Peterson LF, Yan M, Zhang DE.. The p21Waf1 pathway is involved in blocking leukemogenesis by the t(8;21) fusion protein AML1-ETO. Blood 109: 4392-4398

Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, CA 92037, USA.
Blood (Impact Factor: 10.45). 06/2007; 109(10):4392-8. DOI: 10.1182/blood-2006-03-012575
Source: PubMed


The 8;21 translocation is a major contributor to acute myeloid leukemia (AML) of the M2 classification occurring in approximately 40% of these cases. Multiple mouse models using this fusion protein demonstrate that AML1-ETO requires secondary mutagenic events to promote leukemogenesis. Here, we show that the negative cell cycle regulator p21(WAF1) gene is up-regulated by AML1-ETO at the protein, RNA, and promoter levels. Retroviral transduction and hematopoietic cell transplantation experiments with p21(WAF1)-deficient cells show that AML1-ETO is able to promote leukemogenesis in the absence of p21(WAF1). Thus, loss of p21(WAF1) facilitates AML1-ETO-induced leukemogenesis, suggesting that mutagenic events in the p21(WAF1) pathway to bypass the growth inhibitory effect from AML1-ETO-induced p21(WAF1) expression can be a significant factor in AML1-ETO-associated acute myeloid leukemia.

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    • "p21, a CDK inhibitor, is an important cell cycle regulator, and participates in negative control of the cell checkpoint by blocking CDK activity. It had been shown that AML1-ETO upregulates expression of p21 and that AML1-ETO (+) leukemia can be inhibited by activation of the p21 pathway (Liu S, Klisovic RB, et al, 2007; and Peterson LF, Yan M, et al, 2007).27,28 Using semiquantitative reverse transcriptase PCR to test whether valproic acid upregulates expression of p21, we found that valproic acid induced a significant increase in expression of both p21 mRNA (Figure 6A) and p21 protein (Figure 6B) in a mouse xenograft model. "
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    ABSTRACT: The chimeric fusion protein, AML1-ETO, generated by translocation of t(8;21), abnormally recruits histone deacetylase (HDAC) to the promoters of AML1 target genes, resulting in transcriptional repression of the target genes and development of t(8;21) acute myeloid leukemia. Abnormal expression of cyclin-dependent kinase inhibitors, especially p21, is considered a possible mechanism of the arrested maturation and differentiation seen in leukemia cells. A new generation of HDAC inhibitors is becoming an increasing focus of attention for their ability to induce differentiation and apoptosis in tumor cells and to block the cell cycle. Our previous research had demonstrated that valproic acid induces G0/G1 arrest of Kasumi-1 cells in t(8;21) acute myeloid leukemia. In this study, we further confirmed that valproic acid inhibits the growth of Kasumi-1 cells in a murine xenograft tumor model, and that this occurs via upregulation of histone acetylation in the p21 promoter region, enhancement of p21 expression, suppression of phosphorylation of retinoblastoma protein, blocking of transcription activated by E2F, and induction of G0/G1 arrest.
    OncoTargets and Therapy 06/2013; 6:733-40. DOI:10.2147/OTT.S46135 · 2.31 Impact Factor
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    • "Despite the attractiveness of this model, there is increasing evidence that AML-ETO mediated leukemogenesis is more complex than simple repression of RUNX1 target genes. AML1-ETO has also been shown to effect activation of some target genes, such as p21 [Peterson et al., 2007b], BCL-2 [Klampfer et al., 1996] and the differentiation blocking microRNA, miR-24 [Zaidi et al., 2009], as well as regulate genes that are not targets of endogenous CBFβ/RUNX1 [Gardini et al., 2008; Shimada et al., 2000]. Consistent with these findings, it has been demonstrated that AML1-ETO, but not RUNX1, preferentially binds promoters with duplicated RUNX1 consensus sites [Okumura et al., 2008]. "
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    ABSTRACT: The core binding factor (CBF) acute myeloid leukemias (AMLs) are a prognostically distinct subgroup that includes patients with the inv(16) and t(8:21) chromosomal rearrangements. Both of these rearrangements result in the formation of fusion proteins, CBFB-MYH11 and AML1-ETO, respectively, that involve members of the CBF family of transcription factors. It has been proposed that both of these fusion proteins function primarily by dominantly repressing normal CBF transcription. However, recent reports have indicted that additional, CBF-repression independent activities may be equally important during leukemogenesis. This article will focus on these recent advances.
    Journal of Cellular Biochemistry 08/2010; 110(5):1039-45. DOI:10.1002/jcb.22596 · 3.26 Impact Factor
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    • "Taken together, it is possible that AML1-ETO prevents the repressive action of AML1 on p21 WAF1/CIP1 as a means to enhance self-renewal during an oncogene-induced stress response. To confound matters, AML1-ETO has also been shown to cooperate with loss of p21 WAF1/CIP1 to promote leukemia formation in a mouse model using retroviral delivery of the AML1-ETO gene into mouse fetal liver hematopoietic progenitor cells in a p21 WAF1/CIP1 -null background (Peterson et al., 2007). How these different data converge on a common unifying mechanism of AML1-ETO action are unclear; it is likely that differences may reside in the unique approaches and model systems that have been used to address these questions. "
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    ABSTRACT: Hematopoietic development requires coordinated actions from a variety of transcription factors. The core binding factor (CBF), consisting of a Runx protein and the CBFbeta protein, is a transcription factor complex that is essential for emergence of the hematopoietic stem cell (HSC) from an endothelial cell stage. The hematopoietic defects observed in either Runx1 or CBFbeta knockout mice underscore the necessity of this complex for definitive hematopoiesis. Despite the requirement for CBF in establishing definitive hematopoiesis, Runx1 loss has minimal impact on maintaining the HSC state postnatally, while CBFbeta may continue to be essential. Lineage commitment, on the other hand, is significantly affected upon CBF loss in the adult, indicating a primary role for this complex in modulating differentiation. Given the impact of normal CBF function in the hematopoietic system, the severe consequences of disrupting CBF activity, either through point mutations or generation of fusion genes, are obvious. The physiologic role of CBF in differentiation is subverted to an active process of self-renewal maintenance by the genetic aberrations, through several possible mechanisms, contributing to the development of hematopoietic malignancies including myelodysplastic syndrome and leukemia. The major impact of CBF on the hematopoietic system in both development and disease highlights the need for understanding the intricate functions of this complex and reiterate the necessity of continued efforts to identify potential points of therapeutic intervention for CBF-related diseases.
    Journal of Cellular Physiology 01/2010; 222(1):50-6. DOI:10.1002/jcp.21950 · 3.84 Impact Factor
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