Waldenström Macroglobulinemia: Review of Pathogenesis and Management

Yun, Seongseok; Johnson, Aaron N.; Okolo, Onyemaechi; Arnold, Stacy; McBride, Ali; Zhang, Ling; Baz, Rachid; Anwer, Faiz

doi:10.1016/j.clml.2017.02.028

Cited by 43 publications

(52 citation statements)

References 67 publications

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“…Recurrent mutation in MYD88 at L265P was previously associated with mutated IGHV CLL and highly correlated in other non-germinal centre lymphomas, including activated B cell (ABC) subtype of diffuse large B cell lymphoma (DLBCL) and Waldenstr€ om macroglobulinaemia (WM) (Ngo et al, 2011;Puente et al, 2011;Cortese et al, 2014;Baliakas et al, 2015;Yun et al, 2017). The pathogenesis of L265P-mutant MYD88 within the ABC-subtype DLBCL is due to activation of the nuclear factor jB (NF-jB) pathway by initially increasing phosphorylation and activation of interleukin-1 receptor-associated kinase (IRAK) 1 and IRAK4 (Ngo et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Routine sequencing in CLL has prognostic implications and provides new insight into pathogenesis and targeted treatments

Patel

Chen

et al. 2019

Br J Haematol

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Summary Chronic lymphocytic leukaemia (CLL) is a genetically heterogeneous disease characterised by genomic alterations and gene mutations that may portend worse survival or resistance to treatments. A total of 680 blood or bone marrow samples underwent targeted sequencing of 29 genes previously identified as being mutated in CLL, which were correlated to known prognostic clinical characteristics. Overall, 400 (59%) patients were treatment‐naïve (TN) and 280 (41%) were relapsed/refractory (R/R). Most patients (70%) had ≥1 mutation, with TP53 (22%), SF3B1 (18%), NOTCH1 (13%) and ATM (13%) being the most commonly mutated genes. A higher proportion of R/R patients had mutations in SF3B1 (P = 0·01) and TP53 (P < 0·001). Patients with mutated IGHV CLL more often had mutations in KLHL6 (P = 0·001) and MYD88 (P < 0·001). Pairwise associations showed mutational co‐occurrences in the TN group including SF3B1/ATM [false discovery rate (FDR) < 0·05] and NOTCH1/POT1 (FDR < 0·01). Recurrent mutations resulting in premature truncation prior to the ubiquitination domains of NOTCH1 in its PEST domain and BIRC3 in its RING domain can produce proteins that constitutively activate CLL. Frequent missense mutations, such as K700E in SF3B1 and E571K in XPO1, have unknown function but are most likely to be activating mutations. Future directions include using these mutations to identify pathways for therapeutic targeting and rational drug design.

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Section: Discussionmentioning

confidence: 99%

Routine sequencing in CLL has prognostic implications and provides new insight into pathogenesis and targeted treatments

Patel

Chen

et al. 2019

Br J Haematol

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“…A broad spectrum of novel drugs is cur rently available for the therapy, includ ing monoclonal antibodies, proteasome inhibitors and Bruton tyrosine kinase inhibitors. Treatment should be tailored to the individual patient while covering many clinical factors [8].…”

Section: Fig 1 Mutation Myd88 L265p and Cxcr4 S333x In Wmmentioning

confidence: 99%

“…WM patients with cytopenias, organomegaly, lymphadenopathy and IgM related complications as hyperviscosity, cryoglobulinemia, cold agglutinin in disease, amyloidosis and progressive neuropathy, require a treatment [5]. Twenty--five percent of patients with WM show familial predisposition documented by the presence of B-cell malignancies or multiple cases of WM or IgM type of monoclonal gammopathy of undetermined significance (IgM MGUS) in the family [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Diagnostic Tools of Waldenström’s Macroglobulinemia – Best Possibilities for Non-invasive and Long-term Disease Monitoring

Growková¹,

Kufova²,

Ševčíková³

et al. 2017

Klin Onkol

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Waldenströms macroglobulinemia (WM) is a B-cell malignancy characterized by high level of monoclonal immunoglobulin M (IgM) paraprotein in blood serum and associated with the bone marrow infiltration by malignant cells with lymphoplasmacytic differentiation. WM remains incurable advances in therapy. Most of WM cases are associated with a somatic point mutation L265P in MYD88. Significantly higher risk of progression from the IgM monoclonal gammopathy of undetermined significance (IgM MGUS) to WM for patients with mutated MYD88 gene suggests that this mutation is an early oncogenic event and plays a central role in development of malignant clones. The second, most prevalent mutation in WM is found in the CXCR4 gene and is often associated with drug resistance and aggressive disease presentation. Therefore, detection of these mutations (MYD88L265P and CXCR4S338X) could be useful diagnostic and prognostic tool for the patients with WM. While detection of these mutations in bone marrow sample is common, the aim of our study was to compare sensitivity of detection of mutation from different cell fraction from peripheral blood and bone marrow. The results show possibility to describe MYD88 and CXCR4 mutation status even from peripheral blood sample (sensitivity for MYD88L265P was 100%, for CXCR4S338X 91%), which significantly facilitate material collection. Moreover, comparable detection sensitivity of these mutations in bone marrow and peripheral blood samples examined before and during the therapy offers a promising tool for more routine diagnostic and monitoring of disease progression.Key words: Waldenström macroglobulinemia - hematology - neoplasms - lymphoma - mutation - MYD88 - CXCR4.

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“…There are many cytogenetic abnormalities and mutations frequently found in WM patients; common abnormalities are: del(6q) (50%), somatic hyper-mutation in immunoglobulin heavy-chain variable, t(9;14) (p13;q32) (50%), and trisomy 4 (20%). Among these, myeloid differentiation primary response gene 88 L265P (MYD88 L265P ) and CXC chemokine receptor type 4 WHIM (CXCR4 WHIM ) somatic mutations were found in more than 90% and 30-35% of WM patients, respectively, and have been shown to play an important role in WM tumorigenesis [2,3]. WM is characterized by: IgM monoclonal gammopathy of any size, bone marrow infiltration in intertrabecular patterns with small lymphocytes, plasmacytoid lymphocytes or plasma cell greater than or equal to 10%, and the presence of symptoms (Table 1) [4].…”

Section: Background and Epidemiologymentioning

confidence: 99%

Rare Transformation to Double Hit Lymphoma in Waldenstrom’s Macroglobulinemia

et al. 2017

Self Cite

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Waldenström macroglobulinemia (WM) is a lymphoproliferative lymphoma that is characterized by monoclonal immunoglobulin M (IgM) protein and bone marrow infiltration. Its incidence is rare and rarer still is its ability to transform to a B-cell lymphoma, particularly the aggressive diffuse large B-cell lymphoma, which bodes a poor prognosis. When transformation includes mutations of MYC, BCL-2 and/or BCL-6, it is known as a 'double hit' or 'triple hit' lymphoma respectively. This paper presents a rare case of WM with mutations positive for MYC and BCL2, making it a case of double hit B-cell lymphoplasmacytic lymphoma with plasmatic differentiation without morphological transformation to aggressive histology like DLBCL. The paper also broadens to include discussions on current topics in the classification, diagnosis, possible causes of transformation, and treatment of WM, including transformation to double hit lymphoma. The significance of this case lies in that the presence of double hit lymphoma-like genetic mutations in WM have not been previously described in the literature and potentially such changes are harbinger of extra-nodal presentation, aggressive growth, and possibly poor prognosis, if data from other double-hit lymphoma are extrapolated.

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Waldenström Macroglobulinemia: Review of Pathogenesis and Management

Cited by 43 publications

References 67 publications

Routine sequencing in CLL has prognostic implications and provides new insight into pathogenesis and targeted treatments

Routine sequencing in CLL has prognostic implications and provides new insight into pathogenesis and targeted treatments

Diagnostic Tools of Waldenström’s Macroglobulinemia – Best Possibilities for Non-invasive and Long-term Disease Monitoring

Rare Transformation to Double Hit Lymphoma in Waldenstrom’s Macroglobulinemia

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