B cell receptors in TCL1 transgenic mice resemble those of aggressive, treatment-resistant human chronic lymphocytic leukemia

Yan, Xiao‐Jie; Albesiano, Emilia; Zanesi, Nicola; Yancopoulos, Sophia; Sawyer, Alan; Romano, Egidio; Petlickovski, Aleksandar; Efremov, Dimitar G.; Croce, Carlo M.; Chiorazzi, Nicholas

doi:10.1073/pnas.0604564103

Cited by 148 publications

(163 citation statements)

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“…Nucleotide sequence analyses of the fragments amplified from the abnormal B cells confirmed the amplification of the 1-in-frame rearrangement. Prediction of the corresponding IgH protein (Table 1) revealed an enrichment of hydrophilic amino acids (Tyr, Ser, and charged amino acids) in CDR3 regions, as has been described for CLL 28 and murine models resembling human CLL, 29 whatever the genotype of sick mice studied (heterozygous or homozygous Tet2 deletion in Tet2 LacZ ANO and CD19-Cre mice). A set of genes known to be important for B-cell differentiation and transformation showed a reduced expression in purified B220 low cells in comparison with circulating WT CD19 B cells.…”

Section: Resultsmentioning

confidence: 99%

B-cell tumor development in Tet2-deficient mice

et al. 2018

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Key Points• Tet2 is a tumor suppressor in B cells.• Loss of Tet2 in B cells leads to age-dependent transformation that requires AID.The TET2 gene encodes an a-ketoglutarate-dependent dioxygenase able to oxidize 5-methylcytosine into 5-hydroxymethylcytosine, which is a step toward active DNA demethylation. TET2 is frequently mutated in myeloid malignancies but also in B-and Tet2-Aicda-deficient mice. Finally, we show that Tet2 deficiency accelerates and exacerbates T-cell leukemia/lymphoma 1A-induced leukemogenesis. Together, our data establish thatTet2 deficiency predisposes to mature B-cell malignancies, which development might be attributed in part to AID-mediated accumulating mutations and BCR-mediated signaling.

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Section: Resultsmentioning

confidence: 99%

B-cell tumor development in Tet2-deficient mice

et al. 2018

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“…With T regdepleting and T reg -increasing substances in hand, [28][29][30][31] we have the means to test this hypothesis in preclinical tumor models, such as the Tcl1-mouse model for CLL. 32,33 …”

Section: Discussionmentioning

confidence: 99%

Regulatory T cells predict the time to initial treatment in early stage chronic lymphocytic leukemia

Weiß

Melchardt

Egle

et al. 2010

Cancer

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BACKGROUND: Early stage chronic lymphocytic leukemia is characterized by a highly variable course of disease. Because it is believed that regulatory T cells (T regs ) are potent suppressors of antitumor immunity, the authors hypothesized that increased T regs may favor disease progression. METHODS: T reg levels (cluster of differentiation 3 [CD3]-positive, [CD4]-positive, CD25-positive, and CD127-negative) in peripheral blood from 102 patients were analyzed by flow cytometry. Statistical analysis was used to evaluate correlations with clinical data. RESULTS: The relative T reg numbers in CD4-positive T cells were significantly greater in patients with chronic lymphocytic leukemia compared with the numbers in a control group of 170 healthy individuals (P ¼ .001). Patients were divided into 2 groups using a median T reg value of 9.7% (the percentage of CD4-positive T cells). Patients with higher T reg levels had a significantly shorter time to initial treatment (median, 5.9 years) compared with patients who had lower T reg levels (median, 11.7 years; log-rank P ¼ .019). Furthermore, T reg levels (the percentage of CD4-positive T cells) had significant prognostic power to predict the time to initial treatment in univariate analysis (P ¼ .023) and in multivariate Cox regression analysis that included the variables Rai stage, immunoglobulin heavy-chain variable region gene mutational status, chromosomal aberrations, and CD38 expression (P ¼ .028). CONCLUSIONS: Higher T reg levels had significant and independent prognostic power for predicting the time to initial treatment in patients with low to intermediate stage chronic lymphocytic leukemia.

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“…[22][23][24]30 The mean difference between the expressed Ig V(H) genes of these mice and germ line is only 0.5%, thus the TCL1 mouse is thought to model the more aggressive, IgV(H) unmutated form of the disease in humans. 37 Lymphocytes of TCL1-mice with overt leukemia were engrafted in 10 C57BL/6 mice, as previously described. [22][23][24]30 However, two of them died before the start of treatment, indicating that they had advanced tumor progression.…”

Section: Identification Of P53-independent Apoptosis Inducersmentioning

confidence: 99%

Actinomycin D induces p53-independent cell death and prolongs survival in high-risk chronic lymphocytic leukemia

et al. 2012

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Chronic lymphocytic leukemia (CLL) is the most prevalent lymphoid malignancy in the elderly of the Western world. Although treatment options have improved over the past two decades, 10-15% of patients still have a poor prognosis and are often resistant to therapy. Aberrations in the p53 pathway, such as a deleted (del17p13) or mutated p53 gene, are highly enriched in this class of patients. In an extensive screen for p53-independent apoptosis inducers, actinomycin D was identified from 1496 substances and shown to induce apoptosis in primary CLL cells derived from high-risk patients including those with aberrant p53, revealing a novel p53-independent mechanism of action. Both pro-survival genes BCL2 and MCL1 are targeted by actinomycin D, in contrast to fludarabine the backbone of current treatment schedules. In the well-established TCL1 transgenic mouse model for high-risk CLL, actinomycin D treatment was more effective in reducing tumor load than fludarabine, with no evidence of resistance after three treatment cycles and an overall survival increase of over 300%. Tumor load reduction was coupled to BCL2 downregulation. Our results identify the clinically approved compound actinomycin D as a potentially valuable treatment option for CLL high-risk patients.

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B cell receptors in TCL1 transgenic mice resemble those of aggressive, treatment-resistant human chronic lymphocytic leukemia

Cited by 148 publications

References 67 publications

B-cell tumor development in Tet2-deficient mice

B-cell tumor development in Tet2-deficient mice

Regulatory T cells predict the time to initial treatment in early stage chronic lymphocytic leukemia

Actinomycin D induces p53-independent cell death and prolongs survival in high-risk chronic lymphocytic leukemia

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