IntroductionThe pathogenesis of acute myeloid leukemia (AML) is a heterogeneous multistep process affecting cell differentiation, proliferation, and apoptosis, which ultimately leads to malignant transformation of hematopoietic progenitors. Deregulated gene expression, disrupting cellular pathways, has been used for the classification of AML. [1][2][3][4][5] The prognosis of AML depends on well-defined leukemiaspecific prognostic factors, such as the cytogenetic abnormalities t(15;17), t(8;21), and inv(16) with a relatively favorable prognosis and the 3q26 abnormalities, Ϫ5/Ϫ5q and Ϫ7/Ϫ7q with an unfavorable prognosis. [6][7][8] Furthermore, various molecular abnormalities in AML with normal karyotype have apparent prognostic significance, such as the somatic gene mutations in nucleophosmin-1 (NPM1), FMS-like tyrosine kinase 3 (FLT3, internal tandem duplications [ITDs]), and CCAAT/enhancer binding protein alpha (CEBPA). 9-13 NPM1 mutations frequently occur in association with FLT3-ITD mutations. Several studies on the clinical impact in AML subgroups revealed that the subset of AML with NPM1 mutations lacking FLT3-ITD mutations has a significantly better overall survival. 14 MicroRNAs are a class of small noncoding RNAs that regulate translation of protein coding mRNAs and thereby protein expression, by translation inhibition or cleavage of the mRNA transcripts. 15 There is an accumulating body of evidence indicating that microRNAs play important roles in cellular growth and differentiation. 16 MicroRNA expression profiles of tumor samples have recently been shown to provide phenotypic signatures of particular cancer types. [17][18][19][20][21][22] MicroRNAs can act as tumor suppressor. For instance, expression of some microRNAs, such as let-7 23 and the microRNA15a/16-1 cluster, 24 has been reported to be reduced in lung cancer and chronic lymphocytic leukemia (CLL) respectively, suggesting tumor suppressor activities. In contrast, microRNA-17-92 cluster 25 and microRNA-155/BIC 26,27 have been shown to be overexpressed in B-cell lymphomas, indicative of their oncogenic potential.A characteristic microRNA expression signature may aid in the diagnosis of certain types or subtypes of cancers. It has been shown that microRNA profiles of bone marrow samples from patients with acute lymphoblastic leukemia (ALL) discriminated subsets of ALL with different molecular aberrancies. 17 In AML, information about microRNA expression has been gathered only in a limited series of patients so far. Debernardi et al 28 reported in 30 AML patients with normal cytogenetics that microRNA-181a correlates with cytologic subclass. They also reported that the expression of microRNA-10a, microRNA-10b, and microRNA-196a, which are located in intergenic regions in the HOX gene clusters, in AML correlates positively with HOXA and HOXB gene expression, suggesting a role of these microRNAs in aberrant regulation of proliferation and differentiation in leukemogenesis. 28 It was recently reported that microRNA expression signatures discriminate...

Several miRNAs have been reported to be associated with immunoglobulin heavy chain (IgH) mutation and ZAP-70 expression status in blood samples of B-cell chronic lymphocytic leukaemia/small lymphocytic lymphoma (B-CLL/SLL). In the bone marrow and lymphoid tissues, proliferation centres (PCs) represent an important site of activation and proliferation of the neoplastic cells, suggesting that these tissues better reflect the biology of CLL than circulating blood cells. We collected 33 lymph nodes and 37 blood CLL samples and analysed IgH mutation status and ZAP-70 expression status. Expression of 15 miRNAs was analysed by qRT-PCR and RNA-ISH. Sixty-three per cent of the lymph node cases contained mutated IgH genes and 49% of the lymph node cases were ZAP-70-positive, and a significant correlation was observed between ZAP-70 expression and IgH mutation status. Of the blood CLL samples, 49% contained mutated IgH sequences. The miRNA expression pattern in CLL lymph node and blood samples was very similar. Three of 15 miRNAs (miR-16, miR-21, and miR-150) showed a high expression level in both blood and lymph node samples. No difference was observed between ZAP-70-positive or -negative and between IgH-mutated or unmutated cases. No correlation was found between miR-15a and miR-16 expression levels and 13q14 deletion in the blood CLL samples. RNA in situ hybridization (ISH) revealed strong homogeneous staining of miR-150 in the tumour cells outside the PCs. In reverse BIC/pri-miR-155 expression was observed mainly in individual cells including prolymphocytes of the PCs. This reciprocal pattern likely reflects the different functions and targets of miR-150 and miR-155.

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BackgroundCDKN2A/p16INK4a is frequently altered in human cancers and it is the most important melanoma susceptibility gene identified to date. p16INK4a inhibits pRb phosphorylation and induces cell cycle arrest, which is considered its main tumour suppressor function. Nevertheless, additional activities may contribute to the tumour suppressor role of p16INK4a and could help explain its specific association with melanoma predisposition. To identify such functions we conducted a yeast-two-hybrid screen for novel p16INK4a binding partners.ResultsWe now report that p16INK4a interacts with the chromatin remodelling factor BRG1. We investigated the cooperative roles of p16INK4a and BRG1 using a panel of cell lines and a melanoma cell model with inducible p16INK4a expression and BRG1 silencing. We found evidence that BRG1 is not required for p16INK4a-induced cell cycle inhibition and propose that the p16INK4a-BRG1 complex regulates BRG1 chromatin remodelling activity. Importantly, we found frequent loss of BRG1 expression in primary and metastatic melanomas, implicating this novel p16INK4a binding partner as an important tumour suppressor in melanoma.ConclusionThis data adds to the increasing evidence implicating the SWI/SNF chromatin remodelling complex in tumour development and the association of p16INK4a with chromatin remodelling highlights potentially new functions that may be important in melanoma predisposition and chemoresistance.