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Waldenström Macroglobulinemia
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The C-X-C chemokine receptor type 4 (CXCR4) gene mutation represents the second most frequent mutated gene in WM, detected in approximately 30% of patients [33]. The somatic CXCR4 mutations seen in WM closely resemble the germline CXCR4WHIM mutations described in the WHIM syndrome. The “gain-of-function” CXCR4WHIM mutations lead to permanent activation of CXCR4 receptor by its ligand CXCL-12 and results in migration and homing to the bone marrow niches of WM cell which could provide a survival advantage (Figure 82.1) [34]. The CXCR4WHIM mutation has been linked to drug resistance and impacts the response to targeted therapies such as BKT, mTOR, and PI3K inhibitors [35,36].
Primary immunodeficiency diseases
Published in Gabriel Virella, Medical Immunology, 2019
John W. Sleasman, Gabriel Virella
CARD9 deficiency results in predisposition to invasive fungal infection and deep dermatophytoses. In contrast, increased susceptibility to mycobacterial disease is seen in complete interferon-γ receptor deficiency, manifest by disseminated mycobacterial infection in soft tissue, bone, lung, skin, and lymphoid tissues. Similar clinical phenotypes are seen with IL-12 deficiency and STAT 1 loss of function mutations. Susceptibility to viral infections, particularly human papillomaviruses is seen in WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis) due to an autosomal-dominant gain of function mutation in CXCR4.
Emerging drugs for the treatment of Waldenström macroglobulinemia
Published in Expert Opinion on Emerging Drugs, 2020
Fotiou Despina, Dimopoulos Meletios Athanasios, Kastritis Efstathios
Eighty to ninety-five percent of patients with WM harbor a specific somatic mutation in the myeloid differentiation primary response gene (MYD88L265P), which is of great diagnostic and clinical relevance [15]. MYD88L265P leads to the constitutive activation of signaling pathways, which are central to the survival and proliferation of the clonal cells that are BTK (Bruton’s tyrosine kinase) dependent. The exact frequency varies based on the detection method and source of DNA, which can include whole BM, CD19-selected cells, paraffin-embedded tissue or peripheral blood [16,17]. Peripheral blood detection using cell-free DNA is also feasible but sensitivity is lower [16–19]. The presence of MYD88L265P is characteristic of WM but 5–10% of WM patients either have other MYD88 mutations or have wild type MYD88 [20]. Another important mutation, found in 20–40% of WM patients, is the somatic, subclonal mutation in the CXCR4 gene (C-terminal of the C-X-X chemokine receptor type 4) [15,21]. It is analogous to the germline mutation observed in patients with WHIM syndrome (CXCR4WHIM) [21,22].These patients have a distinct clinical presentation with poorer responses to BTK inhibition [23,24]. The same patient can harbor different CXCR4 mutations pointing to the presence of genomic instability [25].
CXCR4 mutations affect presentation and outcomes in patients with Waldenström macroglobulinemia: A systematic review
Published in Expert Review of Hematology, 2019
Jorge J. Castillo, David F. Moreno, Maria I. Arbelaez, Zachary R. Hunter, Steven P. Treon
Based on our observations, CXCR4 could serve as a therapeutic target in WM. The CXCR4 antagonist plerixafor has shown to be safe and effective in patients with WHIM syndrome [52–54]. On plerixafor therapy, WHIM patients experienced improvement in leukopenia, anemia, and thrombocytopenia, as well as decline in wart burden and human papillomavirus-related lesions. Of most importance, the patients’ quality of life improved with the intervention. Preclinical experiences have shown the anti-CXCR4 monoclonal antibody ulocuplumab-induced apoptosis, at nanomolar levels, in chronic lymphocytic leukemia and myeloma cell lines [55,56]. A phase I/II study evaluating ibrutinib in combination with the anti-CXCR4 monoclonal antibody ulocuplumab in symptomatic WM patients with CXCR4 mutations is undergoing accrual (NCT03225716). Other anti-CXCR4 small molecules such as EPI-X4 and X4P-001 are currently at early stages of clinical development.
An evaluation of Ibrutinib for the treatment of Waldenstrom macroglobulinaemia
Published in Expert Opinion on Pharmacotherapy, 2020
Kenneth J. C. Lim, Constantine S. Tam
A second crucial set of mutations in WM are those involving the CXCR4 gene in 30% of WM cases. These mutations include frameshift and nonsense mutations similar to those seen in germline mutations of CXCR4 seen in warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome with the most common and established being the nonsense mutation S338X [17]. These mutations promote prolonged activation of CXCR4 via the ligand CXCL12 through blockade of receptor internalization [18]. CXCR4, being a chemokine receptor, promotes cell migration, adhesion to bone marrow stroma, proliferation, and ultimately survival through up-regulation of kinases such as AKT, ERK, and BTK [19,20]. As such CXCR4 WHIM mutations may have a negative impact on the efficacy of BTK-targeted therapies.