scholarly journals Roles of Histone Deacetylases in Acute Myeloid Leukemia With Fusion Proteins

2021 ◽  
Vol 11 ◽  
Author(s):  
Juan Zhang ◽  
Xuefeng Gao ◽  
Li Yu
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Fate ◽  
Histone Deacetylases ◽  
Fusion Proteins ◽  
Myeloid Leukemia ◽  
Current Knowledge ◽  
Chromosomal Rearrangements ◽  
Chromosomal Translocation ◽  
Transcriptional Switch ◽  
Acute Myeloid

Accurate orchestration of gene expression is critical for the process of normal hematopoiesis, and dysregulation is closely associated with leukemogenesis. Epigenetic aberration is one of the major causes contributing to acute myeloid leukemia (AML), where chromosomal rearrangements are frequently found. Increasing evidences have shown the pivotal roles of histone deacetylases (HDACs) in chromatin remodeling, which are involved in stemness maintenance, cell fate determination, proliferation and differentiation, via mastering the transcriptional switch of key genes. In abnormal, these functions can be bloomed to elicit carcinogenesis. Presently, HDAC family members are appealing targets for drug exploration, many of which have been deployed to the AML treatment. As the majority of AML events are associated with chromosomal translocation resulting in oncogenic fusion proteins, it is valuable to comprehensively understand the mutual interactions between HDACs and oncogenic proteins. Therefore, we reviewed the process of leukemogenesis and roles of HDAC members acting in this progress, providing an insight for the target anchoring, investigation of hyperacetylated-agents, and how the current knowledge could be applied in AML treatment.

scholarly journals Acute myeloid leukemia with the 8q22;21q22 translocation: secondary mutational events and alternative t(8;21) transcripts

Blood ◽  
2007 ◽  
Vol 110 (3) ◽  
pp. 799-805 ◽  
Author(s):  
Luke F. Peterson ◽  
Anita Boyapati ◽  
Eun-Young Ahn ◽  
Joseph R. Biggs ◽  
Akiko Joo Okumura ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Fusion Proteins ◽  
Myeloid Leukemia ◽  
Chromosomal Translocation ◽  
Chromosome 8 ◽  
Chromosome 21 ◽  
Chromosomal Translocations ◽  
Runx1 Gene ◽  
Myeloid Leukemias ◽  
Acute Myeloid

Abstract Nonrandom and somatically acquired chromosomal translocations can be identified in nearly 50% of human acute myeloid leukemias. One common chromosomal translocation in this disease is the 8q22;21q22 translocation. It involves the AML1 (RUNX1) gene on chromosome 21 and the ETO (MTG8, RUNX1T1) gene on chromosome 8 generating the AML1-ETO fusion proteins. In this review, we survey recent advances made involving secondary mutational events and alternative t(8;21) transcripts in relation to understanding AML1-ETO leukemogenesis.

scholarly journals The Role of Hypoxic Bone Marrow Microenvironment in Acute Myeloid Leukemia and Future Therapeutic Opportunities

2021 ◽  
Vol 22 (13) ◽  
pp. 6857
Author(s):  
Samantha Bruno ◽  
Manuela Mancini ◽  
Sara De Santis ◽  
Cecilia Monaldi ◽  
Michele Cavo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Cell Fate ◽  
Myeloid Leukemia ◽  
Hematologic Malignancy ◽  
Bone Marrow Microenvironment ◽  
Metabolic Adaptation ◽  
Cell Fate Decisions ◽  
Wide Range ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a hematologic malignancy caused by a wide range of alterations responsible for a high grade of heterogeneity among patients. Several studies have demonstrated that the hypoxic bone marrow microenvironment (BMM) plays a crucial role in AML pathogenesis and therapy response. This review article summarizes the current literature regarding the effects of the dynamic crosstalk between leukemic stem cells (LSCs) and hypoxic BMM. The interaction between LSCs and hypoxic BMM regulates fundamental cell fate decisions, including survival, self-renewal, and proliferation capacity as a consequence of genetic, transcriptional, and metabolic adaptation of LSCs mediated by hypoxia-inducible factors (HIFs). HIF-1α and some of their targets have been associated with poor prognosis in AML. It has been demonstrated that the hypoxic BMM creates a protective niche that mediates resistance to therapy. Therefore, we also highlight how hypoxia hallmarks might be targeted in the future to hit the leukemic population to improve AML patient outcomes.

Molecular determinants of therapy response of venetoclax-based combinations in acute myeloid leukemia

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Philipp Makowka ◽  
Verena Stolp ◽  
Karoline Stoschek ◽  
Hubert Serve
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Current Knowledge ◽  
Therapy Response ◽  
Secondary Resistance ◽  
Molecular Alterations ◽  
Molecular Features ◽  
Slow Progress ◽  
Molecular Aberrations ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a heterogeneous, highly malignant disease of the bone marrow. After decades of slow progress, recent years saw a surge of novel agents for its treatment. The most recent advancement is the registration of the Bcl-2 inhibitor ventoclax in combination with a hypomethylating agent (HMA) in the US and Europe for AML patients not eligible for intensive chemotherapy. Treatment of newly diagnosed AML patients with this combination results in remission rates that so far could only be achieved with intensive treatment. However, not all AML patients respond equally well, and some patients relapse early, while other patients experience longer periods of complete remission. A hallmark of AML is its remarkable genetic, molecular and clinical heterogeneity. Here, we review the current knowledge about molecular features of AML that help estimate the probability of response to venetoclax-containing therapies. In contrast to other newly developed AML therapies that target specific recurrent molecular alterations, it seems so far that responses are not specific for a certain subgroup. One exception is spliceosome mutations, where good response has been observed in clinical trials with venetoclax/azacitidine. These mutations are rather associated with a more unfavorable outcome with chemotherapy. In summary, venetoclax in combination with hypomethylating agents represents a significant novel option for AML patients with various molecular aberrations. Mechanisms of primary and secondary resistance seem to overlap with those towards chemotherapy.

scholarly journals The ETO Protein Disrupted in t(8;21)-Associated Acute Myeloid Leukemia Is a Corepressor for the Promyelocytic Leukemia Zinc Finger Protein

2000 ◽  
Vol 20 (6) ◽  
pp. 2075-2086 ◽  
Author(s):  
Ari M. Melnick ◽  
Jennifer J. Westendorf ◽  
Adam Polinger ◽  
Graeme W. Carlile ◽  
Sally Arai ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Transcription Factor ◽  
Zinc Finger ◽  
Transcriptional Repression ◽  
Histone Deacetylases ◽  
Myeloid Leukemia ◽  
Histone Deacetylase Inhibitors ◽  
Promyelocytic Leukemia ◽  
Promyelocytic Leukemia Zinc Finger ◽  
Acute Myeloid

ABSTRACT The ETO protein was originally identified by its fusion to the AML-1 transcription factor in translocation (8;21) associated with the M2 form of acute myeloid leukemia (AML). The resulting AML-1–ETO fusion is an aberrant transcriptional regulator due to the ability of ETO, which does not bind DNA itself, to recruit the transcriptional corepressors N-CoR, SMRT, and Sin3A and histone deacetylases. The promyelocytic leukemia zinc finger (PLZF) protein is a sequence-specific DNA-binding transcriptional factor fused to retinoic acid receptor α in acute promyelocytic leukemia associated with the (11;17)(q23;q21) translocation. PLZF also mediates transcriptional repression through the actions of corepressors and histone deacetylases. We found that ETO is one of the corepressors recruited by PLZF. The PLZF and ETO proteins associate in vivo and in vitro, and ETO can potentiate transcriptional repression by PLZF. The N-terminal portion of ETO forms complexes with PLZF, while the C-terminal region, which was shown to bind to N-CoR and SMRT, is required for the ability of ETO to augment transcriptional repression by PLZF. The second repression domain (RD2) of PLZF, not the POZ/BTB domain, is necessary to bind to ETO. Corepression by ETO was completely abrogated by histone deacetylase inhibitors. This identifies ETO as a cofactor for a sequence-specific transcription factor and indicates that, like other corepressors, it functions through the action of histone deactylase.

scholarly journals The possible significance of trisomy 8 in acute myeloid leukemia

2017 ◽  
Vol 5 (6) ◽  
pp. 2652 ◽  
Author(s):  
Salil N. Vaniawala ◽  
Monika V. Patel ◽  
Pratik D. Chavda ◽  
Shivangi H. Zaveri ◽  
Pankaj K. Gadhia
Keyword(s):  
Acute Myeloid Leukemia ◽  
Chromosomal Aberrations ◽  
Myeloid Leukemia ◽  
Chromosomal Abnormalities ◽  
Prognostic Significance ◽  
Chromosomal Translocation ◽  
Banding Technique ◽  
Trisomy 8 ◽  
Increased Risk ◽  
Acute Myeloid

Background: Acute myeloid leukemia (AML) is a heterogeneous disorder that results from a block in the differentiation of haematopoietic progenitor cells along with uncontrolled proliferation. Trisomy 8 is the most common recurring numerical chromosomal aberrations in acute myeloid leukemia (AML). It occurs either as a sole anomaly or together with other additional chromosomal aberrations. The prognostic significance of trisomy 8 in presence of other additional chromosomal abnormality depends on clonal cytogenetic changes. The patients with trisomy 8 had shorter survival with significantly increased risk with other chromosomal abnormality.Methods: Total 139 patients were screened between January 2016 to November 2016 who were suspected of AML cases. Bone marrow cultures were set up using conventional cytogenetic methods. Chromosomal preparation was made and subjected to GTG banding technique. Banded metaphases were analysed and karyotyped for further analysis.Results: Cytogenetic evaluation of karyotyped of 139 suspected AML patients showed 52 with t(8;21)(q22;q22), 36 with t(15;17)(q22;q12), and 11 with inv(16)(p13;q22). The rest 40 cases found with additional chromosomal abnormalities, of which 16 were sole trisomy 8 and 24 cases were found with other chromosomal abnormalities In addition, only one person found with t(8;21) and trisomy 8, while  three person having t(15;17) with trisomy 8.Conclusions: AML is considered to be one of the most important cytogenetic prognostic determinants. Recurrent chromosomal translocation with trisomy 8 varying 1.9% for t(8;21) and 8.3% for t(15;17). In the present study trisomy 8 in AML with known favourable anomalies is very small. Therefore, it cannot be taken as a prognostic marker.

scholarly journals Inhibition of EZH2 by chidamide exerts antileukemia activity and increases chemosensitivity through Smo/Gli-1 pathway in acute myeloid leukemia

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Xuejie Jiang ◽  
Ling Jiang ◽  
Jiaying Cheng ◽  
Fang Chen ◽  
Jinle Ni ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Histone Deacetylases ◽  
Myeloid Leukemia ◽  
Hdac Inhibitors ◽  
Annexin V ◽  
Fluorescein Isothiocyanate ◽  
Gli 1 ◽  
Acute Myeloid

Abstract Background Epigenetic dysregulation plays important roles in leukemogenesis and the progression of acute myeloid leukemia (AML). Histone acetyltransferases (HATs) and histone deacetylases (HDACs) reciprocally regulate the acetylation and deacetylation of nuclear histones. Aberrant activation of HDACs results in uncontrolled proliferation and blockade of differentiation, and HDAC inhibition has been investigated as epigenetic therapeutic strategy against AML. Methods Cell growth was assessed with CCK-8 assay, and apoptosis was evaluated by flow cytometry in AML cell lines and CD45 + and CD34 + CD38- cells from patient samples after staining with Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI). EZH2 was silenced with short hairpin RNA (shRNA) or overexpressed by lentiviral transfection. Changes in signaling pathways were detected by western blotting. The effect of chidamide or EZH2-specific shRNA (shEZH2) in combination with adriamycin was studied in vivo in leukemia-bearing nude mouse models. Results In this study, we investigated the antileukemia effects of HDAC inhibitor chidamide and its combinatorial activity with cytotoxic agent adriamycin in AML cells. We demonstrated that chidamide suppressed the levels of EZH2, H3K27me3 and DNMT3A, exerted potential antileukemia activity and increased the sensitivity to adriamycin through disruption of Smo/Gli-1 pathway and downstream signaling target p-AKT in AML cells and stem/progenitor cells. In addition to decreasing the levels of H3K27me3 and DNMT3A, inhibition of EZH2 either pharmacologically by chidamide or genetically by shEZH2 suppressed the activity of Smo/Gli-1 pathway and increased the antileukemia activity of adriamycin against AML in vitro and in vivo. Conclusions Inhibition of EZH2 by chidamide has antileukemia activity and increases the chemosensitivity to adriamycin through Smo/Gli-1 pathway in AML cells (Fig. 5). These findings support the rational combination of HDAC inhibitors and chemotherapy for the treatment of AML.

scholarly journals Acute Myeloid Leukemia Stem Cells: The Challenges of Phenotypic Heterogeneity

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3742
Author(s):  
Marlon Arnone ◽  
Martina Konantz ◽  
Pauline Hanns ◽  
Anna M. Paczulla Stanger ◽  
Sarah Bertels ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Current Knowledge ◽  
Phenotypic Variability ◽  
Cellular Level ◽  
Patient Specific ◽  
Heterogeneous Landscape ◽  
Cells Of Origin ◽  
Acute Myeloid

Patients suffering from acute myeloid leukemia (AML) show highly heterogeneous clinical outcomes. Next to variabilities in patient-specific parameters influencing treatment decisions and outcome, this is due to differences in AML biology. In fact, different genetic drivers may transform variable cells of origin and co-exist with additional genetic lesions (e.g., as observed in clonal hematopoiesis) in a variety of leukemic (sub)clones. Moreover, AML cells are hierarchically organized and contain subpopulations of more immature cells called leukemic stem cells (LSC), which on the cellular level constitute the driver of the disease and may evolve during therapy. This genetic and hierarchical complexity results in a pronounced phenotypic variability, which is observed among AML cells of different patients as well as among the leukemic blasts of individual patients, at diagnosis and during the course of the disease. Here, we review the current knowledge on the heterogeneous landscape of AML surface markers with particular focus on those identifying LSC, and discuss why identification and targeting of this important cellular subpopulation in AML remains challenging.

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