Peptidomimetic blockade of MYB in acute myeloid leukemia

Ramaswamy, Kavitha; Forbes, Lauren; Minuesa, Gerard; Gindin, Tatyana; Brown, Fiona C.; Kharas, Michael G.; Krivtsov, Andrei V.; Armstrong, Scott A.; Still, Eric; Stanchina, Elisa de; Knoechel, Birgit; Koche, Richard P.; Kentsis, Alex

doi:10.1101/222620

Cited by 9 publications

(18 citation statements)

References 63 publications

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“…In prior work, we used genetic and structural evidence to design a peptidomimetic inhibitor of the MYB:CBP/P300 transcription coactivation complex, termed MYBMIM (Ramaswamy et al, 2018). To elucidate its mechanisms of action in an unbiased manner, we carried out a genome-wide CRISPR knockout screen to identify genes whose depletion affects the susceptibility of AML cells to MYBMIM.…”

Section: Genome-wide Crispr Screen Identifies Cbp Requirement For the Susceptibility Of Aml Cells To Peptidomimetic Blockade Of Myb:cbp/pmentioning

confidence: 99%

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Convergent organization of aberrant MYB complex controls oncogenic gene expression in acute myeloid leukemia

Takao

Forbes

Uni

et al. 2021

eLife

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Dysregulated gene expression contributes to most prevalent features in human cancers. Here, we show that most subtypes of acute myeloid leukemia (AML) depend on the aberrant assembly of MYB transcriptional co-activator complex. By rapid and selective peptidomimetic interference with the binding of CBP/P300 to MYB, but not CREB or MLL1, we find that the leukemic functions of MYB are mediated by CBP/P300 co-activation of a distinct set of transcription factor complexes. These MYB complexes assemble aberrantly with LYL1, E2A, C/EBP family members, LMO2 and SATB1. They are organized convergently in genetically diverse subtypes of AML, and are at least in part associated with inappropriate transcription factor co-expression. Peptidomimetic remodeling of oncogenic MYB complexes is accompanied by specific proteolysis and dynamic redistribution of CBP/P300 with alternative transcription factors such as RUNX1 to induce myeloid differentiation and apoptosis. Thus, aberrant assembly and sequestration of MYB:CBP/P300 complexes provide a unifying mechanism of oncogenic gene expression in AML. This work establishes a compelling strategy for their pharmacologic reprogramming and therapeutic targeting for diverse leukemias and possibly other human cancers caused by dysregulated gene control.

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Section: Genome-wide Crispr Screen Identifies Cbp Requirement For the Susceptibility Of Aml Cells To Peptidomimetic Blockade Of Myb:cbp/pmentioning

confidence: 99%

“…Recently, we developed a peptidomimetic inhibitor of MYB:CBP/P300 (Ramaswamy et al, 2018). Here, we report its second-generation version that has significantly increased potency, and consequently suppresses leukemic MYB functions in most AML subtypes tested, while relatively sparing normal hematopoietic progenitor cells.…”

Section: Introductionmentioning

confidence: 99%

Convergent organization of aberrant MYB complex controls oncogenic gene expression in acute myeloid leukemia

Takao

Forbes

Uni

et al. 2021

eLife

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“…84 In addition to its interaction with TAF12, MYB has been shown to interact with the KIX domain of CREB-binding protein (CBP)/P300, an interaction that is amenable to pharmacological inhibition ( Figure 4A). [85][86][87] Therefore, interrupting interactions between oncogenic TFs and particular subunits of large epigenetic complexes has the potential to specifically disrupt oncogenic transcriptional programs, circumventing the issues associated with targeting TFs directly. However, given that many of these interactions between TFs and epigenetic complexes are driven by "fuzzy" interactions between low-complexity domains, the degree of specificity between TFs and a particular epigenetic domains/subunit remains unclear.…”

Section: Blocking Interactions Between Tfs and Epigenetic Complexesmentioning

confidence: 99%

Epigenetic therapies in acute myeloid leukemia: where to from here?

Fennell

Bell

Dawson

2019

Blood

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“…Therefore, PAX8-AS1 may act as a risk factor for childhood ALL (37). CREB-binding protein/P300 coactivation derived by MYB is necessary for ALL and AML, and MYB activity plays a critical role in maintaining AML (38). MYB expression is increased in T cell ALL, and the oncogene MYB could be a therapeutic target for the disease (39,40).…”

Section: Discussionmentioning

confidence: 99%

Construction of a 14‑lncRNA risk score system predicting survival of children with acute myelocytic leukemia

Guo

et al. 2020

Exp Ther Med

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Acute myelocytic leukemia (AML) is a frequent type of acute leukemia. The present study was performed to build a risk score system for the prognostic prediction of AML. AML RNA-sequencing data from samples from 111 children were downloaded from The Cancer Genome Atlas database. Using the DEseq and edgeR packages, the differentially expressed long non-coding RNAs (DE-lncRNAs) between bad and good prognosis groups were identified. A survival package was used to screen prognosis-associated lncRNAs and clinical factors. The optimal lncRNA combination was selected using the penalized package, and the risk-score system was built and evaluated. After the lncRNA-mRNA expression correlation network was constructed, the potential pathways involving the key lncRNAs were enriched using Gene Set Enrichment Analysis. Among the 61 DE-lncRNAs, 48 lncRNAs were significantly associated with prognosis. Relapse was an independent prognostic factor. The optimal 14-lncRNA risk score system was constructed. After 730 differentially expressed mRNAs were identified between the good and bad prognosis groups divided using a prognostic index, the lncRNA-mRNA expression correlation network was constructed. Enrichment analysis showed that semaphorin-3C [SEMA3C; regulated by probable leucine-tRNA ligase, mitochondrial (LARS2-AS1)] and secreted frizzled-related protein 5 [SFRP5; mediated by WASH complex subunit 5 (WASHC5)-antisense RNA 1 (AS1)] were involved in axon guidance and the Wnt signaling pathway, respectively. A 14-lncRNA (including paired box protein Pax8-AS1 and MYB AS1) risk-score system might be effective in predicting the prognosis of AML. Axon guidance (involving SEMA3C and LARS2-AS1) and the Wnt signaling pathway (involving SFRP5 and WASHC5-AS1) might be two important pathways affecting the prognosis of AML.

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Peptidomimetic blockade of MYB in acute myeloid leukemia

Cited by 9 publications

References 63 publications

Convergent organization of aberrant MYB complex controls oncogenic gene expression in acute myeloid leukemia

Convergent organization of aberrant MYB complex controls oncogenic gene expression in acute myeloid leukemia

Epigenetic therapies in acute myeloid leukemia: where to from here?

Construction of a 14‑lncRNA risk score system predicting survival of children with acute myelocytic leukemia

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