Macroglobulinemia de Waldenström. Estudios citogenéticos y moleculares.

Waldenstrom Macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with bone marrow (BM) involvement and the presence of a monoclonal IgM gammopathy. The most frequent cytogenetic alteration is the deletion of part of the long arm of chromosome 6 observed in 30-54% of cases, associated with adverse prognostic factors in WM. The introduction of next generation sequencing allowed the detection of mutations in the MYD88 and CXCR4 genes, with diagnostic and prognostic value in this pathology. The activating mutation of the MYD88 gene determines the change of the amino acid leucine for proline at position 265 of the protein (MYD88L265P) that was observed in 93-97% of patients with WM and in 40-60% of cases of monoclonal gammapathy of undetermined significance (MGUS) IgM. CXCR4 mutations were found in 30-40% of patients with WM, being less frequent in MGUS-IgM (4-20%). The most common variant, CXCR4S338X (50% of mutations), generates a stop codon leading to a truncated protein at amino acid 338 and to the loss of 15 amino acids in the C-regulatory domain. Some patients have multiple mutations in different subclones. Cases with MYD88WT/CXCR4WHIM/WT have the worst prognosis with short overall and progression-free survival. Patients with MYD88L265P/CXCR4WHIM//WT have a good response to treatment, whereas those with both mutated genes have an intermediate prognosis. Undoubtedly, the analysis of these mutations has allowed the increase of the biological characterization of WM, making possible in the future to expand the probability of having new therapeutic targets.