A novel recurrent AML1–ETO fusion: tight in vivo association with BCR–ABL1

Solari, Leticia; Bauer, Tilman; Dicker, Frank; Haferlach, Claudia; Grießhammer, Martin; Schnittger, Susanne; Becker, Heiko; Lübbert, Michael

doi:10.1038/leu.2013.53

Cited by 4 publications

(7 citation statements)

References 15 publications

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“…Recently, t(8;21) was detected in a few cases of advanced chronic myeloid leukemia. 32 Interestingly, fusion between RUNX1 exon 6 and RUNX1T1 exon 2 was detected in at least 2 patients with chronic myeloid leukemia, which correlated with RUNX1-RUNXT1 fusion protein with additional 64 amino acids. Currently, it is unknown whether the presence or absence of exon 6 of human RUNX1 contributes to the distinguished phenotypes of these categories of leukemia.…”

Section: 38mentioning

confidence: 99%

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Runx1 exon 6–related alternative splicing isoforms differentially regulate hematopoiesis in mice

Komeno¹,

Yan²,

Matsuura³

et al. 2014

Blood

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• Human RUNX1a orthologs are only found in primates.• Alternative splicing of Runx1 involving exon 6 affects the pool size of hematopoietic stem cells.RUNX1 is an important transcription factor for hematopoiesis. There are multiple alternatively spliced isoforms of RUNX1. The best known isoforms are RUNX1a from use of exon 7A and RUNX1b and c from use of exon 7B. RUNX1a has unique functions due to its lack of C-terminal regions common to RUNX1b and c. Here, we report that the ortholog of human RUNX1a was only found in primates. Furthermore, we characterized 3 Runx1 isoforms generated by exon 6 alternative splicing. Runx1bEx6 2 (Runx1b without exon 6) and a unique mouse Runx1bEx6e showed higher colony-forming activity than the fulllength Runx1b (Runx1bEx6

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Section: 38mentioning

confidence: 99%

“…27,32 However, the RUNX1 isoforms generated by alternative splicing of exon 6 have not been thoroughly described and characterized.…”

mentioning

confidence: 99%

Runx1 exon 6–related alternative splicing isoforms differentially regulate hematopoiesis in mice

Komeno¹,

Yan²,

Matsuura³

et al. 2014

Blood

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“…Indeed, the co‐expression of ETV6‐RUNX1 and BCR‐ABL1 fusion transcripts was only recently reported in one case of B‐cell ALL (Balatzenko et al, ). However, several other RUNX1 rearrangements have been described in the blastic phase of BCR‐ABL1 ‐positive chronic myeloid leukemia, including the t(3;21)(q26;q22), t(8;21)(q22;q22) and t(1;21)(p36;q22), along with one case of transformed myeloproliferative neoplasm with a FGFR1 translocation (Agerstam et al, ; Maki et al, ; Roche‐Lestienne et al, ; Solari et al, ).…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel fusion gene involving RUNX1 and the antisense strand of SV2B in a BCR‐ABL1‐positive acute leukemia

Giguère

2013

Genes Chromosomes & Cancer

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RUNX1, a key regulator of hematopoiesis, is frequently mutated or implicated in chromosomal translocations in acute leukemia. About half of RUNX1 translocations remain uncharacterized at the molecular level. We describe here one such event, a t(15;21)(q26.1;q22) translocation identified in an adult patient diagnosed with a t(9;22)(q34;q11.2)-positive acute leukemia. This previously unreported rearrangement yields a fusion of RUNX1 with the antisense strand of the SV2B gene, a new translocation partner of RUNX1, resulting in the expression of out-of-frame mRNA chimeric transcripts and the production of putative truncated RUNX1 isoforms. The t(15;21) translocation also dissociates the P1 promoter of RUNX1 from its open reading frame, reducing RUNX1 expression levels in the patient's leukemic cells. Our data suggest that RUNX1 haploinsufficiency collaborates with the BCR-ABL1 oncogene in this leukemia. The description of this atypical gene fusion is an important addition to the characterization of the pathogenomic mechanisms leading to RUNX1 structural and functional alterations. Furthermore, our data strongly suggests that inadequate dosage of this gene plays an essential role in leukemogenesis.

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“…The t(8;21) translocation generates a canonical genomic breakpoint that lies between AML1 exon 5 and ETO exon 2. The chromatin organization at intron 5 of the AML1 gene, where most but not all of the sequenced breakpoints have been mapped, predisposes to chromosomal stress via an epigenetic signature that is rich in histone H3 hyperacetylation and characterized by low histone H1 levels [21]. While the simple reciprocal Fig.…”

Section: Introductionmentioning

confidence: 99%

“…Double-stranded synthetic DNA fragments can be utilized to clone novel AML1/ETO splice variants into the retroviral MSCV-IRES-GFP overexpression construct (ref. [ 21 ]) by utilizing intrinsic restriction enzyme sites. D RT-PCR using exon-specific and exon-junction-spanning primers for the AML1 exon 6 splice event following retroviral transfection of 293T cells with the novel AE/AE6 and AE9a/A6 constructs, as well as the previously published AE and AE9a constructs and a no transfection control (Empty).…”

Section: Introductionmentioning

confidence: 99%

AML1/ETO and its function as a regulator of gene transcription via epigenetic mechanisms

2021

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The chromosomal translocation t(8;21) and the resulting oncofusion gene AML1/ETO have long served as a prototypical genetic lesion to model and understand leukemogenesis. In this review, we describe the wide-ranging role of AML1/ETO in AML leukemogenesis, with a particular focus on the aberrant epigenetic regulation of gene transcription driven by this AML-defining mutation. We begin by analyzing how structural changes secondary to distinct genomic breakpoints and splice changes, as well as posttranscriptional modifications, influence AML1/ETO protein function. Next, we characterize how AML1/ETO recruits chromatin-modifying enzymes to target genes and how the oncofusion protein alters chromatin marks, transcription factor binding, and gene expression. We explore the specific impact of these global changes in the epigenetic network facilitated by the AML1/ETO oncofusion on cellular processes and leukemic growth. Furthermore, we define the genetic landscape of AML1/ETO-positive AML, presenting the current literature concerning the incidence of cooperating mutations in genes such as KIT, FLT3, and NRAS. Finally, we outline how alterations in transcriptional regulation patterns create potential vulnerabilities that may be exploited by epigenetically active agents and other therapeutics.

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A novel recurrent AML1–ETO fusion: tight in vivo association with BCR–ABL1

Cited by 4 publications

References 15 publications

Runx1 exon 6–related alternative splicing isoforms differentially regulate hematopoiesis in mice

Runx1 exon 6–related alternative splicing isoforms differentially regulate hematopoiesis in mice

Identification of a novel fusion gene involving RUNX1 and the antisense strand of SV2B in a BCR‐ABL1‐positive acute leukemia

AML1/ETO and its function as a regulator of gene transcription via epigenetic mechanisms

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