RUNX1 repression‐independent mechanisms of leukemogenesis by fusion genes CBFB–MYH11 and AML1–ETO (RUNX1–RUNX1T1)

Hyde, R. Katherine; Liu, P. Paul

doi:10.1002/jcb.22596

Cited by 19 publications

(14 citation statements)

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“…Cbfb þ/56M , Mx1-Cre þ or Cbfb þ/56M , Mx1-Cre þ , Gt(ROSA) 26Sor tm4(ACTB-tdTomato, -EGFP/Luo /J) (Rosa26 tdT/GFP ; The Jackson Laboratory) mice were maintained on a mixed C57Bl6/129S6 background, genotyped, and treated to develop leukemia, as described previously (15,(23)(24)(25). Leukemia cells from primary mice were expanded by transplantation into congenic C57Bl6/129S6 F1 6to 10-week-old mice (Taconic), as described previously (14).…”

Section: Micementioning

confidence: 99%

HDAC1 Is a Required Cofactor of CBFβ-SMMHC and a Potential Therapeutic Target in Inversion 16 Acute Myeloid Leukemia

Richter

Wang

Becker

et al. 2019

Molecular Cancer Research

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Section: Micementioning

confidence: 99%

HDAC1 Is a Required Cofactor of CBFβ-SMMHC and a Potential Therapeutic Target in Inversion 16 Acute Myeloid Leukemia

Richter

Wang

Becker

et al. 2019

Molecular Cancer Research

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“…Finally, gene ontology analysis of genomic regions associated with AML1-ETO/N-CoR enrichment was more relevant to the differentiation block exhibited by Kasumi-1 cells compared to those regions enriched in AML1-ETO/p300. Thus, although AML1-ETO both represses and activates genes at the single-gene level [ 31 ], our genome-wide data show that AML1-ETO predominatly acts as a repressor. Our studies provide a new understanding of the global mechanisms that regulate the t(8;21) leukemic phenotype.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide co-occupancy of AML1-ETO and N-CoR defines the t(8;21) AML signature in leukemic cells

et al. 2015

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BackgroundMany leukemias result from chromosomal rearrangements. The t(8;21) chromosomal translocation produces AML1-ETO, an oncogenic fusion protein that compromises the function of AML1, a transcription factor critical for myeloid cell differentiation. Because of the pressing need for new therapies in the treatment of acute myleoid leukemia, we investigated the genome-wide occupancy of AML1-ETO in leukemic cells to discover novel regulatory mechanisms involving AML-ETO bound genes.ResultsWe report the co-localization of AML1-ETO with the N-CoR co-repressor to be primarily on genomic regions distal to transcriptional start sites (TSSs). These regions exhibit over-representation of the motif for PU.1, a key hematopoietic regulator and member of the ETS family of transcription factors. A significant discovery of our study is that genes co-occupied by AML1-ETO and N-CoR (e.g., TYROBP and LAPTM5) are associated with the leukemic phenotype, as determined by analyses of gene ontology and by the observation that these genes are predominantly up-regulated upon AML1-ETO depletion. In contrast, the AML1-ETO/p300 gene network is less responsive to AML1-ETO depletion and less associated with the differentiation block characteristic of leukemic cells. Furthermore, a substantial fraction of AML1-ETO/p300 co-localization occurs near TSSs in promoter regions associated with transcriptionally active loci.ConclusionsOur findings establish a novel and dominant t(8;21) AML leukemia signature characterized by occupancy of AML1-ETO/N-CoR at promoter-distal genomic regions enriched in motifs for myeloid differentiation factors, thus providing mechanistic insight into the leukemic phenotype.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1445-0) contains supplementary material, which is available to authorized users.

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“…Previous studies suggest that the physical interactions between RUNX1 fusion proteins (RUNX1-ETO and TEL-RUNX1) and CBFβ, and between the CBFβ fusion protein (CBFβ-SMMHC) and RUNX1 are critical for the pathogenesis of CBF leukemias (11)(12)(13). We therefore hypothesize that inhibitors of the RUNX1-CBFβ interaction will be therapeutic for all CBF leukemias.…”

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Identification of benzodiazepine Ro5-3335 as an inhibitor of CBF leukemia through quantitative high throughput screen against RUNX1–CBFβ interaction

Cunningham¹,

Finckbeiner²,

Hyde³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Core binding factor (CBF) leukemias, those with translocations or inversions that affect transcription factor genes RUNX1 or CBFB, account for ∼24% of adult acute myeloid leukemia (AML) and 25% of pediatric acute lymphocytic leukemia (ALL). Current treatments for CBF leukemias are associated with significant morbidity and mortality, with a 5-y survival rate of ∼50%. We hypothesize that the interaction between RUNX1 and CBFβ is critical for CBF leukemia and can be targeted for drug development. We developed high-throughput AlphaScreen and time-resolved fluorescence resonance energy transfer (TR-FRET) methods to quantify the RUNX1-CBFβ interaction and screen a library collection of 243,398 compounds. Ro5-3335, a benzodiazepine identified from the screen, was able to interact with RUNX1 and CBFβ directly, repress RUNX1/CBFB-dependent transactivation in reporter assays, and repress runx1-dependent hematopoiesis in zebrafish embryos. Ro5-3335 preferentially killed human CBF leukemia cell lines, rescued preleukemic phenotype in a RUNX1-ETO transgenic zebrafish, and reduced leukemia burden in a mouse CBFB-MYH11 leukemia model. Our data thus confirmed that RUNX1-CBFβ interaction can be targeted for leukemia treatment and we have identified a promising lead compound for this purpose.T ranscription factors RUNX1 and CBFβ form a heterodimer for DNA binding and regulation of gene expression. Genes encoding both proteins play key roles in hematopoiesis (1) and are involved in leukemogenesis through recurrent chromosome abnormalities (2), such as a chromosome 16 inversion [(inv)16] that generates a fusion gene between CBFB and MYH11 (encoding the smooth muscle myosin heavy chain, SMMHC) in acute myeloid leukemia (AML) subtype M4Eo (3, 4), a translocation between chromosomes 8 and 21 that generates a fusion gene between RUNX1 and ETO in AML subtype M2 (5), and a translocation between chromosomes 12 and 21 that generates a fusion gene called TEL-RUNX1 in pediatric precursor B-cell acute lymphocytic leukemia (ALL) (6). All together, the CBF leukemias, which contain translocations involving RUNX1 or CBFB, account for 24% of adult AML cases (7) and 25% of pediatric ALL cases (8). Although core binding factor (CBF) leukemias are generally associated with relatively favorable prognoses, long-term survival for adult patients with CBF AML is only about 50% (9). Although children with CBF leukemias have survival rates of >80% (8, 10), standard therapy takes years to complete. Moreover, the current standard of care for all patients is frequently associated with significant morbidity and mortality. Therefore, targeted treatments for CBF leukemia with high efficacy and low toxicity are clearly desirable.Previous studies suggest that the physical interactions between RUNX1 fusion proteins (RUNX1-ETO and TEL-RUNX1) and CBFβ, and between the CBFβ fusion protein (CBFβ-SMMHC) and RUNX1 are critical for the pathogenesis of CBF leukemias (11-13). We therefore hypothesize that inhibitors of the RUNX1-CBFβ interaction will be therapeutic for all...

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RUNX1 repression‐independent mechanisms of leukemogenesis by fusion genes CBFB–MYH11 and AML1–ETO (RUNX1–RUNX1T1)

Cited by 19 publications

References 58 publications

HDAC1 Is a Required Cofactor of CBFβ-SMMHC and a Potential Therapeutic Target in Inversion 16 Acute Myeloid Leukemia

HDAC1 Is a Required Cofactor of CBFβ-SMMHC and a Potential Therapeutic Target in Inversion 16 Acute Myeloid Leukemia

Genome-wide co-occupancy of AML1-ETO and N-CoR defines the t(8;21) AML signature in leukemic cells

Identification of benzodiazepine Ro5-3335 as an inhibitor of CBF leukemia through quantitative high throughput screen against RUNX1–CBFβ interaction

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