Functional Dissection and Targeting Of Bmi1 Independence Of MN1 Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 474-474
Author(s):  
Jan-Henrik Mikesch ◽  
Maria F Arteaga ◽  
Clemence Virely ◽  
Chi Wai Eric So
Keyword(s):  
Transcription Factors ◽  
Differentially Expressed ◽  
Transformed Cells ◽  
Fusion Partner ◽  
Functional Difference ◽  
Wild Type ◽  
Leukemic Transformation ◽  
Over Expression ◽  
Independent Transformation

While PcG protein, Bmi1, plays a critical role in development of leukemic stem cells (LSCs), we have recently shown a differential Bmi1 dependency for LSCs initiated by different oncogenic transcription factors associated with distinct prognostic outcomes. PML-RARA and AML1-ETO leukemias associated with good prognosis are dependent on Bmi1, whereas poor prognostic leukemia induced by MLL fusion that is capable of activating multiple Hox genes is Bmi1 independent. However the role of Bmi1 and the mechanisms of over-coming Bmi1 dependency in other acute myeloid leukemia (AML) subtypes are still largely unknown. Aberrations of the MN1 gene mostly as an over-expression or rarely as a fusion partner of TEL in patients carrying the translocation t(12;22)(p13;q11) are frequently found in AML and myelodysplastic syndrome (MDS). Forced expression of MN1 induces aggressive AML with a 100% penetrance in mouse models within a few weeks, a latency significantly shorter than myeloid malignancy induced by MN1-TEL. Consistently, MN1 over-expression correlates with reduced drug response and poor prognosis of AML patients as well as high level of Bmi1 expression. In spite of these striking experimental and clinical features, the molecular mechanisms underlying MN1 leukemia are still largely unknown, and little progress has been made in targeting this leukemia. In the current study, we sought out to investigate the role of Bmi1 for MN1 mediated leukemic transformation and the mechanisms underlying this aggressive leukemia. In contrast to MN1-TEL that is dependent on Bmi1 for transformation of murine primary hematopoietic cells, MN1 over-expression could transform Bmi1-/- hematopoietic progenitor cells (HPCs) and induced serially transplantable AML in mice with the same latency as MN1 transformed wild type (wt) HPCs. Further molecular analyses revealed a significant up-regulation of p16Ink4a and cellular senescence in MN1-TEL Bmi1-/- HPCs, which was absent in MN1 transformed cells. Senescence in MN1-TEL Bmi1-/- cells could be rescued by re-expression of Bmi1 or suppression of p16 respectively, consistently suggesting an inherent functional difference between MN1 and MN1-TEL reflected by contrasting Bmi1 dependences. To identify the functional domain critical for the Bmi1 independency, structure/function analysis revealed that the removal of DNA binding domain (DBD) in the TEL moiety conferred Bmi1 independent transformation to MN1-TEL (MN1-TELΔDBD). MN1-TELΔDBD was able to induce transplantable leukemia in both the wild type and Bmi1 deficient cells. Conversely, fusion of TEL DBD to full length MN1 abolished its Bmi1 independence, and failed to transform Bmi1 deficient cells. These results strongly suggest that MN1 regulated molecules/pathways critical for Bmi1 independent transformation are misguided by the TEL DBD in MN1-TEL leukemia, providing a unique platform to dissect the pathways for Bmi1 independent transformation in AML. By performing global gene expression analyses on MN1, MN1-TEL and MN1-TELΔDBD transformed cells, we identified 1727 genes differentially expressed in MN1 transformed cells compared with MN1-TEL transformed cells; whereas only 44 genes were differentially expressed in MN1-TEL versus MN1-TELΔDBD transformed cells. When we overlapped these two gene sets together, we generated a unique gene set containing 34 genes associated with Bmi1 independence, including metabolic enzymes, signaling molecules and transcription factors such as Hoxa gene that has previously implicated in Bmi1 independent leukemic transformation. To assess the functional significance and the potential of targeting the candidates in this gene list in overcoming Bmi1 independent transformation, we performed functional analyses using shRNA approaches with a focus on those pharmacologically tractable candidates to suppress Bmi1 independent leukemic transformation. As a result, we were able to identify and demonstrate two different classes of enzymes with rigid catalytic domains that are required for Bmi1 independent transformation by MN1. Together, we dissect the mechanisms underlying Bmi1-independent leukemic transformation, and provide promising novel targets for MN1 leukemia. Disclosures: No relevant conflicts of interest to declare.

scholarly journals GAGA Factor Isoforms Have Distinct but Overlapping Functions In Vivo

2001 ◽  
Vol 21 (24) ◽  
pp. 8565-8574 ◽  
Author(s):  
Anthony J. Greenberg ◽  
Paul Schedl
Keyword(s):  
Fusion Protein ◽  
Transcriptional Activation ◽  
Functional Difference ◽  
Wild Type ◽  
Gaga Factor ◽  
Phenotypic Analysis ◽  
Alternatively Spliced

ABSTRACT The Drosophila melanogaster GAGA factor (encoded by the Trithorax-like [Trl] gene) is required for correct chromatin architecture at diverse chromosomal sites. The Trl gene encodes two alternatively spliced isoforms of the GAGA factor (GAGA-519 and GAGA-581) that are identical except for the length and sequence of the C-terminal glutamine-rich (Q) domain. In vitro and tissue culture experiments failed to find any functional difference between the two isoforms. We made a set of transgenes that constitutively express cDNAs coding for either of the isoforms with the goal of elucidating their roles in vivo. Phenotypic analysis of the transgenes in Trl mutant background led us to the conclusion that GAGA-519 and GAGA-581 perform different, albeit largely overlapping, functions. We also expressed a fusion protein with LacZ disrupting the Q domain of GAGA-519. This LacZ fusion protein compensated for the loss of wild-type GAGA factor to a surprisingly large extent. This suggests that the Q domain either is not required for the essential functions performed by the GAGA protein or is exclusively used for tetramer formation. These results are inconsistent with a major role of the Q domain in chromatin remodeling or transcriptional activation. We also found that GAGA-LacZ was able to associate with sites not normally occupied by the GAGA factor, pointing to a role of the Q domain in binding site choice in vivo.

scholarly journals The role of IL-1 in adipose browning and muscle wasting in CKD-associated cachexia

2021 ◽  
Author(s):  
Wai W Cheung ◽  
Ronghao Zheng ◽  
Sheng Hao ◽  
Zhen Wang ◽  
Alex Gonzalez ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Energy Homeostasis ◽  
Muscle Wasting ◽  
Differentially Expressed ◽  
Wild Type ◽  
Tnf Α ◽  
Fiber Size ◽  
Muscle Genes ◽  
Muscle Fat Infiltration

Abstract Cytokines such as IL-6, TNF-α and IL-1β trigger inflammatory cascades which may play a role in the pathogenesis of chronic kidney disease (CKD)-associated cachexia. CKD was induced by 5/6 nephrectomy in mice. We studied energy homeostasis in Il1β −/−/CKD, Il6−/−/CKD and Tnfα −/−/CKD mice and compared with wild type (WT)/CKD controls. Parameters of cachexia phenotype were completely normalized in Il1β −/−/CKD mice but were only partially rescued in Il6−/−/CKD and Tnfα −/−/CKD mice. We tested the effects of anakinra, an IL-1 receptor antagonist, on CKD-associated cachexia. WT/CKD mice were treated with anakinra (2.5 mg.kg.day, IP) or saline for 6 weeks and compared with WT/sham controls. Anakinra normalized food intake and weight gain, fat and lean mass content, metabolic rate and muscle function, and also attenuated molecular perturbations of energy homeostasis in adipose tissue and muscle in WT/CKD mice. Anakinra attenuated browning of white adipose tissue in WT/CKD mice. Moreover, anakinra normalized gastrocnemius weight and fiber size as well as attenuated muscle fat infiltration in WT/CKD mice. This was accompanied by correcting the increased muscle wasting signaling pathways while promoting the decreased myogenesis process in gastrocnemius of WT/CKD mice. We performed qPCR analysis for the top 20 differentially expressed muscle genes previously identified via RNAseq analysis in WT/CKD mice versus controls. Importantly, 17 differentially expressed muscle genes were attenuated in anakinra treated WT/CKD mice. In conclusion, IL-1 receptor antagonism may represent a novel targeted treatment for adipose tissue browning and muscle wasting in CKD.

Role of strain differences on host resistance and the transcriptional response of macrophages to infection withYersinia enterocolitica

2006 ◽  
Vol 25 (1) ◽  
pp. 75-84 ◽  
Author(s):  
Katrin van Erp ◽  
Kristina Dach ◽  
Isabel Koch ◽  
Jürgen Heesemann ◽  
Reinhard Hoffmann
Keyword(s):  
Transcription Factors ◽  
Host Resistance ◽  
Genetic Background ◽  
Antibacterial Properties ◽  
Differentially Expressed ◽  
Transcriptional Responses ◽  
Yersinia Infection ◽  
Ifn Γ ◽  
The Impact

The outcome of a host-pathogen encounter is determined by virulence factors of the pathogen and defense factors of the host. We characterized the impact of host factors [resistant (C57BL/6) or susceptible (BALB/c) genetic background and exposure to interferon (IFN)-γ] on transcriptional responses of bone marrow-derived macrophages (BMDM) to infection with Yersinia enterocolitica. IFN-γ treatment more profoundly altered the transcriptome of BMDM than did bacterial infection or genetic background. In BALB/c BMDM, 1,161 genes were differentially expressed in response to Yersinia infection with or without IFN-γ prestimulation. Fourteen genes (1.2%) could only be induced by BALB/c BMDM in response to Yersinia infection after IFN-γ pretreatment. These genes inhibit apoptosis, activate NF-κB and Erk signaling, are chemotactic to neutrophils, and are involved in cytoskeletal reorganization, hence possibly in phagocytosis. Ten of these genes possess a common module of binding sites for Hox, Pou, and Creb transcription factors in 2 kb of upstream genomic sequence, suggesting a possible novel role of these transcription factors in regulation of immune responses. Fifty-two of one thousand fifty differentially expressed genes (4.9%) were induced more strongly by C57BL/6 BMDM in response to Yersinia infection than BALB/c BMDM. These genes activate NK cells, have antibacterial properties, or are involved in sensing chemokines and lipopolysaccharide (LPS). These data show that host resistance factors modulate a surprisingly small, but identifiable and functionally significant, portion of the macrophage transcriptome in response to Yersinia infection.

Role of HFE in Hepatic Iron Overload: Novel Findings Demonstrate Direct Effects of Mutant C282Y on Hepcidin and Calreticulin mRNA Expression.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1549-1549
Author(s):  
Jorge P. Pinto ◽  
Pedro Ramos ◽  
Sergio de Almeida ◽  
Susana Oliveira ◽  
Laura Breda ◽  
...  
Keyword(s):  
Protective Effect ◽  
Cell Line ◽  
Mononuclear Cells ◽  
Hepatic Cell ◽  
Wild Type ◽  
Peripheral Blood Mononuclear ◽  
Mutant Proteins ◽  
Over Expression ◽  
Blood Mononuclear Cells

Abstract Studies done in non-hepatic cell lines, focusing on the interaction between HFE with TFR1 and β-2M proved insufficient to explain the discrepancies found in the clinical penetrance of hemochromatosis in subjects carrying the C282Y mutation. Our first goal was to investigate the role of HFE wild type (wt) and mutant proteins (C282Y and H63D) in a human hepatic cell line, focusing on the cellular localization and interaction of HFE with the expression of other iron related proteins. HFE mutant C282Y was found to be retained in the endoplasmic reticulum (ER). Thus, in addition, we investigated the effect of HFE wt and mutant proteins on Calreticulin, which is a chaperon protein that responds to ER stress and has a protective effect on oxidative damage in some cell lines. Here we report setting up a stable transfection of wt- and mutant-HFE in a hepatic cell line (HepG2) and examine the intracellular distribution of wt- and HFE mutants, their effect on iron intake independently of TFR1 and on the expression of other iron and ER stress response genes, namely Hepcidin and Calreticulin. In addition, we validated some of the novel effects of HFE on Calreticulin using peripheral blood mononuclear cells from HFE patients. The localization of the HFE variants was analyzed using KDEL and Golgin-97 as ER and the Golgi complex markers, respectively. HFE C282Y shows a high degree of overlap with the ER markers, confirming a retention of this variant in this organelle. Over-expression of the HFE wt impaired the intake of 55Fe relatively to transfected control cells (P<0.008) independently of TFR1, as demonstrated by RNAi silencing. Hamp RNA expression was decreased in cells over expressing C282Y in comparison to HFE wt cells (P<0.011). Finally over-expression of HFE wt decreases Calreticulin mRNA, whereas the C282Y had an opposite effect, compared to the control cell line. A similar result was observed in peripheral blood mononuclear cells (PMBC) of C282Y homozygous HFE patients, compared to wild type blood donors (P<0.006). Interestingly, this data suggest that synthesis of the HFE mutant C282Y triggers a protective effect on oxidative damage mediated by Calreticulin. In fact, HepG2 cells over-expressing C282Y showed lower levels of ROS than HFE wt (P<0.004). This observation might contribute to explain some of the discrepancies seen in the clinical penetrance of the disease in C282Y carrying subjects. The direct effect of the mutant HFE C282Y on mRNA expression of hepcidin also demonstrated here for the first time corroborates and provides a molecular basis for earlier reports of low hepcidin levels in HH patients and in Hfe-KO mice.

scholarly journals MBNL1 As a New Therapeutic Target in MLL-Fusion Gene Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 462-462 ◽  
Author(s):  
Svetlana S Itskovich ◽  
Jason Clark ◽  
James C. Mulloy ◽  
Matthew D Disney ◽  
Ashish R Kumar
Keyword(s):  
Bone Marrow ◽  
Cord Blood ◽  
Peripheral Blood ◽  
Fusion Gene ◽  
Leukemia Cell ◽  
Leukemia Cells ◽  
Transformed Cells ◽  
Wild Type

Abstract Translocations of the Mixed Lineage Leukemia (MLL) gene located on chromosome 11 are commonly found in infants with AML or ALL and in secondary leukemia at all ages. A majority of patients with these translocations have a poor prognosis. Gene expression profiling studies demonstrate that one of the most consistently overexpressed genes in these leukemias (compared to all other leukemias) is muscleblind-like 1 (MBNL1). Further, MBNL1 was also identified as a direct transcriptional target of MLL-fusion proteins. An RNA-binding protein, MBNL1 is known to be a key factor in the pathophysiology of Myotonic Dystrophy Type I (DM), where sequestration of MBNL1 leads to splicing defects in muscle and neuronal cells. However, the role of MBNL1 in hematopoiesis and leukemogenesis is unknown. To determine the role of MBNL1 in normal hematopoiesis we studied MBNL1-/- mice. Compared to littermate controls, MBNL1-/- mice showed no differences in peripheral blood counts or bone marrow cellularity. When challenged with 5-FU, both MBNL1-/- and wild type mice displayed similar kinetics of peripheral blood cytopenia and recovery. Next we examined the role of MBNL1 in hematopoietic stem cell function using a competitive transplantation assay. Lethally irradiated mice were transplanted with a 1:1 mix of CD45.1 and CD45.2 bone marrow, with the latter being wild-type or MBNL1-/-. Flow cytometry analysis of peripheral blood at 4 weeks post-transplant showed donor chimerism being 53±4.14% in recipients of wild type marrow and 25±5.41 % in the MBNL1-/- recipients. Successive analyses every 4 weeks showed the chimerism to be stable over the next 16 weeks. To determine the role of MBNL1 in leukemia, we transformed MBNL1-/- or wild type bone marrow cells with various oncogenes delivered via retroviral transduction and compared them in methylcellulose colony replating assays. Absence of MBNL1 significantly reduced colony formation in MLL-AF9 and E2A-HLF transformed cells by 59.5% (± 27.1) and 50.7% (± 23) respectively, compared to controls. To assess the role of MBNL1 in leukemia in vivo, we transplanted MLL-AF9-transformed wild type or MBNL1-/- cells into irradiated mice. All recipients injected with wild-type MLL-AF9-transformed cells succumbed to leukemia with a median time of 106 days. In contrast, the majority of recipients of MBNL1-/- cells survived leukemia-free for at least 140 days post-transplantation (p=0.0017, log rank test). We next assessed the role of MBNL1 in human leukemia cells. Lentiviral-shRNA knockdown of MBNL1 in leukemia cell lines (MV4;11, THP-1) significantly inhibited cell growth, both in liquid culture and methylcellulose colony forming assays. To determine the requirement of MBNL1 for leukemia propagation in vivo, we used cord blood-derived leukemia cells bearing the MLL-AF9 fusion gene and mutant NRAS (MA9NRAS). MA9NRAS cells transduced with MBNL1-specific or control (non-targeting, NT) shRNA were transplanted into immunodeficient mice. Six weeks after transplant, bone marrow aspirates showed persistence of lentiviral-transduced cells in 85% of the NT-group. On the other hand, MBNL1-shRNA transduced cells were not detected in any of the recipient mice. These results suggest that MBNL1 is essential for leukemia cell propagation in vivo. Finally, we tested therapeutic targeting of MBNL1 in MLL-fusion gene leukemia. A lead inhibitor that prevents binding of MBNL1 to its targets was recently identified. Treatment of MA9NRAS cells with the inhibitor for 48 hours led to significant apoptosis whereas normal cord blood CD34+ cells were relatively less sensitive. Blockade of MBNL1 in leukemia cells either by shRNA-knockdown or by the inhibitor showed identical changes in splicing patterns of known MBNL1 target genes. Collectively, our data suggest that MBNL1 is required for the initiation and propagation of MLL-fusion gene leukemia while it appears relatively dispensable for normal hematopoiesis. Further, we have identified a promising lead inhibitor that could be developed for novel treatments for therapy-resistant leukemias. Disclosures No relevant conflicts of interest to declare.

scholarly journals THE ROLE OF TRANSCRIPTION FACTORS DFOXO, DSIR2 AND HSP70 IN LIFESPAN ALTERATION OF DROSOPHILA MELANOGASTER IN DIFFERENT LIGHT CONDITIONS

2010 ◽  
Vol 8 (3) ◽  
pp. 67-80 ◽  
Author(s):  
Aleksey A Moskalev ◽  
Olga A Malysheva
Keyword(s):  
Drosophila Melanogaster ◽  
Transcription Factors ◽  
Stress Response ◽  
Life Span ◽  
Light Regime ◽  
Light Conditions ◽  
Wild Type ◽  
Stress Response Genes ◽  
Significant Difference

It was investigated the role of stress-response genes (dFOXO, dSir2, Hsp70) in regulation of life span of Drosophila in response to light regime alteration. It was revealed the FOXO-dependant mechanism of lifespan increasing at darkness conditions. The distance of lifespan of FOXO homozygous mutants at different light conditions were absent 3 times from 4 times. It was shown, that homozygotes with deletion of dSir2 have more significant difference between lifespan at standard light and darkness conditions with comparing to wild type and heterozygous strain. The same tendency was also detected the in the strains with Hsp70 deletions. It was produced the evidences of two mechanisms of light regime influence on lifespan: metabolism intensification at light conditions and neuroendocrine-determinated lifespan increasing at darkness conditions.

scholarly journals Transcriptomic and Proteomic Profiling Reveal the Key Role of AcMYB16 in the Response of Pseudomonas syringae pv. actinidiae in Kiwifruit

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaojie Wang ◽  
Yawei Li ◽  
Yuanyuan Liu ◽  
Dongle Zhang ◽  
Min Ni ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Pseudomonas Syringae ◽  
Regulatory Element ◽  
Differentially Expressed ◽  
Resistant Cultivar ◽  
Proteomic Profiling ◽  
Phenylpropanoid Biosynthesis ◽  
R2r3 Myb ◽  
Important Disease

Kiwifruit bacterial canker caused by Pseudomonas syringae pv. actinidiae (Psa), is an important disease of kiwifruit (Actinidia Lind.). Plant hormones may induce various secondary metabolites to resist pathogens via modulation of hormone-responsive transcription factors (TFs), as reported in past studies. In this study, we showed that JA accumulated in the susceptible cultivar Actinidia chinensis ‘Hongyang’ but decreased in the resistant cultivar of A. chinensis var. deliciosa ‘Jinkui’ in response to Psa. Integrated transcriptomic and proteomic analyses were carried out using the resistant cultivar ‘Jinkui’. A total of 5,045 differentially expressed genes (DEGs) and 1,681 differentially expressed proteins (DEPs) were identified after Psa infection. Two pathways, ‘plant hormone signal transduction’ and ‘phenylpropanoid biosynthesis,’ were activated at the protein and transcript levels. In addition, a total of 27 R2R3-MYB transcription factors (TFs) were involved in the response to Psa of ‘Jinkui,’ including the R2R3-MYB TF subgroup 4 gene AcMYB16, which was downregulated in ‘Jinkui’ but upregulated in ‘Hongyang.’ The promoter region of AcMYB16 has a MeJA responsiveness cis-acting regulatory element (CRE). Transient expression of the AcMYB16 gene in the leaves of ‘Jinkui’ induced Psa infection. Together, these data suggest that AcMYB16 acts as a repressor to regulate the response of kiwifruit to Psa infection. Our work will help to unravel the processes of kiwifruit resistance to pathogens and will facilitate the development of varieties with resistance against bacterial pathogens.

scholarly journals Transcriptome Analysis Revealed GhWOX4 Intercedes Myriad Regulatory Pathways to Modulate Drought Tolerance and Vascular Growth in Cotton

2021 ◽  
Vol 22 (2) ◽  
pp. 898
Author(s):  
Muhammad Sajjad ◽  
Xi Wei ◽  
Lisen Liu ◽  
Fuguang Li ◽  
Xiaoyang Ge
Keyword(s):  
Transcription Factors ◽  
Drought Stress ◽  
Drought Tolerance ◽  
Plant Growth ◽  
Growth And Development ◽  
Differentially Expressed ◽  
Growth And Yield ◽  
Regulatory Pathways ◽  
Vascular Growth

Cotton is a paramount cash crop around the globe. Among all abiotic stresses, drought is a leading cause of cotton growth and yield loss. However, the molecular link between drought stress and vascular growth and development is relatively uncharted. Here, we validated a crucial role of GhWOX4, a transcription factor, modulating drought stress with that of vasculature growth in cotton. Knock-down of GhWOX4 decreased the stem width and severely compromised vascular growth and drought tolerance. Conversely, ectopic expression of GhWOX4 in Arabidopsis enhanced the tolerance to drought stress. Comparative RNAseq analysis revealed auxin responsive protein (AUX/IAA), abscisic acid (ABA), and ethylene were significantly induced. Additionally, MYC-bHLH, WRKY, MYB, homeodomain, and heat-shock transcription factors (HSF) were differentially expressed in control plants as compared to GhWOX4-silenced plants. The promotor zone of GhWOX4 was found congested with plant growth, light, and stress response related cis-elements. differentially expressed genes (DEGs) related to stress, water deprivation, and desiccation response were repressed in drought treated GhWOX4-virus-induced gene silencing (VIGS) plants as compared to control. Gene ontology (GO) functions related to cell proliferation, light response, fluid transport, and flavonoid biosynthesis were over-induced in TRV: 156-0 h/TRV: 156-1 h (control) in comparison to TRV: VIGS-0 h/TRV: VIGS-1 h (GhWOX4-silenced) plants. This study improves our context for elucidating the pivotal role of GhWOX4 transcription factors (TF), which mediates drought tolerance, plays a decisive role in plant growth and development, and is likely involved in different regulatory pathways in cotton.

Nucleoside and Non-Nucleoside DOT1L Inhibitors：Dawn of MLLrearranged Leukemia

2021 ◽  
Vol 21 ◽  
Author(s):  
Meng Cao ◽  
Tong Li ◽  
Yuxiang Chen ◽  
Xin Zhai
Keyword(s):  
Clinical Trial ◽  
Cancer Treatment ◽  
Orphan Drug ◽  
Therapeutic Target ◽  
Mixed Lineage Leukemia ◽  
Fusion Partner ◽  
Over Expression ◽  
Pharmacokinetic Properties ◽  
Active Transcription

: Herein, the underlying role of disruptor of telomeric silencing 1-like (DOT1L) as a therapeutic target for mixed lineage leukemia (MLL)-rearranged were comprehensively clarified. DOT1L can be aberrantly recruited by MLL fusion partner, thereby occasion several leukemia relevant genes over-expression, and eventually lead to leukemia. As the unique histone methyltransferase (HMT), DOT1L possessed the function to specifically methylate H3K79, which was identified as hallmark of active transcription. Accordingly, blockading of DOT1L has been recognized as an effective approach for cancer treatment. Currently, nucleoside DOT1L inhibitors have been developed successfully with the only EPZ5676 entering phase Ⅰ clinical trial in 2013, which was validated as ‘orphan drug’ toward MLL-rearranged leukemia by FDA. In order to find compounds with better pharmacokinetic properties as DOT1L inhibitors, other types of non-nucleoside skeletons have also been reported successively.

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