LSD1-mediated repression of GFI1 super-enhancer plays an essential role in erythroleukemia

Tatsumi, Goichi; Kawahara, M.; Yamamoto, Ryusuke; Hishizawa, Masakatsu; Kiura, Katsuyuki; Suzuki, Takayoshi; Takaori‐Kondo, Akifumi; Andoh, Akira

doi:10.1038/s41375-019-0614-6

Cited by 26 publications

(13 citation statements)

References 60 publications

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“…Notably, in previously described nongenetic ruxolitinib-persister/resistant HEL92.1.7-RuxP and SET-2-RuxP cells, unlike in parental SET-2 or HEL92.1.7 cells, pre-treatment with INCB for 48 h, markedly enhanced ruxolitinib-induced apoptosis in HEL-RuxP and SET-2-RuxP cells ( p < 0.001) (Fig. 5G ) 47 . Pre-treatment with INCB or ORY1001 for 48 h, sensitized ruxolitinib-resistant PD CD34+ blast progenitor cells (3 samples) to ruxolitinib-induced loss of cell viability (Fig.…”

Section: Resultsmentioning

confidence: 47%

“…Additional findings highlighted here are that disruption of LSD1-CoREST-HDAC1/2 complex derepresses GFI1/1B SE/Es to cause early induction of GFI1/1B 47 , which could serve as a predictive early biomarker of achieving biologically effective intracellular levels of LSD1i in AML and post-MPN sAML cells. LSD1-KO also increased H3K27Ac and BRD4 occupancy at the GFI1 locus inducing GFI1 in AML cells.…”

Section: Discussionmentioning

confidence: 75%

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Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells

et al. 2021

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There is an unmet need to overcome nongenetic therapy-resistance to improve outcomes in AML, especially post-myeloproliferative neoplasm (MPN) secondary (s) AML. Studies presented describe effects of genetic knockout, degradation or small molecule targeted-inhibition of GFI1/LSD1 on active enhancers, altering gene-expressions and inducing differentiation and lethality in AML and (MPN) sAML cells. A protein domain-focused CRISPR screen in LSD1 (KDM1A) inhibitor (i) treated AML cells, identified BRD4, MOZ, HDAC3 and DOT1L among the codependencies. Our findings demonstrate that co-targeting LSD1 and one of these co-dependencies exerted synergistic in vitro lethality in AML and post-MPN sAML cells. Co-treatment with LSD1i and the JAKi ruxolitinib was also synergistically lethal against post-MPN sAML cells. LSD1i pre-treatment induced GFI1, PU.1 and CEBPα but depleted c-Myc, overcoming nongenetic resistance to ruxolitinib, or to BETi in post-MPN sAML cells. Co-treatment with LSD1i and BETi or ruxolitinib exerted superior in vivo efficacy against post-MPN sAML cells. These findings highlight LSD1i-based combinations that merit testing for clinical efficacy, especially to overcome nongenetic therapy-resistance in AML and post-MPN sAML.

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Section: Resultsmentioning

confidence: 47%

Section: Discussionmentioning

confidence: 75%

Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells

et al. 2021

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“…Anticancer drug Lysine-specific demethylase 1 (LSD1) inhibitor (NCD38) activates GFI1-SE and induces lineage switch from erythroid to myeloid by activating differentiation in leukemic cells [ 56 , 57 ]. NCD38 evicts the histone repressive modifiers such as LSD1, CoREST, HDAC1, and HDAC2 from GFI1-SE [ 57 ]. Mediator-associated kinases such as CDK8 act as negative regulators of SE-mediated transcription.…”

Section: Constituents and Identification Of Super-enhancersmentioning

confidence: 99%

Super-Enhancers, Phase-Separated Condensates, and 3D Genome Organization in Cancer

Tang

Vijayakumar

Zhang

et al. 2022

Cancers

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3D chromatin organization plays an important role in transcription regulation and gene expression. The 3D genome is highly maintained by several architectural proteins, such as CTCF, Yin Yang 1, and cohesin complex. This structural organization brings regulatory DNA elements in close proximity to their target promoters. In this review, we discuss the 3D chromatin organization of super-enhancers and their relationship to phase-separated condensates. Super-enhancers are large clusters of DNA elements. They can physically contact with their target promoters by chromatin looping during transcription. Multiple transcription factors can bind to enhancer and promoter sequences and recruit a complex array of transcriptional co-activators and RNA polymerase II to effect transcriptional activation. Phase-separated condensates of transcription factors and transcriptional co-activators have been implicated in assembling the transcription machinery at particular enhancers. Cancer cells can hijack super-enhancers to drive oncogenic transcription to promote cell survival and proliferation. These dysregulated transcriptional programs can cause cancer cells to become highly dependent on transcriptional regulators, such as Mediator and BRD4. Moreover, the expression of oncogenes that are driven by super-enhancers is sensitive to transcriptional perturbation and often occurs in phase-separated condensates, supporting therapeutic rationales of targeting SE components, 3D genome organization, or dysregulated condensates in cancer.

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“…PU.1 and CEBPα) ultimately induced the differentiation of AML blasts. 13,[17][18][19][20][21][22][23] Consequently, various irreversible LSD1 inhibitors have been developed in recent years, with some currently undergoing clinical trials for AML. [24][25][26][27] To further enhance the anti-leukemic effects of existing treatments, various drug combinations containing LSD1 inhibitors have been studied to date, and shown synergy in the induction of differentiation and cytotoxicity, e.g.…”

Section: Introductionmentioning

confidence: 99%

Combining LSD1 and JAK-STAT inhibition targets Down syndrome-associated myeloid leukemia at its core

Grimm

Bhayadia

Gack

et al. 2022

Preprint

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Children with Down syndrome (DS) are predisposed to developing megakaryoblastic leukemia (ML-DS) and often experience severe toxicities from chemotherapy, highlighting the need for targeted therapies with beneficial risk profiles. The genomic landscape of ML-DS is characterized by a combination of mutations in signaling pathway genes and epigenetic modifiers, while aberrant lysine specific demethylase 1 (LSD1) and JAK-STAT activation have both been implicated in leukemogenesis. Here, we demonstrate that combined LSD1 and JAK1/2 inhibition exerts synergistic anti-leukemic effects specifically in ML-DS, both in vitro and in patient derived xenografts in vivo. The JAK1/2 inhibitor ruxolitinib enhanced the LSD1 inhibitor-induced differentiation, proliferation arrest and apoptosis in patient-derived leukemic blasts. At the transcriptional level, the combination synergistically repressed gene expression signatures essential for cell division. We further observed an immunogenic gene expression pattern in the form of increased cytokine signaling, which - by sensitizing ML-DS blasts to the JAK-STAT signaling blockade induced by ruxolitinib - could explain the increased susceptibility of ML-DS blasts to combination therapy. Taken together, we establish combined LSD1 and JAK-STAT inhibition as an efficacious therapeutic regimen specifically designed to target important steps in ML-DS leukemogenesis, paving the way for targeted therapies in this entity.

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LSD1-mediated repression of GFI1 super-enhancer plays an essential role in erythroleukemia

Cited by 26 publications

References 60 publications

Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells

Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells

Super-Enhancers, Phase-Separated Condensates, and 3D Genome Organization in Cancer

Combining LSD1 and JAK-STAT inhibition targets Down syndrome-associated myeloid leukemia at its core

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