Expression signature of human endogenous retroviruses in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is one of the most diagnosed forms of leukemia worldwide and it is usually classified into two forms: indolent and aggressive. These two forms are characterized by distinct molecular features that drive different responses to treatment and clinical outcomes. In this context, a better understanding of the molecular landscape of the CLL forms may potentially lead to the development of new drugs or the identification of novel biomarkers.

Complete miRNA-15/16 loss in mice promotes hematopoietic progenitor expansion and a myeloid-biased hyperproliferative state.

Dysregulated apoptosis and proliferation are fundamental properties of cancer, and microRNAs (miRNA) are critical regulators of these processes. Loss of miR-15a/16-1 at chromosome 13q14 is the most common genomic aberration in chronic lymphocytic leukemia (CLL). Correspondingly, the deletion of either murine miR-15a/16-1 or miR-15b/16-2 locus in mice is linked to B cell lymphoproliferative malignancies.

tRNA-derived fragments (tRFs) in cancer.

tRNA fragments (tRNA derived fragments or tRFs) are small single stranded RNA molecules derived from pre-tRNAs and mature tRNAs. tRFs have been known for a number of years, but previously they were believed to be not important products of tRNA degradation. tRFs can be unique, like tRF-1 s, or redundant, like tRF-3 s and tRF-5 s.

A large fraction of trisomy 12, 17p, and 11q CLL cases carry unidentified microdeletions of .

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia and is characterized by chromosomal aberrations including 13q, 11q, and 17p deletions and a trisomy of chromosome 12 (T12). 13q deletions are often associated with 11q and 17p deletions in aggressive cases. Conversely, T12 CLLs show a variable prognosis, and association with 13q deletions is uncommon.

Dysregulation of different classes of tRNA fragments in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is the most common human leukemia, and dysregulation of tRNA-derived short noncoding RNA (tsRNA) (tRF-1) expression is an accompanying event in the development of this disease. tsRNAs are fragments originating from the 3' end of tRNA precursors and do not contain mature tRNA sequences. In contrast to tsRNAs, mature tRFs (tRF-3s, tRF-5s, and internal tRFs) are produced from mature tRNA sequences and are redundant fragments.

Noncoding RNA genes in cancer pathogenesis.

By using chronic lymphocytic leukemia as target for discovery in cancer pathogenesis we discovered that the great majority of CLLs (75-85%) carry a deletion of miR-15a and miR-16-1 at 13q14. We also discovered that miR-15/16 are negative regulators of the BCL2 oncogene. Thus the loss of the two negative regulators causes BCL2 overexpression and leukemia.

and expression predicts Richter syndrome in chronic lymphocytic leukemia patients.

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia. It is characterized by the accumulation of CD19/CD5 lymphocytes and can have variable outcomes. Richter syndrome (RS) is a lethal complication in CLL patients that results in aggressive B-cell lymphomas, and there are no tests to predict its occurrence.

BCL2 and miR-15/16: from gene discovery to treatment.

In 1984, we investigated the t(14;18) chromosomal translocations that frequently occur in patients with follicular lymphoma. We first identified a locus on chromosome 18 involved in these translocations with the chromosome 14 containing the immunoglobulin heavy chain locus. Within this region on chromosome 18, we then discovered a gene that we called BCL2, which was activated by the translocations.

dysregulation to identify therapeutic target combinations for chronic lymphocytic leukemia.

Loss of is the most common genetic lesion in chronic lymphocytic leukemia (CLL), promoting overexpression of , which factors in leukemia pathogenesis. Indeed, an inhibitor of Bcl2, venetoclcax, is highly active in the treatment of patients with CLL. However, single-agent venetoclcax fails to eradicate minimal residual disease in most patients.

Role of the tRNA-Derived Small RNAs in Cancer: New Potential Biomarkers and Target for Therapy.

Noncoding RNAs are untranslated RNA molecules that can be divided into two main types: infrastructural, including transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), and regulatory, including long ncRNAs (lncRNAs) and small ncRNAs (sRNA). Among small ncRNA, the role of microRNAs (miRNAs) and Piwi-interacting RNAs (piRNAs) in cancer is well documented. Recently, other small ncRNAs have been described.

tsRNA signatures in cancer.

Small, noncoding RNAs are short untranslated RNA molecules, some of which have been associated with cancer development. Recently we showed that a class of small RNAs generated during the maturation process of tRNAs (tRNA-derived small RNAs, hereafter "tsRNAs") is dysregulated in cancer. Specifically, we uncovered tsRNA signatures in chronic lymphocytic leukemia and lung cancer and demonstrated that the cluster (now called "" and "," respectively), , and are down-regulated in these malignancies.

Dysregulation of a family of short noncoding RNAs, tsRNAs, in human cancer.

Chronic lymphocytic leukemia (CLL) is the most common human leukemia, and transgenic mouse studies indicate that activation of the T-cell leukemia/lymphoma 1 (TCL1) oncogene is a contributing event in the pathogenesis of the aggressive form of this disease. While studying the regulation of TCL1 expression, we identified the microRNA cluster miR-4521/3676 and discovered that these two microRNAs are associated with tRNA sequences and that this region can produce two small RNAs, members of a recently identified class of small noncoding RNAs, tRNA-derived small RNAs (tsRNAs). We further proved that miR-3676 and miR-4521 are tsRNAs using Northern blot analysis.

miR-181b as a therapeutic agent for chronic lymphocytic leukemia in the Eµ-TCL1 mouse model.

The involvement of microRNAs (miRNAs) in chronic lymphocytic leukemia (CLL) pathogenesis suggests the possibility of anti-CLL therapeutic approaches based on miRNAs. Here, we used the Eµ-TCL1 transgenic mouse model, which reproduces leukemia with a similar course and distinct immunophenotype as human B-CLL, to test miR-181b as a therapeutic agent.In vitro enforced expression of miR-181b mimics induced significant apoptotic effects in human B-cell lines (RAJI, EHEB), as well as in mouse Eµ-TCL1 leukemic splenocytes.

The long journey of TCL1 transgenic mice: lessons learned in the last 15 years.

The first transgenic mouse of the TCL1 oncogene was described more than 15 years ago, and since then, the overexpression of the gene in T- and B-cells in vivo has been extensively studied to reveal the molecular details in the pathogenesis of some lymphocytic leukemias. This review discusses the main features of the original TCL1 models and the different lines of research successively developed with particular attention to genetically compound mice and the therapeutic applications in drug development.

TCL1 targeting miR-3676 is codeleted with tumor protein p53 in chronic lymphocytic leukemia.

B-cell chronic lymphocytic leukemia (CLL) is the most common human leukemia and dysregulation of the T-cell leukemia/lymphoma 1 (TCL1) oncogene is a contributing event in the pathogenesis of the aggressive form of this disease based on transgenic mouse studies. To determine a role of microRNAs on the pathogenesis of the aggressive form of CLL we studied regulation of TCL1 expression in CLL by microRNAs. We identified miR-3676 as a regulator of TCL1 expression.

MicroRNA profiles discriminate among colon cancer metastasis.

MicroRNAs are being exploited for diagnosis, prognosis and monitoring of cancer and other diseases. Their high tissue specificity and critical role in oncogenesis provide new biomarkers for the diagnosis and classification of cancer as well as predicting patients' outcomes. MicroRNAs signatures have been identified for many human tumors, including colorectal cancer (CRC).

Translocation t(2;11) in CLL cells results in CXCR4/MAML2 fusion oncogene.

Recent investigations of chromosomal aberrations in chronic lymphocytic leukemia (CLL) led to a better understanding of the molecular causes of CLL. Here we report a rearrangement between MAML2 (mastermind-like protein 2) and CXCR4 (specific receptor for CXC chemokine stromal cell-derived factor-1) in CLL cells of a patient with a t(2;11)(q22.1;q21) chromosomal translocation.

B-cell malignancies in microRNA Eμ-miR-17~92 transgenic mice.

miR-17∼92 is a polycistronic microRNA (miR) cluster (consisting of miR-17, miR-18a, miR-19a, miR-19b, miR-20a, and miR-92a) which frequently is overexpressed in several solid and lymphoid malignancies. Loss- and gain-of-function studies have revealed the role of miR-17∼92 in heart, lung, and B-cell development and in Myc-induced B-cell lymphomas, respectively. Recent studies indicate that overexpression of this locus leads to lymphoproliferation, but no experimental proof that dysregulation of this cluster causes B-cell lymphomas or leukemias is available.

Novel insights in molecular mechanisms of CLL.

B-cell chronic lymphocytic leukemia (CLL), the most common leukemia, originates from an expansion of a rare population of CD5+CD19+ mature B-cells. CLL occurs in two forms, aggressive and indolent. For the most part aggressive CLL shows high ZAP-70 expression and unmutated IgH V(H), while indolent CLL is characterized by low ZAP-70 expression and mutated IgH V(H).

NOTCH1 mutations in CLL associated with trisomy 12.

Two recent studies reported whole-genome sequencing of chronic lymphocytic leukemia (CLL) samples and found repeated mutations in the XPO1 and NOTCH1 genes. XPO1 was found mutated in 2.4% of cases, while NOTCH1 was found mutated in 12.

Tcl1 interacts with Atm and enhances NF-κB activation in hematologic malignancies.

The T-cell leukemia/lymphoma 1 (TCL1) oncogene is a target of chromosomal translocations and inversions at 14q31.2, and its rearrangement in T cells causes T-cell prolymphocytic leukemias. TCL1 dysregulation in B cells is responsible for the development of an aggressive form of chronic lymphocytic leukemia (CLL), the most common human leukemia.

IRF4 mutations in chronic lymphocytic leukemia.

Interferon regulatory factor 4 (IRF4) is a member of the interferon regulatory factor family of transcription factors and has been shown to have critical functions at several stages of B-cell development. Genome-wide association study identified a polymorphism in the 3' untranslated region of IRF4 as a chronic lymphocytic leukemia risk locus. In this study, we report a recurrent heterozygous somatic mutation in the DNA-binding domain of IRF4 detected in 7 of 457 chronic lymphocytic leukemia patients (1.