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Chronic Lymphocytic Leukemia (CLL)


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Chronic Lymphocytic Leukemia (CLL)

Unlike solid tumors, which are highly proliferative, chronic lymphocytic leukemia (CLL) is an indolent malignancy characterized by the relentless accumulation of quiescent, immunologically dysfunctional mature B cells that fail to undergo apoptosis. These cells reside in different compartments such as bone marrow, spleen, lymph nodes, and peripheral blood which provide diverse microenvironments. While the population is either slowly proliferating or quiescent, these cells are transcriptionally and translationally active, suggesting that CLL cells are not inert and should have an active metabolomics profile.

Deletions of the long arm of chromosome 13, specifically involving band 13q14 (del(13q14)), are the single most frequently observed cytogenetic aberration in CLL, occurring in around 55% of all cases. An isolated del(13q14) is generally characterized by a benign course of the disease. Deletions of the long arm of chromosome 11 (del(11q)) can be found in ∼25% of chemotherapy‐naïve patients with advanced disease stages and 10% of patients with early stage disease. Deletions of the short arm of chromosome 17 (del(17p)) are found in 5–8% of chemotherapy‐naïve patients. Recent work using whole exome sequencing in CLL has led to the characterization of the genomic landscape of this disease. In addition to the above described chromosomal aberrations, a total number of 44 recurrently mutated genes and 11 recurrent somatic copy number variations have been identified. These include the genes NOTCH1, MYD88, TP53, ATM, SF3B1, FBXW7, POT1, CHD2, RPS15, IKZF3, ZNF292, ZMYM3, ARID1A, and PTPN11. These analyses collectively identify RNA processing and export, MYC activity, and MAPK signaling as central pathways involved in CLL. Besides, proteins critically involved in DNA damage signaling and DNA repair are often involved. Intriguingly, both del(17p) and del(11q) and inactivating somatic mutations in TP53 and ATM are enriched in patients with secondary resistance to DNA‐damaging chemotherapy.

B cell receptor (BCR) signaling plays a significant pathogenic role in chronic lymphocytic leukemia (CLL) and B cell lymphomas, based on structural restrictions of the BCR, and BCR-dependent survival and growth of the malignant B cells. The lymphatic tissues are the apparent principal site of BCR activation for normal and malignant B cells. BCR activation can be induced by antigen or can be ligand-independent (‘tonic’ BCR signaling), and triggers a cascade of signaling events that normally cause B cell selection, proliferation, differentiation, and antibody production. Thereby, BCR signaling allows for the expansion of selected, foreign antigen-specific B cells, and deletion of unwanted, self-reactive B cells. In B cell malignancies, such as CLL and diffuse large B cell lymphoma (DLBCL), BCR signaling plays a critical role in pathogenesis, even though the mechanisms of BCR stimulation are heterogeneous and to some degree controversial. In CLL, based on high response rates and durable remissions in early-stage clinical trials, there is rapid clinical development of inhibitors targeting BCR-associated kinases [Bruton’s tyrosine kinase (BTK), phosphoinositide 3-kinase (PI3K)d], which will change treatment paradigms in CLL and other B cell malignancies.

Creative Biogene, as a leading biotechnology company, is able to offer various CLL pathway related products including stable cell lines, viral particles and clones for your pathogenesis study and drug discovery projects.

References:

  1. Vangapandu H V, et al. Abstract 3547: B cell receptor signaling regulates cellular metabolism in Chronic Lymphocytic Leukemia. Cancer Research, 2017, 77(13 Supplement):3547-3547.
  2. Burger J A , Chiorazzi N . B cell receptor signaling in chronic lymphocytic leukemia. Trends in Immunology, 2013, 34(12):592-601.
  3. Hallek, Michael. Chronic lymphocytic leukemia: 2017 update on diagnosis, risk stratification, and treatment. American Journal of Hematology, 2017, 92(9):946-965.

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