scholarly journals Aberrant Expression of and Cell Death Induction by Engagement of the MHC-II Chaperone CD74 in Anaplastic Large Cell Lymphoma (ALCL)

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 5012
Author(s):  
Kathrin Wurster ◽  
Mariantonia Costanza ◽  
Stephan Kreher ◽  
Selina Glaser ◽  
Björn Lamprecht ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Lymphoid Cells ◽  
Aberrant Expression ◽  
Mhc Ii ◽  
Anaplastic Lymphoma ◽  
Large Cell Lymphoma

In 50–60% of cases, systemic anaplastic large cell lymphoma (ALCL) is characterized by the t(2;5)(p23;q35) or one of its variants, considered to be causative for anaplastic lymphoma kinase (ALK)-positive (ALK+) ALCL. Key pathogenic events in ALK-negative (ALK−) ALCL are less well defined. We have previously shown that deregulation of oncogenic genes surrounding the chromosomal breakpoints on 2p and 5q is a unifying feature of both ALK+ and ALK− ALCL and predisposes for occurrence of t(2;5). Here, we report that the invariant chain of the MHC-II complex CD74 or li, which is encoded on 5q32, can act as signaling molecule, and whose expression in lymphoid cells is usually restricted to B cells, is aberrantly expressed in T cell-derived ALCL. Accordingly, ALCL shows an altered DNA methylation pattern of the CD74 locus compared to benign T cells. Functionally, CD74 ligation induces cell death of ALCL cells. Furthermore, CD74 engagement enhances the cytotoxic effects of conventional chemotherapeutics in ALCL cell lines, as well as the action of the ALK-inhibitor crizotinib in ALK+ ALCL or of CD95 death-receptor signaling in ALK− ALCL. Additionally, a subset of ALCL cases expresses the proto-oncogene MET, which can form signaling complexes together with CD74. Finally, we demonstrate that the CD74-targeting antibody-drug conjugate STRO-001 efficiently and specifically kills CD74-positive ALCL cell lines in vitro. Taken together, these findings enabled us to demonstrate aberrant CD74-expression in ALCL cells, which might serve as tool for the development of new treatment strategies for this lymphoma entity.

Primary Cutaneous CD30-Positive Anaplastic Large Cell Lymphoma in Childhood: Report of 4 Cases and Review of the Literature

2005 ◽  
Vol 8 (1) ◽  
pp. 52-60 ◽  
Author(s):  
Shimareet Kumar ◽  
Stefania Pittaluga ◽  
Mark Raffeld ◽  
Michael Guerrera ◽  
Nita L. Seibel ◽  
...  
Keyword(s):  
T Cell ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Subcutaneous Tissue ◽  
Pediatric Population ◽  
Large Cell ◽  
Lymphoid Cells ◽  
Cell Phenotype ◽  
Anaplastic Lymphoma ◽  
Large Cell Lymphoma

We present the clinicopathologic findings in 4 children with primary cutaneous anaplastic large cell lymphoma (C-ALCL). The patients ranged in age from 13 months to 8 years, with 3 females and 1 male. All presented with a rapidly enlarging mass involving the skin and subcutaneous tissue. Histologic evaluation showed sheets of large pleomorphic lymphoid cells that were diffusely and strongly CD30+. Tumor cells were CD45+ in 1 of 4 cases. Cells were of T-cell phenotype, with variable positivity for CD3 (3 of 4 cases) and CD5 (2 of 4 cases). All 4 cases were positive for CD4 and clusterin. Staining for anaplastic lymphoma kinase was negative in all cases. No evidence of systemic involvement was noted at initial presentation or over a follow-up of 5 to 78 months, although 3 patients had cutaneous recurrences. Primary C-ALCL has only rarely been described in the pediatric population. The high-grade histologic appearance of this lymphoma belies its generally favorable clinical course and prognosis. Recognition of this entity and its differentiation from other T-cell lymphomas that secondarily involve the skin is important to avoid unnecessarily aggressive therapy in these children.

Bortezomib Induces Caspase-9-Mediated Apoptosis through Activation of the BH3-Only Proteins Noxa, Bik and Puma In Both ALK-Positive and ALK-Negative Anaplastic Large Cell Lymphoma Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2847-2847
Author(s):  
Saskia AGM Cillessen ◽  
Nathalie J Hijmering ◽  
Laura M Moesbergen ◽  
Gert J. Ossenkoppele ◽  
Joost J Oudejans ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Caspase 9 ◽  
Lymphoma Cells ◽  
Induction Of Apoptosis ◽  
Large Cell Lymphoma ◽  
Alk Positive

Abstract Abstract 2847 Anaplastic large cell lymphoma (ALCL) is a CD30 positive T-cell lymphoma that can be divided into a systemic and a primary cutaneous type. Systemic ALCL can be further divided into an anaplastic lymphoma kinase (ALK) expressing type and an ALK-negative type. Despite intensive treatment regimens, the disease will be fatal in 20–30% of the systemic ALK-positive and 50–70% of the systemic ALK-negative ALCL patients. A recent study in primary ALCL samples has demonstrated an increased expression of a fraction of NF-κB target genes, suggesting upregulation of NF-κB activity in ALCL tumor cells. NF-κB activity can be inhibited by the proteasome inhibitor bortezomib resulting in induction of apoptosis. In this study, we therefore investigated if bortezomib can induce apoptosis of cultured lymphoma cells of three systemic ALK-positive and three ALK-negative ALCL patients and seven ALCL cell lines and we examined the mechanisms by which bortezomib induced cytotoxicity in these ALCL cells. Treatment with bortezomib resulted in induction of apoptosis in all ALK-positive and ALK-negative ALCL patient samples and ALCL cell lines tested, when we compared the percentage cell death with the non-neoplastic CD4- and CD8-positive PBMC and tonsil T-cells from healthy donors. The lethal dose (LD50) varied between 54nM and more than 100nM after 24 hours and varied between 21nM and 52nM after 48 hours of exposure. ALK-negative ALCL cases were more sensitive to bortezomib and showed significant lower LD50 values than ALK-positive ALCL cells. We show that bortezomib-induced cell death in ALK-positive and ALK-negative ALCL is dependent on caspase-9 and/or caspase-8 mediated apoptosis and that bortezomib induces depolarization of the mitochondrial membrane. mRNA-expression and protein analysis revealed clearly upregulation of the BH3-only proteins Noxa, Bik and Puma, resulting in Bak and Bax release from the anti-apoptotic proteins Mcl-1 and Bcl-2. We also demonstrated that ALCL cells relatively resistant to bortezomib were characterized by high expression of Bcl-2A1, suggesting the possibility of pre-defining patients most likely to benefit from bortezomib therapy. Our preclinical data support the therapeutic application of bortezomib as potential drug in the treatment of ALCL, especially ALK-negative ALCL patients to improve their prognosis. Disclosures: No relevant conflicts of interest to declare.

NPM-ALK Fusion Tyrosine Kinase of Anaplastic Large Cell Lymphoma Exerts Its Transforming Potential by Increasing Translation of JUNB through mTOR and S6K1.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1428-1428
Author(s):  
Philipp B. Staber ◽  
Paul Vesely ◽  
Rene Ott ◽  
Naznin Haq ◽  
Werner Linkesch ◽  
...  
Keyword(s):  
Cell Lines ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Mek Inhibitor ◽  
Pi3 Kinase ◽  
Mrna Levels ◽  
Anaplastic Lymphoma ◽  
Large Cell Lymphoma ◽  
Alk Positive

Abstract The nucleophosmin (NPM) - anaplastic lymphoma kinase (ALK) fusion protein, which is the product of the balanced chromosomal rearrangement t(2;5)(p23;q35), occurs in about 50% of nodal anaplastic large cell lymphoma (ALCL). Expression of this fusion kinase results in neoplastic transformation by modulating multiple intracellular signaling molecules, such as the PI3-kinase and the ERK1/2 kinases. Here we show high activation of JunB in various human ALCL cell lines. Moreover, using human embryonic kidney (HEK293) and murine hematopoietic Ba/F3 cells ectopically expressing NPM-ALK, we demonstrate that NPM-ALK is the trigger for JunB activation. Knock down of JUNB in NPM-ALK expressing cells using RNA interference results in upregulation of p16INK4a and downregulation of Cyclin D1, causing G1/S cell cycle arrest. Thus, JunB plays a critical oncogenic role in NPM-ALK transformed cells. Using the PI3-kinase inhibitor LY294002 and the MEK-inhibitor UO126, we demonstrate that NPM-ALK-induced JunB activity as well as cellular proliferation are dependent on both PI3-kinase and MEK-ERK signaling. Moreover, we illustrate that NPM-ALK and subsequently PI3-kinase activate AKT and mTOR/S6K1 which are implicated in the translational control of specific mRNA molecules containing a polypyrimidine motif (see pathway diagram). Since JUNB mRNA harbors such a motif we confirmed that JUNB mRNA is translated in large polysomes using ribosomal gradient preparations. Selective block of mTOR with the immunosuppressant rapamycin decreases proliferation and reduces protein but not mRNA levels of JunB in human and murine NPM-ALK positive cell lines. A similar effect is seen when inhibiting the upstream activator of mTOR, PI3-kinase. In contrast, a significant decrease of JUNB mRNA levels is shown in cells treated by the MEK-inhibitor UO126. An analogous effect of NPM-ALK is observed in ALCL patient samples. Hyperphosphorylation of S6K1 at Thr389 indicating activated mTOR/S6K1 is seen in 9/10 NPM-ALK positive ALCL cases in contrast to only 1/15 of NPM-ALK negative ALCL samples (P < 0,001). Hence, these findings suggest that the signaling cascade NPM-ALK→PI3K→AKT→mTOR/S6K1 is crucial to induce JUNB translation in human NPM-ALK positive ALCL. In conclusion, we reveal that JunB acts as an oncogene in NPM-ALK positive neoplastic cells and therefore represents a valid therapeutic target. Our data indicate a novel mechanism for regulation of AP-1 activity in general and suggest a new therapeutic approach to specifically modulate translation of an oncogene. Figure Figure

scholarly journals An Exploration into the Origins and Pathogenesis of Anaplastic Large Cell Lymphoma, Anaplastic Lymphoma Kinase (ALK)-positive

2017 ◽  
Author(s):  
Suzanne Turner
Keyword(s):  
T Cells ◽  
T Cell ◽  
Anaplastic Large Cell Lymphoma ◽  
Anaplastic Lymphoma Kinase ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Aberrant Expression ◽  
Anaplastic Lymphoma ◽  
Non Hodgkin Lymphoma ◽  
Large Cell Lymphoma

T cell Non-Hodgkin lymphoma is a heterogeneous disease ranging from malignancies arising from thymic T cells halted in development, through to mature, circulating peripheral T cells. The latter cases are diagnostically problematic with many entering the category of peripheral T cell lymphoma, not otherwise specified (PTCL, NOS). Anaplastic Large Cell Lymphoma is one of the exceptions to this whereby aberrant expression of Anaplastic Lymphoma Kinase and distinctive presence of cell surface CD30 places this entity in its own class. Besides expression of a well-studied oncogenic translocation, ALCL, ALK+ may also have a unique pathogenesis with a thymic origin like T lymphoblastic lymphoma but a peripheral presentation akin to PTCL. This review discusses evidence towards the potential origin of ALCL, ALK+ and mechanisms that may give rise to its unique phenotype.

Anaplastic lymphoma kinase activity is essential for the proliferation and survival of anaplastic large-cell lymphoma cells

Blood ◽  
2006 ◽  
Vol 107 (4) ◽  
pp. 1617-1623 ◽  
Author(s):  
Weihua Wan ◽  
Mark S. Albom ◽  
Lihui Lu ◽  
Matthew R. Quail ◽  
Nadine C. Becknell ◽  
...  
Keyword(s):  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Leukemia Cell ◽  
Large Cell ◽  
Leukemia Cell Line ◽  
G1 Arrest ◽  
Dependent Manner ◽  
Aberrant Expression ◽  
Anaplastic Lymphoma ◽  
Large Cell Lymphoma

The roles of aberrant expression of constitutively active ALK chimeric proteins in the pathogenesis of anaplastic large-cell lymphoma (ALCL) have been well defined; nevertheless, the notion that ALK is a molecular target for the therapeutic modulation of ALK+ ALCL has not been validated thus far. Select fused pyrrolocarbazole (FP)–derived small molecules with ALK inhibitory activity were used as pharmacologic tools to evaluate whether functional ALK is essential for the proliferation and survival of ALK+ ALCL cells in culture. These compounds inhibited interleukin 3 (IL-3)–independent proliferation of BaF3/NPM-ALK cells in an ALK inhibition-dependent manner and significantly blocked colony formation in agar of mouse embryonic fibroblast (MEF) cells harboring NPM-ALK. Inhibition of NPM-ALK phosphorylation in the ALK+ ALCL-derived cell lines resulted in significant inhibition of cell proliferation and induction of apoptotic-cell death, while having marginal effects on the proliferation and survival of K562, an ALK- leukemia cell line. ALK inhibition resulted in cell-cycle G1 arrest and inactivation of ERK1/2, STAT3, and AKT signaling pathways. Potent and selective ALK inhibitors may have therapeutic application for ALK+ ALCL and possibly other solid and hematologic tumors in which ALK activation is implicated in their pathogenesis.

scholarly journals Pathobiology of ALK+ anaplastic large-cell lymphoma

Blood ◽  
2007 ◽  
Vol 110 (7) ◽  
pp. 2259-2267 ◽  
Author(s):  
Hesham M. Amin ◽  
Raymond Lai
Keyword(s):  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Clinical Manifestations ◽  
Large Cell ◽  
Experimental Models ◽  
Lymphoid Cells ◽  
Anaplastic Lymphoma ◽  
Large Cell Lymphoma

Anaplastic large-cell lymphoma (ALCL) was initially recognized on the basis of morphologic features and the consistent expression of CD30. It then became evident that the majority of these tumors are derived from lymphoid cells of T or null immunophenotype. The subsequent finding that t(2;5)(p23;q35) occurs in 40% to 60% of ALCL patients established a distinct clinicopathologic entity. This chromosomal translocation induces the formation of the chimeric protein nucleophosmin–anaplastic lymphoma kinase (NPM-ALK), which possesses significant oncogenic potential resulting from the constitutive activation of the tyrosine kinase ALK. In addition to its specific pathophysiologic events, NPM-ALK–expressing lymphoma presents with consistent clinical manifestations. Only 13 years after the identification of NPM-ALK, tremendous progress has been made in our understanding of this molecule because of the relentless efforts of multiple investigators who have dissected its biologic roles using in vitro and in vivo experimental models. Several upstream modulators, cross-reacting oncogenes, and downstream effectors of NPM-ALK have been identified and characterized. Understanding these interacting oncogenic systems is expected to facilitate the design of new therapeutic strategies and agents. In this review, we briefly discuss ALCL and focus on NPM-ALK.

scholarly journals Increased Tenascin C, Osteopontin and HSP90 Levels in Plasmatic Small Extracellular Vesicles of Pediatric ALK-Positive Anaplastic Large Cell Lymphoma: New Prognostic Biomarkers?

Diagnostics ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 253
Author(s):  
Federica Lovisa ◽  
Anna Garbin ◽  
Sara Crotti ◽  
Piero Di Battista ◽  
Ilaria Gallingani ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Enrichment Analysis ◽  
Heat Shock Protein 90 ◽  
Large Cell ◽  
Tenascin C ◽  
Anaplastic Lymphoma ◽  
Large Cell Lymphoma ◽  
Alk Positive

Over the past 15 years, several biological and pathological characteristics proved their significance in pediatric anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALCL) prognostic stratification. However, the identification of new non-invasive disease biomarkers, relying on the most important disease mechanisms, is still necessary. In recent years, plasmatic circulating small extracellular vesicles (S-EVs) gathered great importance both as stable biomarker carriers and active players in tumorigenesis. In the present work, we performed a comprehensive study on the proteomic composition of plasmatic S-EVs of pediatric ALCL patients compared to healthy donors (HDs). By using a mass spectrometry-based proteomics approach, we identified 50 proteins significantly overrepresented in S-EVs of ALCL patients. Gene Ontology enrichment analysis disclosed cellular components and molecular functions connected with S-EV origin and vesicular trafficking, whereas cell adhesion, glycosaminoglycan metabolic process, extracellular matrix organization, collagen fibril organization and acute phase response were the most enriched biological processes. Of importance, consistently with the presence of nucleophosmin (NPM)-ALK fusion protein in ALCL cells, a topological enrichment analysis based on Reactome- and Kyoto Encyclopedia of Genes and Genomes (KEGG)-derived networks highlighted a dramatic increase in proteins of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway in ALCL S-EVs, which included heat shock protein 90-kDa isoform alpha 1 (HSP90AA1), osteopontin (SPP1/OPN) and tenascin C (TNC). These results were validated by Western blotting analysis on a panel of ALCL and HD cases. Further research is warranted to better define the role of these S-EV proteins as diagnostic and, possibly, prognostic parameters at diagnosis and for ALCL disease monitoring.

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