scholarly journals The mechanism of MYB transcriptional regulation by MLL-AF9 oncoprotein

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Lu Cao ◽  
Partha Mitra ◽  
Thomas J. Gonda
Keyword(s):  
Cell Proliferation ◽  
Transcriptional Regulation ◽  
Acute Myeloid Leukaemia ◽  
Promoter Region ◽  
Transcriptional Regulator ◽  
Transcriptional Regulators ◽  
Therapeutic Approaches ◽  
New Therapeutic Approaches ◽  
H3k79 Methylation ◽  
Acute Myeloid

AbstractAcute leukaemias express high levels of MYB which are required for the initiation and maintenance of the disease. Inhibition of MYB expression or activity has been shown to suppress MLL-fusion oncoprotein-induced acute myeloid leukaemias (AML), which are among the most aggressive forms of AML, and indeed MYB transcription has been reported to be regulated by the MLL-AF9 oncoprotein. This highlights the importance of understanding the mechanism of MYB transcriptional regulation in these leukaemias. Here we have demonstrated that the MLL-AF9 fusion protein regulates MYB transcription directly at the promoter region, in part by recruiting the transcriptional regulator kinase CDK9, and CDK9 inhibition effectively suppresses MYB expression as well as cell proliferation. However, MYB regulation by MLL-AF9 does not require H3K79 methylation mediated by the methyltransferase DOT1L, which has also been shown to be a key mediator of MLL-AF9 leukemogenicity. The identification of specific, essential and druggable transcriptional regulators may enable effective targeting of MYB expression, which in turn could potentially lead to new therapeutic approaches for acute myeloid leukaemia with MLL-AF9.

scholarly journals New Therapeutic Approaches for Acute Myeloid Leukaemia

2021 ◽  
pp. 82-89
Author(s):  
Ruth M Risueno ◽  
Laia Cuesta-Casanovas ◽  
Jose M Carbo ◽  
Josep M Cornet-Masana
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Treatment Options ◽  
Gemtuzumab Ozogamicin ◽  
Therapeutic Approaches ◽  
New Therapeutic Approaches ◽  
Therapeutic Landscape ◽  
Unfit Patients ◽  
Druggable Targets ◽  
Acute Myeloid

Acute myeloid leukaemia (AML) is a genetically heterogeneous haematopoietic neoplasm characterised by the accumulation of transformed immature blood progenitors in bone marrow. Since 1973, the backbone treatment has relied on the combination of cytarabine and an anthracycline, followed by allogeneic haematopoietic transplant if eligible. Therefore, the treatment decisions have largely revolved around chemotherapy drug intensity. Despite advances in our understanding of the underlying biology over the past decades, AML remains a therapeutic challenge as the overall survival is poor and treatment options are limited for relapsed/refractory AML or for unfit patients. After four decades without substantial changes, eight new noncytostatic drugs have been granted approval: vyxeos, enasidenib, gilteritinib, glasdegib, gemtuzumab ozogamicin, ivosidenib, midostaurin, and venetoclax. Despite promising preliminary results, some indications are based on early efficacy data, obtained in single-arm nonrandomised trials, highlighting the necessity for further validation in extended clinical trials. Interestingly, several druggable targets have been identified recently, associated with specific target-directed drugs. Based on the preclinical data available, great impact on clinical outcomes for patients with AML is expected, potentially increasing the therapeutic landscape for this disease.

scholarly journals Regulation of vanillate and syringate catabolism by a MarR-type transcriptional regulator DesR in Sphingobium sp. SYK-6

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Takuma Araki ◽  
Shusuke Umeda ◽  
Naofumi Kamimura ◽  
Daisuke Kasai ◽  
Shuta Kumano ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Dna Binding ◽  
Promoter Region ◽  
Transcriptional Regulator ◽  
Ring Cleavage ◽  
Effector Molecules ◽  
Repeat Sequences ◽  
Reverse Transcription Pcr ◽  
Consecutive Reactions ◽  
Intermediate Metabolites

AbstractVanillate and syringate are major intermediate metabolites generated during the microbial degradation of lignin. In Sphingobium sp. SYK-6, vanillate is O demethylated to protocatechuate by LigM; protocatechuate is then catabolized via the protocatechuate 4,5-cleavage pathway. Syringate is O demethylated to gallate by consecutive reactions catalyzed by DesA and LigM, and then gallate is subjected to ring cleavage by DesB. Here, we investigated the transcriptional regulation of desA, ligM, and desB involved in vanillate and syringate catabolism. Quantitative reverse transcription-PCR analyses indicated that the transcription of these genes was induced 5.8–37-fold in the presence of vanillate and syringate. A MarR-type transcriptional regulator, SLG_12870 (desR), was identified as the gene whose product bound to the desB promoter region. Analysis of a desR mutant indicated that the transcription of desB, ligM, and desR is negatively regulated by DesR. Purified DesR bound to the upstream regions of desB, ligM, and desR, and the inverted repeat sequences similar to each other in these regions were suggested to be essential for DNA binding of DesR. Vanillate and syringate inhibited DNA binding of DesR, indicating that these compounds are effector molecules of DesR. The transcription of desA was found to be regulated by an as-yet unidentified regulator.

scholarly journals Homeostatic T Cell Proliferation after Islet Transplantation

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Paolo Monti ◽  
Lorenzo Piemonti
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Islet Transplantation ◽  
T Cell Proliferation ◽  
Pancreatic Islet Transplantation ◽  
Therapeutic Approaches ◽  
Cell Responses ◽  
New Therapeutic Approaches ◽  
Alloreactive T Cell

Pancreatic islet transplantation in patients with type 1 diabetes mellitus is performed under immunosuppression to avoid alloreactive T cell responses and to control the reactivation of autoreactive memory T cells. However, lymphopenia associated with immunosuppression and T cell depletion can induce a paradoxical expansion of lymphocyte subsets under the influence of homeostatic proliferation. Homeostatic T cell proliferation is mainly driven by the IL-7/IL-7 receptor axis, a molecular pathway which is not affected by standard immune-suppressive drugs and, consequently, represents a novel potential target for immuno-modulatory strategies. In this review, we will discuss how homeostatic T cell proliferation can support autoimmunity recurrence after islet transplantation and how it can be targeted by new therapeutic approaches.

scholarly journals CCS1477: A Novel Small Molecule Inhibitor of p300/CBP Bromodomain for the Treatment of Acute Myeloid Leukaemia and Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2560-2560 ◽  
Author(s):  
Nigel Brooks ◽  
Meera Raja ◽  
Barbara W Young ◽  
Gary J Spencer ◽  
Tim CP Somervaille ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Acute Myeloid Leukaemia ◽  
Tumour Growth ◽  
Potent Inhibitor ◽  
Xenograft Model ◽  
Standard Of Care ◽  
Employment Equity ◽  
Equity Ownership ◽  
Acute Myeloid

E1A binding protein (p300) and CREB binding protein (CBP) are two closely related histone acetyl transferases with oncogenic roles in acute myeloid leukaemia (AML) and multiple myeloma (MM). Here we describe the pre-clinical characterization of CCS1477, an orally bioavailable, potent and selective inhibitor of the bromodomain of p300/CBP and its therapeutic application in AML and MM. CCS1477 binds to p300 and CBP with high affinity (KD=1.3/1.7nM), and selectivity (e.g. KD=222nM; BRD4) in a surface plasmon resonance assay. It is a potent inhibitor of cell proliferation in a panel of 16 AML and 9 MM human cell lines. MM cells were particularly sensitive to CCS1477 with the majority of lines having a GI50 below 100nM. In stromal co-culture assays CCS1477 also inhibited proliferation of primary patient AML blast cells from a range of patients with a variety of molecular subtypes. These anti-proliferative effects were due to a combination of cell cycle arrest (with a decrease of cells in S-phase and an increase in cells in G1/G0) and induction of differentiation, as confirmed by up regulation of selected differentiation markers (e.g. CD11b & CD86) flow cytometric analyses. In xenograft models of AML (MOLM-16) and MM (OPM-2), daily oral dosing with CCS1477 as monotherapy, caused a dose-dependent reduction in tumour growth with regressions observed at the highest dose of 20mg/kg. After cessation of treatment with 20mg/kg CCS1477, there was sustained inhibition of tumour growth for approximately 11 days before re-growth began. The inhibition of tumour growth during drug treatment, was accompanied by significant reduction in tumour expression of MYC and IRF4 by qPCR in the OPM-2 model and in MYC expression in MOLM-16. The effects of CCS1477 were further evaluated in murine models by comparison with candidate standard of care regimens for AML & MM. In the MOLM-16 (AML) model, CCS1477 administered daily by oral gavage (10mg/kg) demonstrated superior tumour growth inhibition by comparison with azacitidine or cytarabine. There was also a significant combination benefit of CCS1477 when administered with these two agents in this model. In OPM-2 MM cells that are sensitive to lenalidomide, CCS1477 was a significantly more potent inhibitor of cell proliferation (GI50 = 5nM; CCS1477 vs. 100nM; lenalidomide). CCS1477 also retains exquisite anti-proliferative potency in MM cells that are either intrinsically resistant to lenalidomide (KMS-11 and RPMI 8226) or in OPM-2 cells that have developed resistance after long-term culture in lenalidomide. CCS1477 shows significant synergy when combined with lenalidomide in OPM-2 cells in vitro and also in an OPM-2 xenograft model in vivo. Significant combination benefit of CCS1477 with vorinostat or velcade is also observed in this xenograft model. These data support the clinical testing of CCS1477 in haematological malignancies, including MM and AML, with a strong pre-clinical rationale for use as monotherapy or in combination with standard of care agents, such as lenalidomide. CCS1477 is currently in Phase I/II clinical trials. Disclosures Brooks: CellCentric Ltd: Employment, Equity Ownership. Somervaille:Novartis: Consultancy. Pegg:CellCentric Ltd: Employment, Equity Ownership.

Association of MEG3 Hypermethylation and MiR-21 Upregulation with the Incidence in Iraqi Acute Myeloid Leukaemia Patients

2021 ◽  
Vol 19 (6) ◽  
pp. 122-128
Author(s):  
Noha Mohammed Saleh ◽  
Hameed Majeed Jasim
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Promoter Region ◽  
Hematologic Malignancy ◽  
Vital Role ◽  
Healthy Controls ◽  
Expression Levels ◽  
Elevated Expression ◽  
Acute Myeloid

Background: Acute myeloid leukaemia (AML) can be defined as a hematologic malignancy that distinguished by genetic defects and epigenetics alterations. LncRNA MEG3 was shown to play the role of tumour suppressor, and play a pivotal role in leukemogenesis, MEG3 hypermethylation has been reported to be related to different types of haematological malignancies. MIR-21 is regarded as a significant miRNA, it considered to play a vital role in AML progressions. Results: The levels of methylation in the MEG3 promoter region in AML patients were significantly increased than in healthy controls, as the MEG3 expression levels were significantly lowered (P ≤ 0.05) in AML patients in contrast with healthy controls. On the other hand, results showed elevated expression levels of miR-21 in AML patients compared with healthy controls. Conclusion: The present study indicates that the hypermethylation of MEG-3 promoter region could explain MEG-3 expression level loss. Our findings also revealed that the overexpression of miR-21 supports its function as an oncogene.

Autophagy Inhibition Enhances CDK4/6 Inhibitor-Induced Apoptosis in t(8;21) Acute Myeloid Leukemia Cells

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 50-50
Author(s):  
Kana Nakatani ◽  
Hidemasa Matsuo ◽  
Yutarou Harata ◽  
Moe Higashitani ◽  
Asami Koyama ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
G1 Phase ◽  
Therapeutic Approaches ◽  
Cycle Arrest ◽  
Induced Apoptosis ◽  
Autophagy Inhibition ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a genetically and clinically heterogeneous disease. Although t(8;21) AML patients have a more favorable prognosis than other cytogenetic subgroups, nearly 40% of t(8;21) AML patients experience relapse. Therefore, novel therapeutic approaches based on a better understanding of the biology of t(8;21) AML need to be developed. In this study, at first, we re-analyzed the sequencing data of 149 pediatric t(8;21) AML patients from St. Jude Children's Research Hospital tissue resource core facility and the JPLSG AML-05 study, and 134 adult t(8;21) AML patients from CALGB/Alliance trials and the University Hospital of Ulm. In pediatric patients, 13 CCND2 mutations were detected in 11 patients (11/149, 7.4%), and in adult patients, 14 CCND2 mutations were detected in 12 patients (12/134, 9.0%). In both cohorts, CCND2 mutations were located on the PEST domain, suggesting that the mutations stabilize the cyclin D2 protein. Next, we compared CCND2 mRNA expression between t(8;21) AML patients (n=24) and non-t(8;21) AML patients (n=163) using the TARGET AML cohort. In non-t(8;21) AML patients, CCND2 expression varied from low to high levels, whereas in t(8;21) AML patients, CCND2 expression was restricted to higher levels. Consistently, CCND2 expression was higher in t(8;21) AML cell lines (n=2: Kasumi-1 and SKNO-1), compared with non-t(8;21) AML cell lines (n=32). Kasumi-1 cells transfected with shCCND2 showed cell cycle arrest at G1 phase and impaired cell proliferation. These results suggest that the frequency of CCND2 mutations and CCND2 expression are increased in t(8;21) AML, and high CCND2 expression plays an important role in t(8;21) AML cell proliferation. Because CCND2 is not a druggable target, we examined the effect of CDK4/6 inhibitors (palbociclib and abemaciclib) on t(8;21) AML cells. Analysis of 19 AML cell lines showed that t(8;21) AML cells had lower IC50 values for CDK4/6 inhibitors than non-t(8;21) AML cells. CDK4/6 inhibitors caused cell cycle arrest at G1 phase and impaired cell proliferation in t(8;21) AML cells. To identify potential therapeutic approaches in combination with CDK4/6 inhibitors in t(8;21) AML, we performed microarray analysis and examined the effects of CDK4/6 inhibition. In addition to the pathways associated with the cell cycle (regulation of sister chromatid separation, retinoblastoma gene, and cell cycle), the MAP-ERK and PI3K-AKT-mTOR signaling pathways were downregulated by CDK4/6 inhibition. Because these pathways are involved in autophagy regulation via mTOR, we focused on examining autophagy in subsequent experiments. Assessment of the effect of CDK4/6 inhibition on autophagy in t(8;21) AML cells showed that the CDK4/6 inhibitor (abemaciclib) treatment induced LC3B-I to LC3B-II conversion in both Kasumi-1 and SKNO-1 cells. Transmission electron microscopic examination of autophagosome formation detected a large number of autophagosomes in the cytoplasm of Kasumi-1 and SKNO-1 cells treated with abemaciclib, whereas few autophagosomes were detected in control samples. These results suggest that autophagy is induced by CDK4/6 inhibition in t(8;21) AML cells. Autophagy is involved in the resistance to chemotherapy in cancer cells, therefore, we hypothesized that autophagy inhibition may be a promising therapeutic approach. Treatment of t(8;21) AML cells with the autophagy inhibitors chloroquine (CQ) or LY294002 in combination with abemaciclib significantly increased the frequency of apoptotic (Annexin V positive) cells compared with that in untreated cells, whereas CQ or LY294002 single treatment had no significant effect on apoptosis. Consistently, combinatorial inhibition of CDK4/6 and autophagy upregulated cleaved caspase 3 expression. The combinatorial effect was confirmed by silencing the autophagy-related protein ATG7 using small interfering RNA in abemaciclib-treated t(8;21) AML cells. These results suggest that autophagy inhibition enhances CDK4/6 inhibitor-induced apoptosis in t(8;21) AML cells. In conclusion, the present results indicate that inhibition of CDK4/6 and autophagy may be a novel and promising biomarker-driven therapeutic strategy for the treatment of t(8;21) AML. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A new regulatory mechanism of protein phosphatase 2A activity via SET in acute myeloid leukemia

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Elena Arriazu ◽  
Carmen Vicente ◽  
Raffaella Pippa ◽  
Irene Peris ◽  
Elena Martínez-Balsalobre ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Regulatory Mechanism ◽  
Hematologic Malignancy ◽  
Therapeutic Approaches ◽  
New Therapeutic Approaches ◽  
Phosphatase 2A ◽  
Xenograft Models ◽  
And Migration ◽  
Acute Myeloid

AbstractAcute myeloid leukemia (AML) is an aggressive hematologic malignancy. Although novel emerging drugs are available, the overall prognosis remains poor and new therapeutic approaches are required. PP2A phosphatase is a key regulator of cell homeostasis and is recurrently inactivated in AML. The anticancer activity of several PP2A-activating drugs (e.g., FTY720) depends on their interaction with the SET oncoprotein, an endogenous PP2A inhibitor that is overexpressed in 30% of AML cases. Elucidation of SET regulatory mechanisms may therefore provide novel targeted therapies for SET-overexpressing AMLs. Here, we show that upregulation of protein kinase p38β is a common event in AML. We provide evidence that p38β potentiates SET-mediated PP2A inactivation by two mechanisms: facilitating SET cytoplasmic translocation through CK2 phosphorylation, and directly binding to and stabilizing the SET protein. We demonstrate the importance of this new regulatory mechanism in primary AML cells from patients and in zebrafish xenograft models. Accordingly, combination of the CK2 inhibitor CX-4945, which retains SET in the nucleus, and FTY720, which disrupts the SET-PP2A binding in the cytoplasm, significantly reduces the viability and migration of AML cells. In conclusion, we show that the p38β/CK2/SET axis represents a new potential therapeutic pathway in AML patients with SET-dependent PP2A inactivation.

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