CXCR4 hyperactivation cooperates with TCL1 in CLL development and aggressiveness

Lewis, Richard T.; Maurer, H. Carlo; Singh, Nikita; González-Menéndez, Irene; Wirth, Matthias; Schick, Markus; Le, Zhang; Isaakidis, Konstandina; Scherger, Anna Katharina; Schulze, Veronika; Lu, Junyan; Zenz, Thorsten; Steiger, Katja; Rad, Roland; Quintanilla-Martı́nez, Leticia; Espéli, Marion; Balabanian, Karl; Keller, Ulrich; Habringer, Stefan

doi:10.1038/s41375-021-01376-1

Cited by 9 publications

(5 citation statements)

References 67 publications

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“…Regulating the homing of immune cells, the CXCR4–CXCL12 axis is crucial for the interaction of CLL cells and microenvironment ( 54 – 57 ). In the Eμ-TCL1 mouse model, the introduction of a gain-of-function Cxcr4 mutation ( Cxcr4 C1013G ) that hyperactivates CXCR4 signaling, led to cell cycle dysregulation via PLK1 / FOXM1 ( 58 ). These neoplastic cells showed a transcriptional signature similar to that of patients with RT.…”

Section: Biology Of Rtmentioning

confidence: 99%

Biology and Treatment of Richter Transformation

Condoluci

Rossi

2022

Front. Oncol.

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Richter transformation (RT), defined as the development of an aggressive lymphoma on a background of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), represents a clinical unmet need because of its dismal prognosis. An increasing body of knowledge in the field of RT is arising from the recent development of preclinical models depicting the biology underlying this aggressive disease. Consistently, new therapeutic strategies based on a genetic rationale are exploring actionable pathogenic pathways to improve the outcome of patients in this setting. In this review, we summarize the current understandings on RT biology and the available treatment options.

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Section: Biology Of Rtmentioning

confidence: 99%

Biology and Treatment of Richter Transformation

Condoluci

Rossi

2022

Front. Oncol.

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“…The C-X-C motif chemokine receptor 4 (CXCR4) regulates the movement of B cells toward the chemokine C-X-C motif ligand 12 (CXCL12), its corresponding chemokine ligand. Interaction of CXCL12 with CXCR4 triggers the activation of several downstream pathways such as MAPK/ERK, PI3K/AKT, PLCγ/Ca 2+ and NF-κB signaling ( Figure 4 ) ( 181 , 182 ). For CLL cells, CXCR4 expression is critical for the migration toward specific niches, where the leukemic cells are protected by a survival- and growth-promoting microenvironment ( 183 ).…”

Section: Tumor Microenvironment and Bcr-associated Pathways In Cllmentioning

confidence: 99%

“…In line with this, CLL patients exhibiting low CXCR4 levels are associated with good prognosis as well as a significantly decreased risk of disease progression ( 184 ). An oncogenic hyperactivated form of CXCR4 in Eµ-TCL1 mice was described to collaborate with TCL1 in accelerating the progression of CLL ( 182 ). Upon ibrutinib treatment, a downmodulation of CXCR4 expression levels and CXCR4 signal inhibition in CLL cells could be identified in Eµ-TCL1 mice ( 185 ).…”

Section: Tumor Microenvironment and Bcr-associated Pathways In Cllmentioning

confidence: 99%

B cell receptor signaling and associated pathways in the pathogenesis of chronic lymphocytic leukemia

Schmid,

Hobeika

2024

Front. Oncol.

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B cell antigen receptor (BCR) signaling is a key driver of growth and survival in both normal and malignant B cells. Several lines of evidence support an important pathogenic role of the BCR in chronic lymphocytic leukemia (CLL). The significant improvement of CLL patients’ survival with the use of various BCR pathway targeting inhibitors, supports a crucial involvement of BCR signaling in the pathogenesis of CLL. Although the treatment landscape of CLL has significantly evolved in recent years, no agent has clearly demonstrated efficacy in patients with treatment-refractory CLL in the long run. To identify new drug targets and mechanisms of drug action in neoplastic B cells, a detailed understanding of the molecular mechanisms of leukemic transformation as well as CLL cell survival is required. In the last decades, studies of genetically modified CLL mouse models in line with CLL patient studies provided a variety of exciting data about BCR and BCR-associated kinases in their role in CLL pathogenesis as well as disease progression. BCR surface expression was identified as a particularly important factor regulating CLL cell survival. Also, BCR-associated kinases were shown to provide a crosstalk of the CLL cells with their tumor microenvironment, which highlights the significance of the cells’ milieu in the assessment of disease progression and treatment. In this review, we summarize the major findings of recent CLL mouse as well as patient studies in regard to the BCR signalosome and discuss its relevance in the clinics.

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“…TCL1A tg mice, in particular the well-established Eµ-TCL1A model for CLL, have been crossed with a variety of other alleles (reviewed in [17,18]). This enabled the investigation of novel pathogenic mechanisms, such as interactions with the microenvironment (e.g., Eµ-TCL1A; CD44 −/− [19]; Eµ-TCL1A; CXCR4 C1013G [20]) or signaling (e.g., Eµ-TCL1A; pkcβ −/− [21]; Eµ-TCL1A tg/wt ; Cd19 Cre/wt ; R26-fl-Akt-C [22]), as well as the role of recurrent genomic lesions (e.g., Eµ-TCL1A; CD19 cre/wt ; Trp53 fl/fl or Eµ-TCL1A; CD19 cre/wt ; Atm fl/fl [23]).…”

Section: Of 18mentioning

confidence: 99%

The Modes of Dysregulation of the Proto-Oncogene T-Cell Leukemia/Lymphoma 1A

Stachelscheid

Jiang

Herling

2021

Cancers

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Incomplete biological concepts in lymphoid neoplasms still dictate to a large extent the limited availability of efficient targeted treatments, which entertains the mostly unsatisfactory clinical outcomes. Aberrant expression of the embryonal and lymphatic TCL1 family of oncogenes, i.e., the paradigmatic TCL1A, but also TML1 or MTCP1, is causally implicated in T- and B-lymphocyte transformation. TCL1A also carries prognostic information in these particular T-cell and B-cell tumors. More recently, the TCL1A oncogene has been observed also in epithelial tumors as part of oncofetal stemness signatures. Although the concepts on the modes of TCL1A dysregulation in lymphatic neoplasms and solid tumors are still incomplete, there are recent advances in defining the mechanisms of its (de)regulation. This review presents a comprehensive overview of TCL1A expression in tumors and the current understanding of its (dys)regulation via genomic aberrations, epigenetic modifications, or deregulation of TCL1A-targeting micro RNAs. We also summarize triggers that act through such transcriptional and translational regulation, i.e., altered signals by the tumor microenvironment. A refined mechanistic understanding of these modes of dysregulations together with improved concepts of TCL1A-associated malignant transformation can benefit future approaches to specifically interfere in TCL1A-initiated or -driven tumorigenesis.

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CXCR4 hyperactivation cooperates with TCL1 in CLL development and aggressiveness

Cited by 9 publications

References 67 publications

Biology and Treatment of Richter Transformation

Biology and Treatment of Richter Transformation

B cell receptor signaling and associated pathways in the pathogenesis of chronic lymphocytic leukemia

The Modes of Dysregulation of the Proto-Oncogene T-Cell Leukemia/Lymphoma 1A

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