WHIM Syndrome: from Pathogenesis Towards Personalized Medicine and Cure

Heusinkveld, Lauren E.; Majumdar, Shamik; Gao, Ji-Liang; McDermott, David H.; Murphy, Philip M.

doi:10.1007/s10875-019-00665-w

Cited by 75 publications

(113 citation statements)

References 202 publications

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“…Unfortunately, the analysis of the genomic profile of CXCR4 is not routinely performed in clinics for LPL/WM patients. Importantly, the sensitivity of the used sequencing technique (allele-specific polymerase chain, Sanger, or whole-genome sequencing) and the nature of the analyzed sample (CD19-positive selected lymphocytes or whole BM) represent the most important issues in defining the mutational status of CXCR4 [153,172]. Therefore, universal guidelines are required to standardize the analysis and bring CXCR4 genomic profiling into clinics.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, this evidences clearly indicates that NS and FS mutations behave differently. In WHIM syndrome, very few patients carry FS mutations, whereas NS mutations have been identified in almost all patients [92,153]. Unfortunately, currently no preclinical modeling has been done to understand the activating nature of FS mutations.…”

Section: Cxcr4 Whim-like Mutations In Lpl/wmmentioning

confidence: 99%

“…This region hosts several serine and threonine residues that are phosphorylated by G protein-coupled Receptor Kinase (GRK) kinases upon CXCL12 activation to facilitate β-arrestin recruitment and clathrin-dependent receptor internalization and degradation, thereby promoting receptor desensitization. All but one of the CXCR4 mutations truncate this region, four by premature termination (NS: R334*, G336*, S338*, E343*) and four by frameshifts (FS: G323fs343*, L329fs341*, S339fs342*, S341fs365*) that introduce 3 to 24 additional new amino acids [88,91,92,146,153]. To date, the only exception to the rule is represented by one different type of mutation that causes a change in the net charge of the C-ter (MS: E343K).…”

Section: Appendix Amentioning

confidence: 99%

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New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

et al. 2020

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Deciphering the molecular alterations leading to disease initiation and progression is currently crucial to identify the most relevant targets for precision therapy in cancer patients. Cancers express a complex chemokine network influencing leucocyte infiltration and angiogenesis. Moreover, malignant cells also express a selective repertoire of chemokine receptors that sustain their growth and spread. At present, different cancer types have been shown to overexpress C-X-C chemokine receptor type 4 (CXCR4) and to respond to its ligand C-X-C motif chemokine 12 (CXCL12). The CXCL12/CXCR4 axis influences cancer biology, promoting survival, proliferation, and angiogenesis, and plays a pivotal role in directing migration of cancer cells to sites of metastases, making it a prognostic marker and a therapeutic target. More recently, mutations in the C-terminus of CXCR4 have been identified in the genomic landscape of patients affected by Waldenstrom’s macroglobulinemia, a rare B cell neoplasm. These mutations closely resemble those occurring in Warts, Hypogammaglobulinemia, Immunodeficiency, and Myelokathexis (WHIM) syndrome, an immunodeficiency associated with CXCR4 aberrant expression and activity and with chemotherapy resistance in clinical trials. In this review, we summarize the current knowledge on the relevance of CXCR4 mutations in cancer biology, focusing on its importance as predictors of clinical presentation and response to therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Cxcr4 Whim-like Mutations In Lpl/wmmentioning

confidence: 99%

Section: Appendix Amentioning

confidence: 99%

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New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

et al. 2020

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“…To date, all but one WHIM CXCR4 variant show impaired internalization, with prolonged receptor residence time on the cell surface which is thought to contribute to amplification and prolongation of receptor signaling activity [47]. Thus, paradoxically, a loss of structure from WHIM mutations leads to a gain-of-function by stabilizing the mutant receptor on the cell surface ( Figure 2).…”

Section: Signaling Of Whim Mutationsmentioning

confidence: 99%

Aberrant CXCR4 Signaling at Crossroad of WHIM Syndrome and Waldenstrom’s Macroglobulinemia

Milanesi

Locati

Borroni

2020

IJMS

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Given its pleiotropic functions, including its prominent role in inflammation, immune responses and cancer, the C-X-C chemokine receptor type 4 (CXCR4) has gained significant attention in recent years and has become a relevant target in drug development. Although the signaling properties of CXCR4 have been extensively studied, several aspects deserve deeper investigations. Mutations in the C-term tail of the CXCR4 gene cause WHIM syndrome, a rare congenital immunodeficiency associated by chronic leukopenia. Similar mutations have also been recently identified in 30% of patients affected by Waldenstrom’s macroglobulinaemia, a B-cell neoplasia with bone marrow accumulation of malignant cells. An ample body of work has been generated to define the impact of WHIM mutations on CXCR4 signaling properties and evaluate their role on pathogenesis, diagnosis, and response to therapy, although the identity of disease-causing signaling pathways and their relevance for disease development in different genetic variants are still open questions. This review discusses the current knowledge on biochemical properties of CXCR4 mutations to identify their prototypic signaling profile potentially useful to highlighting novel opportunities for therapeutic intervention.

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“…"How I Treat" reviews have been acclaimed as having been of great practical help worldwide [5,6]. The "CME Reviews" have attracted enormous attention, which is not surprising as they have been written by the very best experts in each field, whom we want to thank warmly for their contribution to the journal [7][8][9][10][11][12][13][14][15][16][17][18][19][20]. We are thrilled to say that we will soon launch a new series, entitled "Conversations with Founders of the Field."…”

mentioning

confidence: 99%