The importance of the genomic landscape in Waldenström's Macroglobulinemia for targeted therapeutical interventions

Sacco, Antonio; Fenotti, Adriano; Affò, Loredana; Bazzana, Stefano; Russo, Domenico; Presta, Marco; Malagola, Michele; Anastasia, Antonella; Motta, Marina; Patterson, Christopher J.; Rossi, Giuseppe; Treon, Steven P.; Ghobrial, Irène M.; Roccaro, Aldo M.

doi:10.18632/oncotarget.16130

Cited by 5 publications

(4 citation statements)

References 62 publications

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“…However, these studies highlight the importance of understanding both MYD88 and CXCR4 mutation statuses in LPL/WM and may provide the basis for a more personalized treatment approach. Nowadays, targeting CXCR4 represents an innovative, interesting therapeutic approach in patients with WM, either harboring or not harboring the CXCR4 WHIM mutation [160]. In addition to plerixafor, several other antagonists to CXCR4 have been developed and are in clinical trials, including uloclupumab, mavorixafor, and burixafor (TG-0054), and could be investigated for use either alone or in combination treatment strategies for LPL/WM patients with CXCR4 mutations.…”

Section: Cxcr4 Whim-like Mutations In Lpl/wmmentioning

confidence: 99%

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: Cxcr4 Whim-like Mutations In Lpl/wmmentioning

confidence: 99%

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

et al. 2020

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“…A very rich literature compared gene expression profiles in tissues collected from healthy and cancer donors to identify the transcriptomic signatures of various cancer phenotypes (e.g., references [1,2,3,4,5]) that are periodically organized in the atlas form (e.g., references [6,7]). Nanostring launched recently a panel claiming to categorize the disease heterogeneity using 32 biological signatures involving 770 genes across 23 key breast cancer pathways ().…”

Section: Introductionmentioning

confidence: 99%

The Gene Master Regulators (GMR) Approach Provides Legitimate Targets for Personalized, Time-Sensitive Cancer Gene Therapy

Iacobaş

Ede

Iacobaş

2019

Genes

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The dynamic and never exactly repeatable tumor transcriptomic profile of people affected by the same form of cancer requires a personalized and time-sensitive approach of the gene therapy. The Gene Master Regulators (GMRs) were defined as genes whose highly controlled expression by the homeostatic mechanisms commands the cell phenotype by modulating major functional pathways through expression correlation with their genes. The Gene Commanding Height (GCH), a measure that combines the expression control and expression correlation with all other genes, is used to establish the gene hierarchy in each cell phenotype. We developed the experimental protocol, the mathematical algorithm and the computer software to identify the GMRs from transcriptomic data in surgically removed tumors, biopsies or blood from cancer patients. The GMR approach is illustrated with applications to our microarray data on human kidney, thyroid and prostate cancer samples, and on thyroid, prostate and blood cancer cell lines. We proved experimentally that each patient has his/her own GMRs, that cancer nuclei and surrounding normal tissue are governed by different GMRs, and that manipulating the expression has larger consequences for genes with higher GCH. Therefore, we launch the hypothesis that silencing the GMR may selectively kill the cancer cells from a tissue.

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“…Recurrent activating somatic mutations (frameshift or nonsense) are also found in C–X–C chemokine receptor type 4 ( CXCR4 ) gene in a frequency of about 30–40% of patients with WM and less often in those with IgM MGUS, representing the second most mutated gene in WM [ 2 , 3 , 12 ]. CXCR4 is a G-protein-coupled receptor, acting as a key regulator of cell trafficking in heamatopoietic stem cells and clonal B cells, also interacting with the related ligand stromal-derived factor 1 [ 13 – 16 ]. Studies have shown the relevance of specific CXCR4 mutations to enhanced WM cell dissemination leading to in vivo disease progression as well as increased resistance to ibrutinib treatment [ 17 – 19 ].…”

Section: Introductionmentioning

confidence: 99%

Detection of MYD88 and CXCR4 mutations in cell-free DNA of patients with IgM monoclonal gammopathies

Bagratuni

Ntanasis‐Stathopoulos

Gavriatopoulou

et al. 2018

Leukemia

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Liquid biopsyis being integrated into cancer diagnostics with profound therapeutic implications. However, its role in Waldenström’s Macroglobulinemia (WM) and IgM monoclonal gammopathies is still unclear. In this study, we evaluated the role of peripheral blood (PB) cell-free DNA (cfDNA) in characterizing the mutational status of MYD88 and CXCR4 of patients with IgM monoclonal gammopathies. Paired bone marrow (BM) tumor DNA (tDNA) and PB cfDNA samples from 98 patients (9 MGUS, 45 with WM in remission, 44 with smoldering WM, newly diagnosed or relapsed WM) and 10 controls with non-IgM monoclonal gammopathies were analyzed. Regarding MYD88L265P mutation, 76 patients had paired tDNA and cfDNA informative samples. Among patients with WM in remission, 65% harbored the MYD88L265P mutation, whereas the corresponding percentage among smoldering/newly diagnosed or relapsed WM was 92%. The overall concordance rate was 94% (72/76). For CXCR4 mutations, 65 patients had paired informative tDNA and cfDNA samples. The overall concordance rate was 90% (59/65). All controls had wild-type MYD88 and CXCR4. In conclusion, PB cfDNA is a useful, minimally invasive, cost-effective, and time-effective tool for the identification of the presence of MYD88 and CXCR4 mutations in patients with IgM monoclonal gammopathies avoiding unnecessary BM assessment.

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The importance of the genomic landscape in Waldenström's Macroglobulinemia for targeted therapeutical interventions

Cited by 5 publications

References 62 publications

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

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

The Gene Master Regulators (GMR) Approach Provides Legitimate Targets for Personalized, Time-Sensitive Cancer Gene Therapy

Detection of MYD88 and CXCR4 mutations in cell-free DNA of patients with IgM monoclonal gammopathies

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