A Novel Glycogen Synthase Kinase-3 Inhibitor Optimized for Acute Myeloid Leukemia Differentiation Activity

Hu, Sophia; Ignatz-Hoover, James; Moreton, Stephen; Chakrabarti, Amit; Xia, Zhiqiang; Karan, Goutam; Lima, Marcos de; Agrawal, Mukesh; Wald, David N.

doi:10.1158/1535-7163.mct-15-0566

Cited by 34 publications

(27 citation statements)

References 44 publications

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“…The treatment of this disease is mainly induced differentiation therapy. [24][25][26][27][28][29] The cell cycle is a series of events that leads to cell division and replication.…”

Section: Discussionmentioning

confidence: 99%

E2F4 functions as a tumour suppressor in acute myeloid leukaemia via inhibition of the MAPK signalling pathway by binding to EZH2

Feng

et al. 2020

J Cellular Molecular Medi

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Acute myeloid leukaemia (AML) is an aggressive and mostly incurable haematological malignancy with frequent relapse after an initial response to standard chemotherapy. Therefore, novel therapies are urgently required to improve AML clinical outcome. Here, we aim to study the dysregulation of a particular transcription factor, E2F4, and its role in the progression of AML. In this study, human clinical data from the Gene Expression Profiling Interactive Analysis (GEPIA) revealed that increased E2F4 expression was associated with poor prognosis in AML patients. Moreover, the experimental results showed that E2F4 was aberrantly overexpressed in human AML patients and cell lines. Depletion of E2F4 inhibited the proliferation, induced the differentiation and suppressed the growth of AML cells in a nude mouse model. By contrast, overexpression of E2F4 promoted the proliferation and inhibited the differentiation of AML cells in vitro. Additionally, E2F4 expression not only is positively correlated with EZH2 but also can bind to EZH2. RNA microarray results also showed that E2F4 can regulate MAPK signalling pathway. EZH2 can reverse the inhibitory effect of E2F4 silencing on MAPK signaling pathway. In summary, our data suggest that E2F4 may be a potential therapeutic target for AML therapy.

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“…The treatment of this disease is mainly induced differentiation therapy. [24][25][26][27][28][29] The cell cycle is a series of events that leads to cell division and replication.…”

Section: Discussionmentioning

confidence: 99%

E2F4 functions as a tumour suppressor in acute myeloid leukaemia via inhibition of the MAPK signalling pathway by binding to EZH2

Feng

et al. 2020

J Cellular Molecular Medi

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“…100 Pentose phosphate pathway activity, cysteine import, GSH, and thioredoxin production represent processes that can be fine-tuned have been considered for the treatment of myeloid leukemia. 104,105 Further insight into the signaling pathways, which render B cells susceptible to GSK3 inhibition, could provide a rationale to extend the use of GSK3 inhibitors to B cell-derived malignancies or improve disease stratification. Lastly, since it is becoming increasingly apparent that B cell metabolism and function are not only regulated by intracel-…”

Section: Con S Equen Ce S Of D Is Rup Ted Me Tabolic Homeos Ta S Ismentioning

confidence: 99%

The role of metabolic checkpoint regulators in B cell survival and transformation

Jellusova

2020

Immunological Reviews

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In response to mitogenic stimulation, B cells activate different pro-anabolic signaling pathways such as c-Myc-and mTORC1-dependent networks to satisfy the energetic demands of biomass synthesis and proliferation. In order to preserve viability and function, cell growth cannot progress unchecked and must be adjusted according to the availability of nutrients. Nutrient-sensing proteins such as AMPK antagonize mTORC1 activity in response to starvation. If pro-anabolic signaling pathways are aberrantly activated, B cells may lack the metabolic capacity to accommodate their energetic needs, which can lead to cell death. On the other hand, metabolic hyperactivation is a salient feature of cancer cells, suggesting that mechanisms exist, which allow B cells to cope with metabolic stress. The aim of this review is to discuss how B cells respond to a mismatch between energy supply and demand and what the consequences are of metabolic dysregulation in normal and malignant B cells. K E Y W O R D Sanabolism, autophagy, B cells, metabolic stress, mTORC1, senescence

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“…Leukaemia cell differentiation is a key factor to evaluate the malignancy. Previous studies put forward many targets, regulation of which was directly correlated with the leukaemia cell differentiation . On the basis of these reports, our study firstly shows that regulation of HoxA9 expression was able to control the HL‐60 and MOLT‐3 cell differentiation (Figure ).…”

Section: Discussionmentioning

confidence: 59%

“…Previous studies put forward many targets, regulation of which was directly correlated with the leukaemia cell differentiation. [16][17][18] On the basis of these reports, our study firstly shows that regulation of HoxA9 expression was able to control the HL-60 and MOLT-3 cell differentiation ( Figure 5). This is a novel finding that HoxA9 was correlated with leukaemia cell differentiation, further demonstrating that this gene is an FIGURE 7 Xenograft experiment indicated that HoxA9 silencing reduced the tumour malignancy.…”

Section: Discussionmentioning

confidence: 64%

HOXA9 is critical in the proliferation, differentiation, and malignancy of leukaemia cells both in vitro and in vivo

Chen

Yu²,

et al. 2017

Cell Biochemistry & Function

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Progress in the understanding of the molecular mechanism for acute myeloid leukaemia is of great significance to generate new potential targets for treatment. Recent studies showed that HOXA9, a homeodomain-containing transcription factor, is commonly deregulated in acute leukaemia. In this study, we elucidated the direct correlation between HoxA9 expression and progression of leukaemia using 2 different types of leukaemia cells HL-60 and MOLT-3. The HoxA9 expression level was decreased in leukaemia cells with the treatment of all-trans retinoic acid or arsenic trioxide (As O ). Downregulation of HoxA9 could impair the proliferation and promote the leukaemia cell death. HoxA9 silencing also potentiated the differentiation of leukaemia cells, and in vivo studies demonstrated that HoxA9 downregulation could interfere the tumour growth. Interestingly, HoxA9 silencing also led to the alteration in miRNA expression, mediating the promoting effect on the leukaemia cell differentiation. Therefore, this work provided a promising and potentially efficient target to leukaemia treatment, indicating that HoxA9 is likely to be an ideal candidate in the gene therapy against acute myeloid leukaemia. In this study, we elucidated the critical role of HoxA9 in the proliferation and differentiation of leukaemia cells both in vitro and in vivo. The effect of HoxA9 modulation was correlated with the clinical effect of all-trans retinoic acid and As O . Furthermore, HoxA9 also regulated the miRNA expression, controlling the leukaemia cell differentiation. Therefore, this work provided new insights into molecular mechanism underlying the leukaemia treatment, potentially putting forward a brand new target to the gene therapy against leukaemia.

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A Novel Glycogen Synthase Kinase-3 Inhibitor Optimized for Acute Myeloid Leukemia Differentiation Activity

Cited by 34 publications

References 44 publications

E2F4 functions as a tumour suppressor in acute myeloid leukaemia via inhibition of the MAPK signalling pathway by binding to EZH2

E2F4 functions as a tumour suppressor in acute myeloid leukaemia via inhibition of the MAPK signalling pathway by binding to EZH2

The role of metabolic checkpoint regulators in B cell survival and transformation

HOXA9 is critical in the proliferation, differentiation, and malignancy of leukaemia cells both in vitro and in vivo

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