Cellular origin and pathophysiology of chronic lymphocytic leukemia

Seifert, Marc; Sellmann, Ludger; Bloehdorn, Johannes; Wein, Frederik; Stilgenbauer, Stephan; Dürig, Jan; Küppers, Ralf

doi:10.1084/jem.20120833

Cited by 231 publications

(215 citation statements)

References 79 publications

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“…We performed gene-expression profiling as well as ICN1 immunoblot analysis in naïve, germinal center (GC) and memory B cells isolated from human tonsils (23). Although the phenotype of the B cell expanding to generate overt CLL remains a matter of debate, naïve and memory B cells are considered the most likely putative normal counterparts of this disease (24)(25)(26). The levels of NOTCH1 mRNA and of the cleaved and active intracellular portion of NOTCH1 ICN1 were abundant in naïve and memory B cells, whereas they were almost undetectable in GC B cells ( Fig.…”

Section: Notch1mentioning

confidence: 99%

Common nonmutationalNOTCH1activation in chronic lymphocytic leukemia

Fabbri

Holmes

Viganotti

et al. 2017

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

112

160

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Activating mutations of NOTCH1 (a well-known oncogene in T-cell acute lymphoblastic leukemia) are present in ∼4-13% of chronic lymphocytic leukemia (CLL) cases, where they are associated with disease progression and chemorefractoriness. However, the specific role of NOTCH1 in leukemogenesis remains to be established. Here, we report that the active intracellular portion of NOTCH1 (ICN1) is detectable in ∼50% of peripheral blood CLL cases lacking gene mutations. We identify a "NOTCH1 gene-expression signature" in CLL cells, and show that this signature is significantly enriched in primary CLL cases expressing ICN1, independent of NOTCH1 mutation. NOTCH1 target genes include key regulators of B-cell proliferation, survival, and signal transduction. In particular, we show that NOTCH1 transactivates MYC via binding to B-cell-specific regulatory elements, thus implicating this oncogene in CLL development. These results significantly extend the role of NOTCH1 in CLL pathogenesis, and have direct implications for specific therapeutic targeting. chronic lymphocytic leukemia | NOTCH1 | transcriptional network

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Section: Notch1mentioning

confidence: 99%

Common nonmutationalNOTCH1activation in chronic lymphocytic leukemia

Fabbri

Holmes

Viganotti

et al. 2017

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

112

160

View full text Add to dashboard Cite

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“…CLL is believed to derive from a normal CD51 B-cell population [134]. The analyses of the clonal organization of the malignant clone also allow the identification of the cell of origin, namely the cell that acquired the very first mutation(s).…”

Section: Intrapatient Heterogeneitymentioning

confidence: 99%

Chronic lymphocytic leukemia: Time to go past genomics?

2016

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Recent advances in massively parallel sequencing technologies have provided a detailed picture of the mutational landscape in CLL and underscored the vast degree of interpatient and intratumor heterogeneities. These studies have led to the characterization of novel putative driver genes and recurrently affected biological pathways, and to the modeling of CLL clonal evolution. We herein review selected aspects including recent advances in the biology of CLL and present cellular and biological processes involved in the development of CLL and potentially other mature B-cell lymphoproliferative neoplasms.

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“…It develops as an expansion of clonal mature CD5 + B cells ( 5,6 ), and gene expression profi les of CLL cells show that these malignant B cells resemble antigen-experienced memory B cells ( 7,8 ). The precise cell-of-origin is debated.…”

Section: Introductionmentioning

confidence: 99%

Access to Follicular Dendritic Cells Is a Pivotal Step in Murine Chronic Lymphocytic Leukemia B-cell Activation and Proliferation

et al. 2014

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In human chronic lymphocytic leukemia (CLL) pathogenesis, B-cell antigen receptor signaling seems important for leukemia B-cell ontogeny, whereas the microenvironment infl uences B-cell activation, tumor cell lodging, and provision of antigenic stimuli. Using the murine Eμ-Tcl1 CLL model, we demonstrate that CXCR5-controlled access to follicular dendritic cells confers proliferative stimuli to leukemia B cells. Intravital imaging revealed a marginal zone B cell-like leukemia cell traffi cking route. Murine and human CLL cells reciprocally stimulated resident mesenchymal stromal cells through lymphotoxin-β-receptor activation, resulting in CXCL13 secretion and stromal compartment remodeling. Inhibition of lymphotoxin/lymphotoxin-β-receptor signaling or of CXCR5 signaling retards leukemia progression. Thus, CXCR5 activity links tumor cell homing, shaping a survival niche, and access to localized proliferation stimuli. SIGNIFICANCE: CLL and other indolent lymphoma are not curable and usually relapse after treatment, a process in which the tumor microenvironment plays a pivotal role. We dissect the consecutive steps of CXCR5-dependent tumor cell lodging and LTβR-dependent stroma-leukemia cell interaction; moreover, we provide therapeutic solutions to interfere with this reciprocal tumor-stroma cross-talk. Cancer Discov; 4(12); 1448-65.

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Cellular origin and pathophysiology of chronic lymphocytic leukemia

Abstract: Unmutated CLL derives from unmutated mature CD5+ B cells and mutated CLL derives from CD5+CD27+ post–germinal center B cells.

Cited by 231 publications

References 79 publications

Common nonmutationalNOTCH1activation in chronic lymphocytic leukemia

Common nonmutationalNOTCH1activation in chronic lymphocytic leukemia

Chronic lymphocytic leukemia: Time to go past genomics?

Access to Follicular Dendritic Cells Is a Pivotal Step in Murine Chronic Lymphocytic Leukemia B-cell Activation and Proliferation

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