Excess bone marrow mast cells constitutively express CD154 (CD40 ligand) in Waldenstrom's macroglobulinemia and may support tumor cell growth through CD154/CD40 pathway

PURPOSE To determine the natural history of amyloidosis associated with Waldenström's macroglobulinemia and immunoglobulin M (IgM) monoclonal gammopathy. PATIENTS AND METHODS From January 1968 to September 1990, 50 patients with a serum IgM monoclonal protein and biopsy-proven amyloidosis were evaluated at the Mayo Clinic. There were 32 men and 18 women (age range, 43 to 93 years). RESULTS Percentages of patients presenting with cardiac, renal, hepatic, and pulmonary amyloid were 44%, 32%, 14%, and 10%, respectively. Forty-two percent of the patients had an M protein value greater than 1.5 g/dL, and 12% had an M component greater than 3 g/dL. Subcutaneous fat, rectum, and bone marrow showed amyloid in 84%, 72%, and 50%, respectively, providing a simple technique for diagnosing amyloidosis. The bone marrow biopsy was consistent with Waldenström's macroglobulinemia in 10, a plasma-cell proliferative disorder in 10, and lymphoma or a lymphoproliferative disorder in 11; results were normal, nondiagnostic, or hypercellular in 17. Forty-three of 50 patients died. The median survival of the entire group was 24.6 months. Fifty-three percent of deaths were due to cardiac amyloid, 12% to respiratory failure, 7% to macroglobulinemia, 7% to liver failure, and 7% to kidney failure. CONCLUSION The presence of amyloid cardiomyopathy and an increased creatinine concentration at diagnosis had an adverse impact on survival. Of the 22 patients who presented with cardiomyopathy, the median survival was 11.1 months, with only two surviving longer than 5 years. The median survival of the 28 patients without cardiomyopathy at diagnosis was 27 months, with eight 5-year survivors (P = .013). All eight amyloid deposits studied stained for Ig light chain, indicating that this amyloidosis is of the primary (AL) type.

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Cell-Free DNA as Alternative to Bone Marrow CD19+ Selection for Diagnostic MYD88 L265P in Waldenstrom’s Macroglobulinemia

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/j.clml.2019.09.511 ◽

2019 ◽

Vol 19 (10) ◽

pp. e311 ◽

Cited By ~ 1

Author(s):

Maria Demos ◽

Lian Xu ◽

Nickolas Tsakmaklis ◽

Amanda Kofides ◽

Jiaji Chen ◽

...

Keyword(s):

Bone Marrow ◽

Waldenström’S Macroglobulinemia ◽

Cell Free Dna ◽

Free Dna ◽

Waldenstrom's Macroglobulinemia ◽

Selection For ◽

Waldenstrom’S Macroglobulinemia ◽

Waldenström's Macroglobulinemia ◽

Myd88 L265p

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B-Lymphocyte Stimulator (BLyS) Is Highly Expressed in Waldenstrom’s Macroglobulinemia.

Blood ◽

10.1182/blood.v104.11.2291.2291 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2291-2291

Author(s):

Stephen M. Ansell ◽

Deanna M. Grote ◽

Steven C. Ziesmer ◽

Thomas E. Witzig ◽

Robert A. Kyle ◽

...

Keyword(s):

Bone Marrow ◽

B Cells ◽

B Cell ◽

B Lymphocyte ◽

Waldenström’S Macroglobulinemia ◽

B Lymphocyte Stimulator ◽

Waldenstrom's Macroglobulinemia ◽

Waldenstrom’S Macroglobulinemia ◽

Waldenström's Macroglobulinemia ◽

Normal Controls

Abstract Waldenstrom’s macroglobulinemia is a serious and frequently fatal illness, however many of the mechanisms leading to this disease are not yet known. It is clear, however, that there is dysregulation of the balance between cell proliferation and programmed cell death. BLyS (B-lymphocyte stimulator) is a newly identified TNF family member expressed by monocytes, macrophages, and dendritic cells. BLyS has been shown to be critical for maintenance of normal B cell development and homeostasis, and has been found to stimulate lymphocyte growth. BLyS is overexpressed in a variety of B-cell malignancies and has been shown to inhibit apoptosis in malignant B-cells. Studies of the effects of BLyS on B cell physiology have shown that it also regulates immunoglobulin secretion. To determine the relevance of the BLyS receptor-ligand system in Waldenstrom’s macroglobulinemia, we examined malignant B cells from 5 patients with Waldenstrom’s macroglobulinemia for their ability to bind soluble BLyS and for the expression of the known BLyS receptors, TACI, BAFF-R, or BCMA. The malignant B cells were found to bind BLyS and express BAFF-R and TACI. BCMA expression was undetectable. We then determined the expression of BLyS in bone marrow specimens from 5 patients with Waldenstrom’s macroglobulinemia by immunohistochemistry and compared it to the expression in 5 normal bone marrow specimens. The lymphoplasmacytic cell infiltrate in the bone marrow of patients with Waldenstrom’s macroglobulinemia showed significantly increased BLyS expression. We further determined the serum BLyS levels by ELISA in stored serum specimens from patients with Waldenstrom’s macroglobulinemia (n=20), and compared them to serum BLyS levels in other patients with lymphoplasmacytic lymphoma without elevated immunoglobulin levels (n=10) and to serum levels in normal controls (n=50). Serum BLyS levels in Waldenstrom’s patients (mean: 49.6ng/ml) as well as those in patients with lymphoplasmacytic lymphoma (mean; 46.7ng/ml) were significantly higher than normal controls (mean 12.6ng/ml). In conclusion, we have demonstrated that malignant B cells from patients with Waldenstrom’s macroglobulinemia express the receptors for BLyS and can bind soluble BLyS. Furthermore, we have found that serum BLyS levels are significantly elevated in patients with Waldenstrom’s macroglobulinemia when compared to controls. Strategies to inhibit BLyS may potentially have significant therapeutic efficacy in Waldenstrom’s macroglobulinemia.

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Histone Deacetylase Inhibitors Demonstrate Significant Preclinical Activity as Single Agents, and in Combination with Bortezomib in Waldenstrom's Macroglobulinemia.

Blood ◽

10.1182/blood.v114.22.4785.4785 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4785-4785

Author(s):

Jenny Sun ◽

Lian Xu ◽

Hsiuyi Tseng ◽

Bryan Ciccarelli ◽

Mariateresa Fulciniti ◽

...

Keyword(s):

Bone Marrow ◽

Histone Deacetylase Inhibitors ◽

Conflicts Of Interest ◽

Trichostatin A ◽

Hdac Inhibitors ◽

Waldenström’S Macroglobulinemia ◽

Over Expression ◽

Waldenstrom's Macroglobulinemia ◽

Waldenstrom’S Macroglobulinemia ◽

Waldenström's Macroglobulinemia

Abstract Abstract 4785 Waldenstrom's Macroglobulinemia (WM) is a B-cell lymphoproliferative disorder characterized by bone marrow infiltration of CD19+ cells and production of a monoclonal IgM protein. Despite advances in treatment, WM remains incurable. As part of these efforts we sought to define the role of HDAC-inhibitors in WM. Gene expression profiling of bone marrow CD19+ cells from 30 WM patients and 10 healthy donors showed over-expression of HDAC4, HDAC9, and Sirt5 in WM patients. Evaluation of the HDAC inhibitors suberoylanilide hydroxamic acid (SAHA or Vorinostat), Trichostatin A (TSA), LBH-589 (Panobinostat), and sirtinol demonstrated dose dependent killing of BCWM.1 cells with IC50 of 3.5 uM, 70 nM, 0.8 uM, and 30 uM, respectively, whilst the combination of these agents with bortezomib resulted in at least additive tumor cell killing. TSA is more potent than bortezomib in inducing apoptosis in primary WM tumor cells in patients with prior treatment. TSA and bortezomib showed synergistic effect in 25% of the patients samples tested. We also observed that TSA and bortezomib-induced apoptosis of BCWM.1 cells depended on the activation of a similar set of caspases. Conversely, changes in cell cycle regulators were distinctly different between TSA and bortezomib treated BCWM.1 cells. The results of these studies demonstrate over-expression of distinct members of HDAC in WM cells, and provide a framework for the examination of HDAC-inhibitors as monotherapy, as well as combination therapy with bortezomib in the treatment of WM. Disclosures: No relevant conflicts of interest to declare.

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Targeting Myddosome Self-Assembly in Waldenstrom's Macroglobulinemia

Blood ◽

10.1182/blood.v126.23.1563.1563 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1563-1563

Author(s):

Xia Liu ◽

Zachary Hunter ◽

Lian Xu ◽

Jie Chen ◽

Jiaji Chen ◽

...

Keyword(s):

Cell Growth ◽

Self Assembly ◽

Caspase 3 ◽

Annexin V ◽

Wild Type ◽

Waldenström’S Macroglobulinemia ◽

Waldenstrom's Macroglobulinemia ◽

Waldenstrom’S Macroglobulinemia ◽

Myd88 Signaling ◽

Waldenström's Macroglobulinemia

Abstract Background: MYD88 mutations are present in over 95% of patients with Waldenstrom's Macroglobulinemia (WM), and promote Myddosome self-assembly that triggers NFκB-dependent survival through BTK and IRAK1/IRAK4 (Blood 122(7):1222-32). While current therapeutic strategies are aimed at blocking these downstream kinases, peptidomimetics that interfere with Myddosome self-assembly may offer a more targeted approach for blocking aberrant MYD88 signaling. Methods: We expressed by lentiviral transduction mini-peptides of MYD88 Toll/Interleukin-1 Receptor (TIR) or Death Domain (DD) sequences in mutated MYD88 WM and wild-type MYD88 control cells (Figure 1). We used phospho-flow analysis to evaluate for changes in pBTK, pIRAK1/IRAK4, and pNFKB, and determined cell growth and survival by Alamar Blue Assay, Annexin V, and cleaved Caspase 3 staining. Results: Transduction of TIR or DD mini-peptides in mutated MYD88 WM cells but not wild-type MYD88 control cells reduced NFKB activation and tumor cell growth, and prompted Annexin V and/or cleaved Caspase 3 staining. TIR interfering mini-peptides impacted BTK but not IRAK1/IRAK4 activation, whereas DD interfering mini-peptides showed an opposite effect. Conclusions: The findings demonstrate differences in BTK versus IRAK1/IRAK4 directed NFKB signaling in response to Myddosome self-assembly in MYD88 mutated WM cells. The feasibility of directly targeting MYD88 homodimerization to block aberrant MYD88 signaling was also recognized, and suitable peptide sequences for the development of peptidomimetics that interfere with Myddosome self-assembly and signaling were identified. The findings provide a framework for direct targeting of the Myddosome in MYD88 mutated WM disease. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

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