khoury, Joseph D.; Masárová, Lucia; Nowak, Agnieszka; Sun, Baohua; Saenz, David N.; Kornblau, Steven M.; Horrigan, Steve; Sharma, Sunil; Qiu, Peng; Crews, Craig M.; Verstovšek, Srđan; Bhalla, Kapil N.

doi:10.1038/s41375-018-0334-3

Cited by 34 publications

(29 citation statements)

References 54 publications

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“…Since there is ample evidence for an interaction of β-catenin, MYC, and WT1 at multiple levels (e.g., [13,23,37,38,39,40,45,68]), we tested with RNAi whether these factors regulate each other in MV4-11 cells.…”

Section: Resultsmentioning

confidence: 99%

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HDAC3 Activity is Essential for Human Leukemic Cell Growth and the Expression of β-catenin, MYC, and WT1

Beyer

Romański

Mustafa

et al. 2019

Cancers

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Therapy of acute myeloid leukemia (AML) is unsatisfactory. Histone deacetylase inhibitors (HDACi) are active against leukemic cells in vitro and in vivo. Clinical data suggest further testing of such epigenetic drugs and to identify mechanisms and markers for their efficacy. Primary and permanent AML cells were screened for viability, replication stress/DNA damage, and regrowth capacities after single exposures to the clinically used pan-HDACi panobinostat (LBH589), the class I HDACi entinostat/romidepsin (MS-275/FK228), the HDAC3 inhibitor RGFP966, the HDAC6 inhibitor marbostat-100, the non-steroidal anti-inflammatory drug (NSAID) indomethacin, and the replication stress inducer hydroxyurea (HU). Immunoblotting was used to test if HDACi modulate the leukemia-associated transcription factors β-catenin, Wilms tumor (WT1), and myelocytomatosis oncogene (MYC). RNAi was used to delineate how these factors interact. We show that LBH589, MS-275, FK228, RGFP966, and HU induce apoptosis, replication stress/DNA damage, and apoptotic fragmentation of β-catenin. Indomethacin destabilizes β-catenin and potentiates anti-proliferative effects of HDACi. HDACi attenuate WT1 and MYC caspase-dependently and -independently. Genetic experiments reveal a cross-regulation between MYC and WT1 and a regulation of β-catenin by WT1. In conclusion, reduced levels of β-catenin, MYC, and WT1 are molecular markers for the efficacy of HDACi. HDAC3 inhibition induces apoptosis and disrupts tumor-associated protein expression.

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Section: Resultsmentioning

confidence: 99%

“…The transcription factor myelocytomatosis oncogene (MYC), which has been implicated in maintaining the stemness of AML cells [13,37,38], can be a target gene of β-catenin in leukemic cells [23,39,40]. Pan- and class I HDACi provoke a downregulation of MYC in cancer cells [19,23,41,42,43,44].…”

Section: Introductionmentioning

confidence: 99%

HDAC3 Activity is Essential for Human Leukemic Cell Growth and the Expression of β-catenin, MYC, and WT1

Beyer

Romański

Mustafa

et al. 2019

Cancers

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“…In AML, the high expression of TCF4 indicates adverse clinical outcomes of the patients [ 52 ]. Additionally, increased TCF4 transcriptional activity contributes to the pathogenesis of transformation of post-myeloproliferative neoplasms into secondary AML, which is related with the abnormal activation of wnt/β-catenin signaling [ 52 – 54 ]. In adult T-cell leukemia, TCF4 up-regulates BIRC5 expression, which probably increase the viability of cell viability [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

LncRNA ANRIL/miR-7-5p/TCF4 axis contributes to the progression of T cell acute lymphoblastic leukemia

Gao

Zhao

et al. 2020

Cancer Cell Int

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Background Antisense non-coding RNA in the INK4 locus (ANRIL) is of great importance in cell biological behaviors, and ANRIL functions in many kinds of cancers including leukemia. However, the mechanism of ANRIL in the progression of T-cell acute lymphoblastic leukemia (T-ALL) has not been clarified clearly. Methods qRT-PCR was performed to detect ANRIL expression in T-ALL samples. T-ALL cell lines (MOLT4, CCRF-CEM and KOPT-K1) were used as the cell models. The function of ANRIL on T-ALL cells was investigated by CCK-8 assays, Transwell assays, and apoptosis experiments in vitro. qRT-PCR, Western blot, luciferase reporter assay and RIP assay were used to confirm the interactions between ANRIL and miR-7-5p, miR-7-5p and its target gene transcription factor 4 (TCF4). Results ANRIL was significantly up-regulated in T-ALL samples. Its knockdown markedly inhibited viability, migration and invasion of T-ALL cells, but its overexpression exerted the opposite effects. TCF4 was proved to be a target gene of miR-7-5p. ANRIL down-regulated miR-7-5p via sponging it and in turn up-regulated TCF4. Conclusions LncRNA ANRIL can modulate malignant phenotypes of T-ALL cells, possibly by regulating miR-7-5p/TCF4 axis, and it serves as a potential therapeutic target for T-ALL.

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“…Moreover, knockdown of β-catenin in AML induced apoptosis of both JAKi-sensitive and JAKi-resistant blast progenitor cells. Preclinical in vitro and in vivo findings highlight a novel therapeutic approach of co-targeting β-catenin and BETP antagonists (bromodomain and extraterminal domain protein) for AML treatment [100].…”

Section: Hematological Malignanciesmentioning

confidence: 99%

Wnt Pathway: An Integral Hub for Developmental and Oncogenic Signaling Networks

Sharma

Pruitt

2020

IJMS

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The Wnt pathway is an integral cell-to-cell signaling hub which regulates crucial development processes and maintenance of tissue homeostasis by coordinating cell proliferation, differentiation, cell polarity, cell movement, and stem cell renewal. When dysregulated, it is associated with various developmental diseases, fibrosis, and tumorigenesis. We now better appreciate the complexity and crosstalk of the Wnt pathway with other signaling cascades. Emerging roles of the Wnt signaling in the cancer stem cell niche and drug resistance have led to development of therapeutics specifically targeting various Wnt components, with some agents currently in clinical trials. This review highlights historical and recent findings on key mediators of Wnt signaling and how they impact antitumor immunity and maintenance of cancer stem cells. This review also examines current therapeutics being developed that modulate Wnt signaling in cancer and discusses potential shortcomings associated with available therapeutics.

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Targeting nuclear β-catenin as therapy for post-myeloproliferative neoplasm secondary AML

Cited by 34 publications

References 54 publications

HDAC3 Activity is Essential for Human Leukemic Cell Growth and the Expression of β-catenin, MYC, and WT1

HDAC3 Activity is Essential for Human Leukemic Cell Growth and the Expression of β-catenin, MYC, and WT1

LncRNA ANRIL/miR-7-5p/TCF4 axis contributes to the progression of T cell acute lymphoblastic leukemia

Wnt Pathway: An Integral Hub for Developmental and Oncogenic Signaling Networks

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