Prognostic relevance of CD69 expression in B cell chronic lymphocytic leukemia

Aref, Salah; Menshawy, Nadia El; El‐Ghonemy, Mohamed Sabry; El-Said, Ghada; Elbaiomy, Mohamed

doi:10.1007/s00580-018-2671-z

Cited by 5 publications

(4 citation statements)

References 32 publications

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“…Other groups have reported in larger studies that patients having higher levels of CD69 1 , CD38 1 , or CD40d 1 CLL cells (microenvironmentally activated multidrugresistant cells) show aggressive disease progression and/or poor response to proapoptotic chemotherapies. [33][34][35]59 Recent clinical evidence is also supportive of our findings. Continuous exposure to venetoclax along with ibrutinib leads slowly to a complete response in some patients who initially showed only a partial response.…”

Section: Discussionsupporting

confidence: 90%

“…Our findings provide mechanistic insight into the reported association between activation marker (CD69/CD38/CD49d) expression and patient outcomes [33][34][35]59 and suggest that functional assays using patient samples to predict treatment outcome must account for the ex vivo lability of microenvironmentally induced resistance.…”

Section: Discussionmentioning

confidence: 70%

“…Using an ex vivo microenvironment model, we performed a drug screen with venetoclax as an anchor drug to identify optimal drug combinations that overcome multidrug resistance in CLL cells. Our investigation identifies multidrug-resistant CLL cells that simultaneously overexpress multiple antiapoptotic proteins in patients de novo, demonstrates that these persist during treatment with proapoptotic therapy (eg, venetoclax), provides a mechanistic rationale for the reported correlation of CD69 expression with poor outcomes, [33][34][35] and identifies therapeutically actionable vulnerabilities that can be explored in clinical trials.…”

Section: Key Pointsmentioning

confidence: 91%

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Extrinsic interactions in the microenvironment in vivo activate an antiapoptotic multidrug-resistant phenotype in CLL

et al. 2021

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The Bcl-2 inhibitor venetoclax (VEN) has yielded exceptional clinical responses in chronic lymphocytic leukemia (CLL). However, de novo resistance can result in failure to achieve negative minimal residual disease and predicts poor treatment outcomes. Consequently, additional pro-apoptotic drugs, such as inhibitors of Mcl-1 and Bcl-xL, are in development. By profiling anti-apoptotic proteins using flow cytometry, we find that leukemic B-cells recently emigrated from the lymph node (LN) (CD69Pos/CXCR4Low) in vivo are enriched for cell clusters simultaneously overexpressing multiple anti-apoptotic proteins (Mcl-1high/Bcl-xLhigh/Bcl-2high), in both treated and treatment naïve CLL patients. These cells exhibited anti-apoptotic resistance to multiple BH-domain antagonists, including inhibitors of Bcl-2, Mcl-1, and Bcl-xL, when tested as single agents in a flow cytometry-based functional assay. Anti-apoptotic multi-drug resistance declines ex vivo, consistent with resistance being generated in vivo by extrinsic microenvironmental interactions. Surviving "persister" cells in patients undergoing venetoclax treatment are enriched for CLL cells displaying the functional and molecular properties of microenvironmentally-induced multi-drug resistance. Overcoming this resistance required simultaneous inhibition of multiple anti-apoptotic proteins, with potential for unwanted toxicities. Using a drug screen performed using patient PBMCs cultured in an ex vivo microenvironment model we identify novel venetoclax drug combinations that induce selective cytotoxicity in multi-drug resistant CLL cells. Thus, we demonstrate that anti-apoptotic multi-drug resistant CLL cells exist in patients de novo, and show that these cells persist during pro-apoptotic treatment such as venetoclax. We validate clinically actionable approaches to selectively deplete this reservoir in patients.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 70%

Section: Key Pointsmentioning

confidence: 91%

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Extrinsic interactions in the microenvironment in vivo activate an antiapoptotic multidrug-resistant phenotype in CLL

et al. 2021

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“…According to statistics, CLL accounted for 25-30% of leukemia diagnoses, giving it the most common kind of leukemia in adults in North America and Europe (1) . The illness is diverse and has a varying clinical history; some people have an indolent course and don't need treatment, while others have an aggressive illness with a short duration and overall survival (2) . As a result, researchers discovered several prognostic biomarkers and staging systems to help clinicians make decisions about whose patients will be in real need to start treatment.…”

Section: Introductionmentioning

confidence: 99%

Prognostic Relevance of CD69, Vascular Endothelial Growth Factor and Thymidine Kinase in B-Chronic Lymphocytic Leukemia

Noreldin¹,

Zaiat²,

Ahmedy³

2023

The Egyptian Journal of Hospital Medicine

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Background: B-chronic-lymphocytic-leukemia (B-CLL) is a heterogeneous illness with a varied clinical history. Some individuals don't require therapy while others have an aggressive disease. Researchers discovered several prognostic biomarkers to help clinicians make decisions about whose patients will be in need to start treatment. Developing immunophenotyping markers such as CD69 and other serum markers such as TK and VEGF are evolving over time.Objective: This study aimed to assess relevance of CD69 as prognostic indicator in CLL cases and its association with Vascular-endothelial-growth factor (VEGF) and Thymidine-kinase (TK) activity. Methods: The research had 80 patients with B-CLL and 17 healthy controls. All subjects underwent routine laboratory investigations, flowcytometric analysis of CLL panel, CD38 and CD69 and TK activity and VEGF level by ELISA. Results: CD69 %, VEGF and TK were significantly higher in patients than in controls. Patients who required treatment had significantly higher CD69% and elevated levels of VEGF and TK than patients who were untreated. Correlation between CD69% with different parameters revealed significant positive correlation between CD69% and age, modified Rai staging, TLC, lymphocyte, B2 microglobulin, LDH, Coombs`test, receiving chemotherapy, CD 38/19%, VEGF and TK. CD69% at cut off levels of > 45% can significantly detect time to start chemotherapy with sensitivity and specificity of 88.89% and 77.27%. Regression analysis showed that age, modified Rai staging, lymphocyte count and HB level were independent variables that can predict CD69 expression. Conclusions: CD69, TK and VEGF could be considered as poor prognostic markers adding a new option for development of new prognosis score system.

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CD markers variations in chronic lymphocytic leukemia: New insights into prognosis

Vosoughi

Bagheri

Hosseinzadeh

et al. 2019

Journal Cellular Physiology

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Chronic lymphocytic leukemia (CLL) is one of the most commonly occurring adult leukemias that is associated with clonal accumulation of mature apoptosis-resistant B-cells in bone marrow, peripheral blood, and specific tissues. Different pathogenesis factors can contribute to the aggression of the clinical course in this disease.Cytogenetic abnormalities and surface biomarkers of neoplastic CLL cells can be effective in the outcome of CLL, and the examination of changing CD markers expressions in the progression of CLL can be related to the prognosis of this disease. Changing expression levels of CD markers on lymphocytes and other cells in CLLpatients can play a role in the aggressive clinical outcomes such as organomegaly, immunodeficiency, and advanced disease stages through their interaction with CLL microenvironment. Given the involvement of CD markers in the pathogenesis of CLL, it can be stated that recognizing the expression changes of CD markers in the cells involved in CLL can be a proper approach to evaluate prognosis among these patients.

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Prognostic relevance of CD69 expression in B cell chronic lymphocytic leukemia

Cited by 5 publications

References 32 publications

Extrinsic interactions in the microenvironment in vivo activate an antiapoptotic multidrug-resistant phenotype in CLL

Extrinsic interactions in the microenvironment in vivo activate an antiapoptotic multidrug-resistant phenotype in CLL

Prognostic Relevance of CD69, Vascular Endothelial Growth Factor and Thymidine Kinase in B-Chronic Lymphocytic Leukemia

CD markers variations in chronic lymphocytic leukemia: New insights into prognosis

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