CD5+CD23+ leukemic cell populations in TCL1 transgenic mice show significantly increased proliferation and Akt phosphorylation

Efanov, Alexey; Zanesi, Nicola; Nazaryan, Natalya; Santanam, Urmila; Palamarchuk, Alexey; Croce, Carlo M.; Pekarsky, Yuri

doi:10.1038/leu.2010.46

Cited by 32 publications

(43 citation statements)

References 18 publications

(40 reference statements)

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“…Lymphocytes from spleens and bone marrow were isolated as previously described (27). Flow cytometry measurements of SRBC immune response, Ig levels, and proliferation of B-cell populations were carried out as previously described (21). To analyze IgH gene rearrangements, Southern blot analysis of spleen lymphocyte DNA was carried out using EcoRI (Roche) digestions and mouse JH4 probe as previously described (15).…”

Section: Methodsmentioning

confidence: 99%

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Chronic lymphocytic leukemia modeled in mouse by targeted miR-29 expression

Santanam

Zanesi

Efanov

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

150

135

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B-cell chronic lymphocytic leukemia (B-CLL), the most common leukemia in the Western world, occurs in two forms, aggressive (showing for the most part high ZAP-70 expression and unmutated IgH V H ) and indolent (showing low ZAP-70 expression and mutated IgH V H ). We found that miR-29a is up-regulated in indolent human B-CLL as compared with aggressive B-CLL and normal CD19 + B cells. To study the role of miR-29 in B-CLL, we generated Eμ-miR-29 transgenic mice overexpressing miR-29 in mouse B cells. Flow cytometric analysis revealed a markedly expanded CD5 + population in the spleen of these mice starting at 2 mo of age, with 85% (34/40) of miR-29 transgenic mice exhibiting expanded CD5 + B-cell populations, a characteristic of B-CLL. On average, 50% of B cells in these transgenic mice were CD5 positive. At 2 y of age the mice showed significantly enlarged spleens and an increase in the CD5 + B-cell population to ∼100%. Of 20 Eμ-miR-29 transgenic mice followed to 24-26 mo of age, 4 (20%) developed frank leukemia and died of the disease. These results suggest that dysregulation of miR-29 can contribute to the pathogenesis of indolent B-CLL.mouse models | microRNA C hronic lymphocytic leukemia (CLL) is the most common human leukemia, accounting for ∼30% of all cases (1), with ∼10,000 new cases observed each year in the United States. Characteristically, CLL is a disease of elderly people, with the incidence increasing linearly with each decade above age 40 y (1, 2). It is known that this disease is characterized by the clonal expansion of CD5 + B cells (2).MicroRNAs, representing between 1% and 3% of all eukaryotic genes, are a class of endogenous noncoding RNAs, 19-25 nt in size, which regulate gene expression at the transcriptional or translational level (3). Approximately half of human microRNAs are located at fragile sites and genomic regions involved in alterations in cancers (4), and alteration of microRNA expression profiles occurs in most cancers, suggesting that individual microRNAs could function as tumor suppressors or oncogenes (5).The 13q14 deletion is the most common CLL aberration and is detected by cytogenetic analysis in approximately half of the cases (6). Analysis of a deletion at 13q14.3 led to the discovery of two physically linked microRNAs, miR-15a and miR-16-1, as targets of these deletions (7). Consequently, miR-15a and miR-16-1 expression is reduced in the majority of CLL cases (7), and further studies indicated that miR-15a/miR-16-1 negatively regulate Bcl2 expression (8). These findings indicated that microRNAs play important roles in CLL and that down-regulation of miR-15/16 and subsequent Bcl2 up-regulation contribute to CLL pathogenesis (7). Because miR-15/16 was identified as a tumor suppressor in indolent CLL, the microRNA expression profile in CLL has been studied extensively, and a signature profile was reported describing 13 microRNAs that differentiate aggressive and indolent CLL (4).We and others observed that miRNA-29 expression is downregulated in aggressive CLL as compared ...

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Section: Methodsmentioning

confidence: 99%

“…Previously, we reported development and characterization of a Tcl1-driven mouse model of CLL (15,20,21) and showed that miR-29 can target TCL1 expression (9). In this mouse model, the TCL1 ORF (lacking 3′ UTR) was under the control of a V H promoterIgH-Eμ enhancer (15).…”

Section: Mir-29 Expression In Cll and Production Of The Eμ-mir-29 Tramentioning

confidence: 99%

Chronic lymphocytic leukemia modeled in mouse by targeted miR-29 expression

Santanam

Zanesi

Efanov

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

150

135

View full text Add to dashboard Cite

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“…We validated the expression of phosphor-SYK (BCR signaling) and p-P65 (NF-κB signaling) in leukemic cells from TCL1 transgenic mouse and patients' LN by using immunohistochemistry ( Figure 4). LN tissue was harvested from TCL1-Tg mice at 37 wks, at which time accumulation of leukemic B-cells (B220/CD5 + ) occur in lymphoid organs (40). A high percentage of leukemic B cells from LN of TCL1-Tg mice were found to be positive for p-SYK (~50%) and p-P65 (~99%) (Figure 4, panel I: A-F).…”

Section: Differentially Expressed Genes Associated With the Seven Majmentioning

confidence: 99%

Chronic Lymphocytic Leukemia Cells in a Lymph Node Microenvironment Depict Molecular Signature Associated with an Aggressive Disease

Mittal

Chaturvedi

Karan

et al. 2014

Mol Med

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Chronic lymphocytic leukemia (CLL) cells survive longer in vivo than in vitro, suggesting that the tissue microenvironment provides prosurvival signals to tumor cells. Primary and secondary lymphoid tissues are involved in the pathogenesis of CLL, and the role of these tissue microenvironments has not been explored completely. To elucidate host-tumor interactions, we performed gene expression profiling (GEP) of purified CLL cells from peripheral blood (PB; n = 20), bone marrow (BM; n = 18), and lymph node (LN; n = 15) and validated key pathway genes by real-time polymerase chain reaction, immunohistochemistry and/or TCL1 transgenic mice. Gene signatures representing several pathways critical for survival and activation of B cells were altered in CLL cells from different tissue compartments. Molecules associated with the B-cell receptor (BCR), B cell-activating factor/a proliferationinducing ligand (BAFF/APRIL), nuclear factor (NF)-κB pathway and immune suppression signature were enriched in LN-CLL, suggesting LNs as the primary site for tumor growth. Immune suppression genes may help LN-CLL cells to modulate antigenpresenting and T-cell behavior to suppress antitumor activity. PB CLL cells overexpressed chemokine receptors, and their cognate ligands were enriched in LN and BM, suggesting that a chemokine gradient instructs B cells to migrate toward LN or BM. Of several chemokine ligands, the expression of CCL3 was associated with poor prognostic factors. The BM gene signature was enriched with antiapoptotic, cytoskeleton and adhesion molecules. Interestingly, PB cells from lymphadenopathy patients shared GEP with LN cells. In Eμ-TCL1 transgenic mice (the mouse model of the disease), a high percentage of leukemic cells from the lymphoid compartment express key BCR and NF-κB molecules. Together, our findings demonstrate that the lymphoid microenvironment promotes survival, proliferation and progression of CLL cells via chronic activation of BCR, BAFF/APRIL and NF-κB activation while suppressing the immune response.

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“…44 This mouse model was built with only the proteincoding part of the TCL1 gene. Another model by Efanov et al 45 comprised the total length of TCL1 gene including the 3 0 UTR that contains binding sites for miR-29 (and miR-181). The fulllength TCL1 transgenic mice developed leukemia with delayed onset compared with the model lacking the 3 0 UTR.…”

Section: Known Mirnas Involved In Leukemogenesismentioning

confidence: 99%

MicroRNAs in acute leukemia: from biological players to clinical contributors

2011

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MicroRNAs (miRNAs) are involved in the management of hematopoiesis. As a consequence, miRNA dysregulation causes disruption of the hematopoietic system and leukemia may arise. We here comprehensively discuss miRNAs found discriminative for cytogenetic and molecular subtypes of acute leukemia. These miRNAs are either known miRNAs involved in leukemogenesis with proven tumor suppressor or oncogenic activities or are newly identified by high-throughput sequencing with yet unknown function. Furthermore, forces are outlined that drive aberrant miRNA function, which include genetic abnormalities (for example, deletions, translocations and mutations) and epigenetic aberrations (for example, aberrant DNA methylation or histone modifications). Interestingly, leukemia-silenced miRNAs can be re-expressed upon treatment with de-methylating agents. Targeting miRNA expression may serve a therapeutical role, albeit at present this way of targeted therapy is in its infancy. However, emerging knowledge about the biology of miRNAs in leukemia may result into a role for these miRNAs in the diagnosis and treatment of acute leukemia.

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CD5+CD23+ leukemic cell populations in TCL1 transgenic mice show significantly increased proliferation and Akt phosphorylation

Cited by 32 publications

References 18 publications

Chronic lymphocytic leukemia modeled in mouse by targeted miR-29 expression

Chronic lymphocytic leukemia modeled in mouse by targeted miR-29 expression

Chronic Lymphocytic Leukemia Cells in a Lymph Node Microenvironment Depict Molecular Signature Associated with an Aggressive Disease

MicroRNAs in acute leukemia: from biological players to clinical contributors

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