Biologic and genetic characterization of the novel amyloidogenic lambda light chain–secreting human cell lines, ALMC-1 and ALMC-2

Arendt, Bonnie K.; Ramı́rez-Alvarado, Marina; Sikkink, Laura A.; Keats, Jonathan J.; Ahmann, Gregory; Dispenzieri, Angela; Fonseca, Rafaël; Ketterling, Rhett P.; Knudson, Ryan A.; Mulvihill, Erin M.; Tschumper, Renee C.; Wu, Xiaosheng; Zeldenrust, Steven R.; Jelinek, Diane F.

doi:10.1182/blood-2008-03-143040

Cited by 64 publications

(91 citation statements)

References 62 publications

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“…We could not detect constitutively P-Axl in ANBL6 (multiple myeloma), ALMC-1 (amyloidosis), 15 or KAS-6/1 (multiple myeloma); however, we found that RAMOS (Burkitt lymphoma) 16 and Mec1 (CLL) 17 cell lines do express constitutive levels of P-Axl ( Figure 1A). …”

Section: Cll B Cells Express Constitutively P-axlmentioning

confidence: 74%

The novel receptor tyrosine kinase Axl is constitutively active in B-cell chronic lymphocytic leukemia and acts as a docking site of nonreceptor kinases: implications for therapy

Ghosh¹,

Secreto²,

Boysen³

et al. 2011

Blood

107

105

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Recently, we detected that chronic lymphocytic leukemia (CLL) B-cell-derived microvesicles in CLL plasma carry a constitutively phosphorylated novel receptor tyrosine kinase (RTK), Axl, indicating that Axl was acquired from the leukemic B cells. To examine Axl status in CLL, we determined the expression of phosphorylated-Axl (P-Axl) in freshly isolated CLL B cells by Western blot analysis. We detected differential levels of P-Axl in CLL B cells, and further analysis showed that expression of P-Axl was correlated with the other constitutively phosphorylated kinases, including Lyn, phosphoinositide-3 kinase, SyK/-associated protein of 70 kDa, phospholipase C ␥2 in CLL B cells. We found that these intracellular signaling molecules were complexed with P-Axl in primary CLL B cells. When Axl and IntroductionThe mainstay therapy for B-cell chronic lymphocytic leukemia (CLL) is cytotoxic chemotherapy with or without immunotherapy; however, CLL remains an incurable disease with most patients developing resistance to therapy. 1 B-cell CLL has been predominantly characterized as a clonal B-cell disorder 2 in which defective apoptosis of CLL B cells is ascribed not only to the intrinsic defects of neoplastic cells but also to extrinsic factors that influence their behavior in the tissue microenvironment. The issue of CLL clinical heterogeneity and the exact reasons for clinical variation of disease progression are unknown. One approach toward the discovery of new therapeutic targets is to explore the nature of intracellular signaling pathways responsible for modulating the proliferation or apoptotic rate or both of CLL B cells.Protein kinases play a significant role in tumor development and progression. Deregulated expression of protein kinases by gene deletion, mutation, or amplification has been found to be important for tumor initiation and progression in cancer cell proliferation, survival, motility, and invasiveness as well as angiogenesis and chemotherapy resistance. 3,4 Since the 1980s, 5 protein kinases have been at the forefront of targeted cancer therapy development because of their critical function in oncogenesis. In CLL, we and others have found that the vascular endothelial growth factor/ vascular endothelial growth factor receptor axis is important for CLL B-cell survival by up-regulating antiapoptotic proteins. [6][7][8] It has been shown that Lyn, a member of the Src family kinases (SFKs), is overexpressed at the protein level in CLL B cells compared with normal B lymphocytes. In normal B lymphocytes Lyn activation depends on B-cell receptor stimulation, but, in resting malignant cells, the constitutive activity of the kinase accounts for high basal protein tyrosine phosphorylation and low responsiveness to immunoglobulin M (IgM) ligation. 9 Recently, we detected that CLL B cell-derived microvesicles (MVs) in CLL plasma carry the constitutively phosphorylated novel receptor tyrosine kinase (RTK) Axl 10 ; indicating they probably acquired Axl from leukemic B cells. We investigated whether CLL B cells expres...

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Section: Cll B Cells Express Constitutively P-axlmentioning

confidence: 74%

The novel receptor tyrosine kinase Axl is constitutively active in B-cell chronic lymphocytic leukemia and acts as a docking site of nonreceptor kinases: implications for therapy

Ghosh¹,

Secreto²,

Boysen³

et al. 2011

Blood

107

105

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“…We developed a secretion reporter for LC by fusing the well-characterized AL-causing Vλ6 LC containing both constant and variable LC domains (named ALLC) (26) to an enhanced Gaussia princeps luciferase (GLuc) reporter, ALLC-GLuc (Fig. 1A) (27,28).…”

Section: Resultsmentioning

confidence: 99%

Unfolded protein response activation reduces secretion and extracellular aggregation of amyloidogenic immunoglobulin light chain

Cooley¹,

Ryno²,

Plate³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

128

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Light-chain amyloidosis (AL) is a degenerative disease characterized by the extracellular aggregation of a destabilized amyloidogenic Ig light chain (LC) secreted from a clonally expanded plasma cell. Current treatments for AL revolve around ablating the cancer plasma cell population using chemotherapy regimens. Unfortunately, this approach is limited to the ∼70% of patients who do not exhibit significant organ proteotoxicity and can tolerate chemotherapy. Thus, identifying new therapeutic strategies to alleviate LC organ proteotoxicity should allow AL patients with significant cardiac and/or renal involvement to subsequently tolerate established chemotherapy treatments. Using a small-molecule screening approach, the unfolded protein response (UPR) was identified as a cellular signaling pathway whose activation selectively attenuates secretion of amyloidogenic LC, while not affecting secretion of a nonamyloidogenic LC. Activation of the UPR-associated transcription factors XBP1s and/or ATF6 in the absence of stress recapitulates the selective decrease in amyloidogenic LC secretion by remodeling the endoplasmic reticulum proteostasis network. Stress-independent activation of XBP1s, or especially ATF6, also attenuates extracellular aggregation of amyloidogenic LC into soluble aggregates. Collectively, our results show that stress-independent activation of these adaptive UPR transcription factors offers a therapeutic strategy to reduce proteotoxicity associated with LC aggregation.ER proteostasis | amyloid L ight-chain amyloidosis (AL) afflicts 8-10 people per million per year, making it the most prominent systemic amyloid disease (1). AL is a gain-of-toxic function disease driven by a clonally expanded plasma cell that secretes amyloidogenic Ig light chains (LCs). These amyloidogenic LCs undergo extracellular misfolding and aggregation into proteotoxic soluble oligomers and amyloid fibrils that interact with distal tissues such as the kidney, heart, and gastrointestinal tract, leading to organ dysfunction and ultimately death by unknown proteotoxicity mechanism(s) (2).The majority of AL patients must combat both a cancer (i.e., the clonally expanded plasma cell) and LC aggregation-associated proteotoxicity. The standard treatment for AL patients is chemotherapy (often combined with stem cell transplant) to eliminate the cancerous plasma cell population (3, 4). The proteasome inhibitor bortezomib, which takes advantage of the stress sensitivity of aggressively proliferating plasma cells, has transformed chemotherapy effectiveness (5-7). Regardless, ∼30% of AL patients with substantial cardiac or renal LC proteotoxicity are too ill at diagnosis to tolerate chemotherapeutics (8-10). Thus, new strategies to reduce LC organ proteotoxicity must be developed to allow more AL patients to take advantage of chemotherapy.LC aggregation requires conformational changes and a sufficient concentration of misfolded LC in plasma, which determine the rate and extent of its concentration-dependent aggregation. Over 500 distinct LC s...

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“…Cytokine-induced cell growth in this cell line was more modest than has been previously reported for other non-WM plasma cell lines, but an increase in the proliferation was still observed after treatment with BAFF, IL-4, IL-10, and interferon-␣ (P Ͻ .001, Figure 6). 21,22 Lastly, genomic DNA isolated from MWCL-1 cells tested positive for the EBV gene product, EBNA1. To determine whether the virus was actively replicating and being shed by MWCL-1 cells, EBV Ϫ Karpas-422 cells were treated with MWCL-1-conditioned media for 96 hours.…”

Section: Biologic Characterization Of Mwcl-1 Cellsmentioning

confidence: 99%

Establishment and characterization of a novel Waldenström macroglobulinemia cell line, MWCL-1

Hodge

Novak

Grote

et al. 2011

Blood

Self Cite

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Waldenströ m macroglobulinemia (WM) is IntroductionWaldenström macroglobulinemia (WM) is an indolent, nonHodgkin lymphoma characterized by bone marrow infiltration and the overproduction of monoclonal immunoglobulin M protein (IgM). 1 Accounting for 1% to 2% of hematologic malignancies, this rare lymphoma, which is often, if not always, preceded by an IgM monoclonal gammopathy of undetermined significance, is more common in males, with a median age at presentation of 63 years. 2 The exact cause of WM is unknown, but multigenerational clustering and familial patterns suggest the possibility of an underlying genetic defect. 3,4 However, cytogenetic analyses have yet to reveal a common abnormality specific to WM disease, as has been reported in other lymphoproliferative disorders. 5,6 Whereas recent gene expression and proteomics studies have advanced our understanding of WM pathogenesis and identified potential therapeutic targets, WM remains incurable given current therapy, with a 5-year survival rate of 50%. 7,8 WM is classified by the World Health Organization as a lymphoplasmacytic lymphoma, and bone marrow aspirates collected from patients with WM reveal a diverse tumor clone consisting of a spectrum of small B lymphocytes, plasma cells, and lymphoplasmacytoid cells. 9 Evidence suggests that WM may arise from a postgerminal center, memory-like B cell that has developed the capacity to secrete IgM through either intrinsic or extrinsic stimuli. Thus, in addition to the positive expression of soluble immunoglobulin IgM and the pan B-cell antigens CD19 and CD20, many WM tumor cells also coexpress the markers of mature plasma cells as well, including CD38 and CD138. 10,11 Clinical findings associated with this malignancy, including mucosal bleeding, retinopathies with visual disturbances, and neuropathies and paresthesias, frequently arise as a result of hyperviscosity syndrome, the development of which is directly related to the high serum levels of IgM. 2,12 Despite its association with significant morbidity, the deregulation of IgM production in WM remains poorly understood. To date, exploratory studies to determine the pathogenesis of IgM dysregulation in WM have been limited mainly by the lack of a validated cell model that is both phenotypically and genetically consistent with the original primary tumor. The WSU-WM cell line was one of the first established from a WM tumor. However, WSU-WM cells maintain a karyotype and morphology more reminiscent of Burkitt lymphoma than WM; and because the cell line was never genetically authenticated against the primary tumor, the exact origin of these cells remains unclear. 13 BCWM.1 cells correspond phenotypically to primary WM cells in their ability to secrete high levels of IgM, and this putative WM cell line has frequently been used as a representative model of this disease. 14 Unfortunately, data confirming a clonal relationship between BCWM.1 cells and the primary tumor from which they were derived are limited. Although these cells remain a useful model for the stu...

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Biologic and genetic characterization of the novel amyloidogenic lambda light chain–secreting human cell lines, ALMC-1 and ALMC-2

Cited by 64 publications

References 62 publications

The novel receptor tyrosine kinase Axl is constitutively active in B-cell chronic lymphocytic leukemia and acts as a docking site of nonreceptor kinases: implications for therapy

The novel receptor tyrosine kinase Axl is constitutively active in B-cell chronic lymphocytic leukemia and acts as a docking site of nonreceptor kinases: implications for therapy

Unfolded protein response activation reduces secretion and extracellular aggregation of amyloidogenic immunoglobulin light chain

Establishment and characterization of a novel Waldenström macroglobulinemia cell line, MWCL-1

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