Whole genome sequencing reveals that recurrent MYD88 and CXCR4 mutations underlie the genomic landscape of Waldenström's macroglobulinemia

Waldenström's Macroglobulinemia (WM) is a rare, indolent, non-Hodgkin's lymphoma whose molecular pathology remains poorly understood. This disease is characterized by the accumulation of IgM-secreting lymphoplasmacytic cells in the bone marrow, and is often histopathologically indistinguishable from marginal zone lymphoma, IgM-secreting myeloma, and chronic lymphocytic leukemia with plasmacytic differentiation. To better understand the genomic landscape of this disease, whole genome sequencing was performed on bone marrow samples from thirty WM patients, ten of which were paired with germline tissue. This study identified two genes that are frequently mutated in WM: MYD88 and CXCR4. MYD88 was somatically mutated in 90% of WM samples, which displayed a single nucleotide variant resulting in a leucine to proline substitution at position 265. As prev iously demonstrated in activated B-cell subtype of diffuse large B-cell lymphoma, this mutation results in constitutive activation of the Toll-like receptor pathway and activation of nuclear factor kappa B (NFB). Highly sensitive allele specific polymerase chain reaction assays were developed to detect MYD88L265P in WM and related hematological malignancies. These studies demonstrated that MYD88L265P could be used to aid in the differential diagnosis, response assessment, and detection of minimal residual disease in WM. Moreover, MYD88L265P was observed in 50% of the precursor condition, IgM monoclonal gammopathy of undetermined significance, suggesting that it is an early event in the pathogenesis of WM. Blocking MYD88 dimerization or the use of downstream IRAK1/4 kinase inhibitors decreased the phosphorylation and nuclear localization of NFB. Somatic mutations in CXCR4 were only found in the regulatory C-terminal tail and were present in 29% of WM patients. These mutations were similar or identical to those found in the germline of patients with the autosomal dominant disease Warts, Hypogammaglobulinemia, Infection, and Myelokathexis (WHIM) syndrome. CXCR4 somatic WHIM-like mutations were found nearly exclusively in MYD88L265P mutated patients. These mutations impaired receptor internalization, increased signaling downstream of CXCR4, and instilled resistance to several WM directed therapeutics. WM patients who were wild type for both CXCR4 and MYD88 demonstrated inferior overall survival. These studies evidence highly recurring somatic events, and provide a genomic basis for the molecular pathogenesis of WM

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

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

Real-world data on the survival outcome of patients with newly diagnosed Waldenström macroglobulinemia

Background/aims: Waldenström macroglobulinemia (WM) is a rare lymphoproliferative disorder that usually follows an indolent clinical course. However, some patients show an aggressive clinical course leading to death. We explored the risk factors predicting poor prognosis in WM patients. Methods: We retrospectively analyzed 47 patients diagnosed with WM between 2000 and 2018 to explore risk factors predicting poor prognosis using various clinical and laboratory parameters and risk models including the International Prognostic Staging System for WM (IPSS-WM). Results: Over a median follow-up duration of 80.4 months, 29 patients died. The main causes of death were disease progression, organ failure related to amyloidosis, and infection. The median overall survival (OS) was 55.1 months, and 14 patients, including three with amyloidosis, died within 2 years. Serum β2-microglobulin level higher than 4 mg/dL was significantly associated with poor OS. Accordingly, the IPSS-WM showed a significant association with poor prognosis compared with other risk models, and the low-risk group had better OS than intermediate- and high-risk groups. In the retrospective analysis using the results of targeted sequencing in two cases representing good and bad prognosis, different patterns of mutation profiles were observed, including mutations of MYD88, TP53, ARID1A, and JAK2 in a refractory case. Conclusion: Serum β2-microglobulin could be a single biomarker strongly predictive of poor survival of WM patients, and the low-risk group of the IPSS-WM risk model including serum β2-microglobulin has better prognostic value than other risk models. Mutation analysis also might provide additional information to predict high-risk patients.ope

Waldenström macroglobulinemia: diagnosis and treatment

Waldenström macroglobulinemia (WM), according to the 2017 World Health Organization classification, is defined as the co-occurrence of lymphoplasmacytic lymphoma involving the bone marrow with monoclonal gammopathy of the IgM class regardless of the concentration of monoclonal protein. It is a rare lymphoproliferative disease with distinctive clinical features. Diagnostic characteristics in WM have changed significantly with the discovery of two molecular markers: MYD88 and CXCR4. The mutational status of these markers both affects clinical presentation and has shown therapeutic implications. The choice of treatment in WM is closely dependent on the patient’s age, risk of treatment-related neuropathy, and risk of immunosuppression or secondary malignancies. The therapeutic landscape has broadened in recent years, and the approvals of ibrutinib and zanubrutinib represent a significant step forward toward better management of the disease

Studies on the Genetic Characterization of Waldenström Macroglobulinemia

In 1944 the Swedish physician Jan Gösta Waldenström (1906-1996) reported two patients, displaying symptoms of oronasal bleeding, lymphadenopathy, anemia, thrombocytopenia, increased erythrocyte sedimentation rate (ESR) and an abnormal serum protein of high molecular weight.1,2 The absence of bone pain, lack of lytic bone lesions on radiographs and the presence of an excess of lymphoid cells in bone marrow, made him understand that this disease entity was different from multiple myeloma, in which lytic bone lesions are common and bone marrow is infiltrated by plasma cells. To this day, his original description of clinical characteristics and laboratory abnormalities still forms the basis of the diagnosis of a distinct clinicopathologic entity, which bears his name, Waldenström macroglobulinemia

Caracterización molecular de la Macroglobulinemia de Waldenström: Implicaciones en el diagnóstico, pronóstico y transformación histológica

Tesis por compendio de publicaciones[ES] La macroglobulinemia de Waldenström (MW) es un síndrome linfoproliferativo (SLP) B poco común caracterizado por infiltración de la médula ósea (MO) por células linfoplasmocíticas y producción de una inmunoglobulina (Ig) monoclonal tipo IgM. Forma parte del grupo de enfermedades denominadas gammapatías monoclonales, en el que también se incluyen el mieloma múltiple (MM) y la gammapatía monoclonal de significado incierto (GMSI). Su nombre deriva de Jan Gosta Waldenström, célebre médico sueco que describió por primera vez dos pacientes con hemorragia de la mucosa oral, epistaxis y linfadenopatía generalizada. Las pruebas de laboratorio de estos pacientes revelaron anemia normocrómica, trombocitopenia, elevación de la velocidad de sedimentación globular (VSG) y disminución del fibrinógeno y la albúmina. Waldenström observó dos diferencias cruciales entre esta afección y el MM: en primer lugar, sus pacientes no presentaban ni dolor ni lesiones óseas y, en segundo lugar, la MO estaba infiltrada por células linfocíticas más que plasmocíticas. Las observaciones preliminares de Waldenström se incluyen en los criterios actuales de diagnóstico para la MW, definidos en el panel consenso que se estableció en la 2ª Reunión Internacional de MW (Atenas, 2002). De acuerdo con ellos, la MW se define por la presencia de una IgM monoclonal (pico M) de cualquier grado, junto con afectación de la MO por infiltrado linfoplasmacítico con patrón predominantemente intertrabecular. Debe considerarse como una entidad clinicopatológica distinta y no como un síndrome clínico secundario a la secreción de IgM.[EN] Transformation of Waldenström’s macroglobulinemia (WM) to diffuse large B-cell lymphoma (DLBCL) occurs in up to 10% of patients and is associated with an adverse outcome. Here we performed the first wholeexome sequencing study of WM patients who evolved to DLBCL and report the genetic alterations that may drive this process. Our results demonstrate that transformation depends on the frequency and specificity of acquired variants, rather than on the duration of its evolution. We did not find a common pattern of mutations at diagnosis or transformation; however, there were certain abnormalities, such as MYD88 and CD79B, that were present in a high proportion of clonal tumor cells and that were conserved during this transition, suggesting that they have a key role as early drivers. In addition, recurrent mutations gained in some genes at transformation (e.g., PIM1, FRYL, HNF1B) represent cooperating events in the selection of the clones responsible for disease progression. Detailed comparison reveals the gene abnormalities at diagnosis and transformation to be consistent with a branching model of evolution. Finally, the frequent mutation observed in the CD79B gene in this specific subset of patients implies that it is a potential biomarker predicting transformation in WM

Etablierung der MYD88-L265P Mutationsanalyse mittels Schmelzpunktanalyse am FFPE-Material lymphoplasmozytischer Lymphome

Bei der Tumorgenese des LPL spielen onkologisch verschiedene Signalkaskaden eine Rolle. Eine davon ist die konstitutionelle Aktivierung des NF-κB- und des JAK-STAT3-Signalweges, welche über das Protein MYD88 vermittelt wird. Die am häufigsten vorkommende Mutation, die zur Aktivierung des NF-κB Signalweges führt, ist die MYD88-L265P Mutation. Durch die dauerhafte Aktivierung des NF-κB-Signalweges wird die Transkription verstärkt, was proliferationsfördernd wirkt und die Apoptose vermindert. Dies wiederum verstärkt die Tumorentstehung und Tumorentwicklung. Es wurden insgesamt 61 Patientenfälle untersucht. Dabei wurden 35 Fälle mit LPL und als Vergleichsgruppen zusätzlich elf Fälle mit B-CLL, neun Fälle mit MZL und sechs Fälle mit MM auf das Vorhandensein der MYD88-L265P Mutation untersucht. Bei der Mutationsanalyse konnte ein problemloser und eindeutiger Mutationsnachweis bei Tumorinfiltrationsgehalten zwischen 10% und nahezu 100% erfolgen. In der Mutationsanalyse konnte bei Patientenproben mit LPL in 94,3% der Fälle eine MYD88-L265P Mutation nachgewiesen werden. Bei den Vergleichsproben mit MZL und B-CLL konnte eine Mutationsrate von 11,1% und 0% nachgewiesen werden