Association of a MicroRNA/TP53 Feedback Circuitry With Pathogenesis and Outcome of B-Cell Chronic Lymphocytic Leukemia

Abstract

HRONIC LYMPHOCYTIC LEUkemia (CLL) is the most common leukemia among a d u l t s i n t h e W e s t e r n world, with an annual incidence in the United States of approximately 10 000 new cases. 1 The clinical stag-ing systems devised by Rai et al 2 and Binet et al 3 are useful for assessing the extent of CLL in a patient, but they fail to differentiate between the indolent and aggressive forms of CLL. Most typically these forms are characterized by low and high levels of zeta-chain (TCR)-associated See also p 95 and Patient Page.

tsRNA signatures in cancer

“…The results of these experiments suggest that tsRNAs could be key effectors in pathways regulated by these oncogenes and that these molecules could have important roles in the cell transformation process and in cancer development/progression. Additionally, the oncogenedriven dysregulation of tsRNA could be involved in feedback loops, as previously shown for miRNAs (34). Indeed, when profiling the gene-expression patterns of ts-46 and ts-101 KO cells, we found that pathways such as PTEN and ceramide signaling are inhibited.…”

Role of miR-15/16 in CLL

“…Similarly, doxorubicin-mediated TP53 activation in MEG-01 cells increased the expression of miR-16, an effect that was abolished when TP53 was silenced by an anti-TP53 oligonucleotide. 30 We also identified a binding site for both miR-15 and miR-16 inside the 3 0 UTR of TP53. A luciferase reporter assay showed that both miR-15 and miR-16 directly target the identified TP53-binding site and significantly reduced the luciferase reporter activity compared with a scrambled oligonucleotide-negative control.…”

“…A luciferase reporter assay showed that TP53 significantly increased the luciferase reporter activity of all the binding site containing vectors. 30 In MEG-01 cells, TP53 transactivation of the miR-15/16 cluster was also confirmed by real-time reverse transcription-PCR. Similarly, doxorubicin-mediated TP53 activation in MEG-01 cells increased the expression of miR-16, an effect that was abolished when TP53 was silenced by an anti-TP53 oligonucleotide.…”

“…Several TP53-binding sites were found upstream of the miR-15/miR-16 chromosome 13q14 and on a homologous miR-15/16 cluster chromosome 3. 30 Chromatin immunoprecipitation analysis revealed that TP53 directly binds to its predicted binding sites on both chromosome 13q14 and chromosome 3, both in cell lines and in primary CLLs with normal cytogenetic profiles. A luciferase reporter assay showed that TP53 significantly increased the luciferase reporter activity of all the binding site containing vectors.…”

“…We concluded that miR-15/16 and TP53 are engaged in feedback circuitry loop in CLL: p53 transactivates miR-15/16, while increased levels of miR-15/16 target TP53 expression (Figure 2). 30 Although BCL2 is arguably the most important target of miR-15/16, several other oncogenes targeted by miR-15/16 were recently identified. For example, it has been shown that miR-15/16 inhibits MCL1 oncogene in CLL BMI1 oncogene in mantle call lymphoma.…”