CD4+ T cells sustain aggressive chronic lymphocytic leukemia in Eμ-TCL1 mice through a CD40L-independent mechanism

Grioni, Matteo; Brevi, Arianna; Cattaneo, Elena; Rovida, Alessandra; Bordini, Jessica; Bertilaccio, Maria Teresa Sabrina; Ponzoni, Maurilio; Casorati, Giulia; Ghia, Paolo; Bellone, Matteo; Calcinotto, Arianna

doi:10.1182/bloodadvances.2020003795

Cited by 17 publications

(9 citation statements)

References 56 publications

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“…In addition, although T‐cells are believed to be indispensable for CLL engraftment of immunodeficient mice, 38 a recent study in a murine model of CLL indicates that this might not be dependent on CD40‐CD40L interaction. 39 These results are in keeping with the notion that CLL cells show a certain degree of functional derangement (reviewed in Ref. 40 ).…”

Section: Discussionsupporting

confidence: 78%

LINC00152 expression in normal and Chronic Lymphocytic Leukemia B cells

Matis

Rossi

Brondolo

et al. 2021

Hematological Oncology

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Long non‐coding RNAs are emerging as essential regulators of gene expression, but their role in normal and neoplastic B cells is still largely uncharacterized. Here, we report on the expression pattern of the LINC00152 in normal B cells and Chronic Lymphocytic Leukemia B cell clones. Higher LINC00152 levels were consistently observed in memory B cell populations when compared to naïve B cells in the normal tissues analyzed [peripheral blood (PB), tonsils, and spleen]. In addition, independent stimulation via Immunoglobulins (IG), CD40, or Toll‐like Receptor 9 (TLR9) upregulated LINC00152 in PB B cells. The expression of LINC00152 in a cohort of 107 early stage Binet A CLL patients was highly variable and did not correlate with known prognostic markers or clinical evolution. TLR9 stimulation, but not CD40 or IG challenge, was able to upregulate LINC00152 expression in CLL cells. In addition, LINC00152 silencing in CLL cell lines expressing LINC00152 failed to induce significant cell survival or apoptosis changes. These data suggest that, in normal B cells, the expression of LINC00152 is regulated by immunomodulatory signals, which are only partially effective in CLL cells. However, LINC00152 does not appear to contribute to CLL cell expansion and/or survival in a cohort of newly diagnosed CLL patients.

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Section: Discussionsupporting

confidence: 78%

LINC00152 expression in normal and Chronic Lymphocytic Leukemia B cells

Matis

Rossi

Brondolo

et al. 2021

Hematological Oncology

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“…CD4 + cells are the main response cells in the immune response. CD8 + cells can produce cell-mediated cytotoxicity on target cells, and at the same time have a regulatory immunosuppressive effect on CD4 + cells [19][20][21]. In the present study, we used ow cytometry to evaluate PD-1 expression on the surface of CD4 + and CD8 + T lymphocytes in the peripheral circulation of AML and ALL patients and its clinical signi cance.…”

Section: Discussionmentioning

confidence: 99%

Clinical Implications of Aberrant PD-1 Expression for Acute Leukemia Prognosis

Ruan

Wang

Zhang

et al. 2022

Preprint

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Background: Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are the most common types of leukemia in adults with an overall poor prognosis. PD-1 alone or combined with other immune checkpoint blockade is a promising research direction for the treatment of acute leukemia (AL) patients. However, clinical Implications of aberrant PD-1 expression in peripheral CD4+ and CD8+ T lymphocytes of AML and ALL patients in assessing the prognosis of diseases, remains inconclusive. Methods: In the present study, we used flow cytometry to evaluate PD-1 expression on the surface of CD4+ and CD8+ T lymphocytes in the peripheral circulation of AML and ALL patients and its clinical significance. A total of 53 AML patients, 44 ALL patients and 28 healthy controls were enrolled in this study and peripheral blood specimens were detected by flow cytometry. Results: Our results indicated that percentages of CD4+PD1+ and CD8+PD1+ T lymphocytes in newly diagnosed and non-remission groups were significantly higher than healthy control both in AML and ALL patients. The high level of CD4+PD1+ and CD8+PD1+ T lymphocyteswere respectively poor prognostic indicators of AML patients and ALL patients but had no significant correlation with most common clinical risks. Conclusions: Our findings show that aberrant PD-1 expression correlates with the prognosis of AL patient and may thus serve as poor prognostic indicators. Immunotherapy using PD-1 inhibitors may be a promising strategy for AML and ALL patients with peripheral circulating CD4+PD1+ and CD8+PD1+ T lymphocytes positively expressed, respectively.

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“…Our data indicate the activated subpopulation shapes the local immune cell composition, specifically of M2 macrophages and activated CD4 + memory T cells, independently confirming conclusions derived from model systems. 36 , 37 , 38 The proportion of activated CLL cells and their capacity to recruit a tumor-supportive TME may underlie the shorter TFS observed in patients with higher expression of the activated CLL signature. Taken together, an identifiable minor tumor subpopulation underlies CLL pathogenesis and drives clinical outcomes.…”

Section: Discussionmentioning

confidence: 99%

The immune microenvironment shapes transcriptional and genetic heterogeneity in chronic lymphocytic leukemia

et al. 2023

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In chronic lymphocytic leukemia (CLL), B-cell receptor signaling, tumor-microenvironment interactions and somatic mutations drive disease progression. To better understand the intersection between the microenvironment and molecular events in CLL pathogenesis, we integrated bulk transcriptome profiling of paired peripheral blood (PB) and lymph node (LN) samples from 34 patients. Oncogenic processes were upregulated in LN compared to PB, and in IGHV unmutated compared to mutated cases. Single-cell RNA sequencing distinguished 3 major cell states: quiescent, activated, and proliferating. The activated subpopulation comprised only 2.2% to 4.3% of the total tumor bulk in LN samples. RNA velocity analysis found that CLL cell fate in LN is unidirectional, starts in the proliferating state, transitions to the activated state, and ends in the quiescent state. A 10-gene signature derived from activated tumor cells was associated with inferior treatment-free survival and positively correlated with the proportion of activated CD4+ memory T cells and M2 macrophages in LN. Whole exome sequencing of paired PB and LN samples showed subclonal expansion in LN in approximately half of patients. Since mouse models have implicated activation-induced cytidine deaminase in mutagenesis, we compared AICDA expression between cases with and without clonal evolution, but did not find a difference. In contrast, the presence of a T-cell inflamed microenvironment in LN was associated with clonal stability. In summary, a distinct minor tumor subpopulation underlies CLL pathogenesis and drives clinical outcome. Clonal trajectories are shaped by the LN milieu where T-cell immunity may contribute to suppress clonal outgrowth. The clinical study is registered at clinicaltrials.gov as NCT00923507.

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CD4+ T cells sustain aggressive chronic lymphocytic leukemia in Eμ-TCL1 mice through a CD40L-independent mechanism

Cited by 17 publications

References 56 publications

LINC00152 expression in normal and Chronic Lymphocytic Leukemia B cells

LINC00152 expression in normal and Chronic Lymphocytic Leukemia B cells

Clinical Implications of Aberrant PD-1 Expression for Acute Leukemia Prognosis

The immune microenvironment shapes transcriptional and genetic heterogeneity in chronic lymphocytic leukemia

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