Suppression of RUNX1/ETO oncogenic activity by a small molecule inhibitor of tetramerization

Schanda, Julia; Lee, Chun-Wei; Wohlan, Katharina; Müller-Kuller, Uta; Kunkel, Hana; Coco, Isabell Quagliano-Lo; Stein, Stefan; Metz, A.; Koch, Joachim; Lausen, Jörn; Platzbecker, Uwe; Medyouf, Hind; Gohlke, Holger; Heuser, Michael; Eder, Matthias; Grez, Manuel; Scherr, Michaela; Wichmann, Christian

doi:10.3324/haematol.2016.161570

Cited by 15 publications

(17 citation statements)

References 15 publications

(6 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Earlier work found that oligomerization of RUNX1–RUNX1T1 through the nervy homology 2 (NHR2) domain of RUNX1T1 was essential for its activity as a transcriptional corepressor and mediator of self-renewal to BM cells (133). Interfering with tetramerization by peptides and by small molecules reduced the oncogenic activity of the RUNX1–RUNXT1 fusion in preclinical models (134, 135). RUNX1–RUNXT1 seems to form stable complexes containing hematopoietic co-factors including E-proteins, of which the interaction, e.g., between the NHR2 domain of RUNX1T1, with a novel binding motif in E proteins seems critical (136).…”

Section: Molecular Targeting Of Pediatric Amlmentioning

confidence: 99%

Pediatric Acute Myeloid Leukemia (AML): From Genes to Models Toward Targeted Therapeutic Intervention

Mercher

Schwaller

2019

Front. Pediatr.

View full text Add to dashboard Cite

This review aims to provide an overview of the current knowledge of the genetic lesions driving pediatric acute myeloid leukemia (AML), emerging biological concepts, and strategies for therapeutic intervention. Hereby, we focus on lesions that preferentially or exclusively occur in pediatric patients and molecular markers of aggressive disease with often poor outcome including fusion oncogenes that involve epigenetic regulators like KMT2A, NUP98, or CBFA2T3, respectively. Functional studies were able to demonstrate cooperation with signaling mutations leading to constitutive activation of FLT3 or the RAS signal transduction pathways. We discuss the issues faced to faithfully model pediatric acute leukemia in mice. Emerging experimental evidence suggests that the disease phenotype is dependent on the appropriate expression and activity of the driver fusion oncogenes during a particular window of opportunity during fetal development. We also highlight biochemical studies that deciphered some molecular mechanisms of malignant transformation by KMT2A, NUP98, and CBFA2T3 fusions, which, in some instances, allowed the development of small molecules with potent anti-leukemic activities in preclinical models (e.g., inhibitors of the KMT2A–MENIN interaction). Finally, we discuss other potential therapeutic strategies that not only target driver fusion-controlled signals but also interfere with the transformed cell state either by exploiting the primed apoptosis or vulnerable metabolic states or by increasing tumor cell recognition and elimination by the immune system.

show abstract

Section: Molecular Targeting Of Pediatric Amlmentioning

confidence: 99%

Pediatric Acute Myeloid Leukemia (AML): From Genes to Models Toward Targeted Therapeutic Intervention

Mercher

Schwaller

2019

Front. Pediatr.

View full text Add to dashboard Cite

show abstract

“…Several authors have been able to prevent ETO-fusion or CBFA2T3-fusion protein oligomerization, and importantly have demonstrated a reversion of the leukemic phenotype using a NHR2-mimicking protein or small molecule inhibitors mimicking the tetramerization interface of NHR2, in particular with RUNX1-ETO fusion [14,[51][52][53][54] or CBFA2T3-GLIS2 fusion [55]. Our results are in line with these previous works, since we demonstrated that exogenously expressed NHR2 domain prevents RUNX1 and CBFA2T3 interaction, downregulates RUNX1 target genes' expression and decreases BCP-ALL cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Reduction of RUNX1 transcription factor activity by a CBFA2T3-mimicking peptide: application to B cell precursor acute lymphoblastic leukemia

et al. 2021

Self Cite

View full text Add to dashboard Cite

Background B Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) is the most common pediatric cancer. Identifying key players involved in proliferation of BCP-ALL cells is crucial to propose new therapeutic targets. Runt Related Transcription Factor 1 (RUNX1) and Core-Binding Factor Runt Domain Alpha Subunit 2 Translocated To 3 (CBFA2T3, ETO2, MTG16) are master regulators of hematopoiesis and are implicated in leukemia. Methods We worked with BCP-ALL mononuclear bone marrow patients’ cells and BCP-ALL cell lines, and performed Chromatin Immunoprecipitations followed by Sequencing (ChIP-Seq), co-immunoprecipitations (co-IP), proximity ligation assays (PLA), luciferase reporter assays and mouse xenograft models. Results We demonstrated that CBFA2T3 transcript levels correlate with RUNX1 expression in the pediatric t(12;21) ETV6-RUNX1 BCP-ALL. By ChIP-Seq in BCP-ALL patients’ cells and cell lines, we found that RUNX1 is recruited on its promoter and on an enhancer of CBFA2T3 located − 2 kb upstream CBFA2T3 promoter and that, subsequently, the transcription factor RUNX1 drives both RUNX1 and CBFA2T3 expression. We demonstrated that, mechanistically, RUNX1 and CBFA2T3 can be part of the same complex allowing CBFA2T3 to strongly potentiate the activity of the transcription factor RUNX1. Finally, we characterized a CBFA2T3-mimicking peptide that inhibits the interaction between RUNX1 and CBFA2T3, abrogating the activity of this transcription complex and reducing BCP-ALL lymphoblast proliferation. Conclusions Altogether, our findings reveal a novel and important activation loop between the transcription regulator CBFA2T3 and the transcription factor RUNX1 that promotes BCP-ALL proliferation, supporting the development of an innovative therapeutic approach based on the NHR2 subdomain of CBFA2T3 protein.

show abstract

“…Although TFs are difficult to target, several promising attempts of RUNX–RUNX1T1 inhibition have been made. Current approaches to directly target RUNX1–RUNX1T1 in vitro include the use of small interfering (si) RNAs targeting the fusion site of chimeric mRNA or suppression of oligomerization by polypeptides or low-molecular-weight compounds [ 172 , 174 , 175 , 176 , 177 ]. Both methods work in AML cell cultures, achieving the loss of leukemia cell self-renewal and overcoming the block of myeloid differentiation.…”

Section: Fusion Proteins As Transcriptional Modulatorsmentioning

confidence: 99%

Gene Transcription as a Therapeutic Target in Leukemia

Khamidullina

Varlamova

Hammoud

et al. 2021

IJMS

View full text Add to dashboard Cite

Blood malignancies often arise from undifferentiated hematopoietic stem cells or partially differentiated stem-like cells. A tight balance of multipotency and differentiation, cell division, and quiescence underlying normal hematopoiesis requires a special program governed by the transcriptional machinery. Acquisition of drug resistance by tumor cells also involves reprogramming of their transcriptional landscape. Limiting tumor cell plasticity by disabling reprogramming of the gene transcription is a promising strategy for improvement of treatment outcomes. Herein, we review the molecular mechanisms of action of transcription-targeted drugs in hematological malignancies (largely in leukemia) with particular respect to the results of clinical trials.

show abstract

Suppression of RUNX1/ETO oncogenic activity by a small molecule inhibitor of tetramerization

Cited by 15 publications

References 15 publications

Pediatric Acute Myeloid Leukemia (AML): From Genes to Models Toward Targeted Therapeutic Intervention

Pediatric Acute Myeloid Leukemia (AML): From Genes to Models Toward Targeted Therapeutic Intervention

Reduction of RUNX1 transcription factor activity by a CBFA2T3-mimicking peptide: application to B cell precursor acute lymphoblastic leukemia

Gene Transcription as a Therapeutic Target in Leukemia

Contact Info

Product

Resources

About