scholarly journals Oncogene Overdose: Too Much of a Bad Thing for Oncogene-Addicted Cancer Cells

2015 ◽  
Vol 7s2 ◽  
pp. BIC.S29326
Author(s):  
Amit Dipak Amin ◽  
Soumya S. Rajan ◽  
Matthew J. Groysman ◽  
Praechompoo Pongtornpipat ◽  
Jonathan H. schatz
Keyword(s):  
Cell Lymphoma ◽  
Acquired Resistance ◽  
Large Cell ◽  
Tumor Control ◽  
Resistance Mutations ◽  
Oncogenic Signaling ◽  
Anaplastic Lymphoma ◽  
Clinical Scenarios ◽  
Targeted Inhibitors ◽  
Mutant Braf

Acquired resistance to targeted inhibitors remains a major, and inevitable, obstacle in the treatment of oncogene-addicted cancers. Newer-generation inhibitors may help overcome resistance mutations, and inhibitor combinations can target parallel pathways, but durable benefit to patients remains elusive in most clinical scenarios. Now, recent studies suggest a third approach may be available in some cases—exploitation of oncogene overexpression that may arise to promote resistance. Here, we discuss the importance of maintaining oncogenic signaling at “just-right” levels in cells, with too much signaling, or oncogene overdose, being potentially as detrimental as too little. This is highlighted in particular by recent studies of mutant-BRAF in melanoma and the fusion kinase nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) in anaplastic large cell lymphoma. Oncogene overdose may be exploitable to prolong tumor control through intermittent dosing in some cases, and studies of acute lymphoid leukemias suggest that it may be specifically pharmacologically inducible.

scholarly journals A novel model of controlling PD-L1 expression in ALK+ anaplastic large cell lymphoma revealed by CRISPR screening

Blood ◽  
2019 ◽  
Vol 134 (2) ◽  
pp. 171-185 ◽  
Author(s):  
Jing-Ping Zhang ◽  
Zhihui Song ◽  
Hong-Bo Wang ◽  
Lang Lang ◽  
Yuan-Zhong Yang ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Anaplastic Large Cell Lymphoma ◽  
Immune Escape ◽  
Cell Lymphoma ◽  
Critical Role ◽  
Large Cell ◽  
Oncogenic Signaling ◽  
Tumor Immune Escape ◽  
Anaplastic Lymphoma ◽  
Large Cell Lymphoma

Abstract The success of programmed cell death protein 1 (PD-1)/PD-L1-based immunotherapy highlights the critical role played by PD-L1 in cancer progression and reveals an urgent need to develop new approaches to attenuate PD-L1 function by gaining insight into how its expression is controlled. Anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALK+ ALCL) expresses a high level of PD-L1 as a result of the constitutive activation of multiple oncogenic signaling pathways downstream of ALK activity, making it an excellent model in which to define the signaling processes responsible for PD-L1 upregulation in tumor cells. Here, using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 library screening, we sought a comprehensive understanding of the molecular effectors required for PD-L1 regulation in ALK+ ALCL. Indeed, we determined that PD-L1 induction is dependent on the nucleophosmin-ALK oncoprotein activation of STAT3, as well as a signalosome containing GRB2/SOS1, which activates the MEK-ERK and PI3K-AKT signaling pathways. These signaling networks, through STAT3 and the GRB2/SOS1, ultimately induce PD-L1 expression through the action of transcription factors IRF4 and BATF3 on the enhancer region of the PD-L1 gene. IRF4 and BATF3 are essential for PD-L1 upregulation, and IRF4 expression is correlated with PD-L1 levels in primary ALK+ ALCL tissues. Targeting this oncogenic signaling pathway in ALK+ ALCL largely inhibited the ability of PD-L1-mediated tumor immune escape when cocultured with PD-1-positive T cells and natural killer cells. Thus, our identification of this previously unrecognized regulatory hub not only accelerates our understanding of the molecular circuitry that drives tumor immune escape but also provides novel opportunities to improve immunotherapeutic intervention strategies.

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.

scholarly journals Analysis with antiidiotype antibody of a patient with chronic lymphocytic leukemia and a large cell lymphoma (Richter's syndrome)

Blood ◽  
1987 ◽  
Vol 70 (1) ◽  
pp. 45-50 ◽  
Author(s):  
LF Bertoli ◽  
H Kubagawa ◽  
GV Borzillo ◽  
M Mayumi ◽  
JT Prchal ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Plasma Cells ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Lymphocytic Leukemia ◽  
Immunoglobulin Gene ◽  
Anaplastic Lymphoma ◽  
Large Cell Lymphoma ◽  
Richter’S Syndrome

Abstract A murine monoclonal antibody made against an idiotypic determinant (Id) of surface IgM/IgD lambda molecules on chronic lymphocytic leukemia (CLL) cells of a 71-year-old woman was used for clonal analysis by two- color immunofluorescence. The anti-Id antibody identified IgM+/IgD+/lambda+ B cells as the predominant cell type of her CLL clone. In addition, substantial proportions of the IgG and IgA B cells and most of the IgM plasma cells in her bone marrow and blood were Id+. Six years after diagnosis, the patient died of respiratory failure due to infiltration of lungs by malignant cells. Autopsy revealed a dramatic change in the tumor cell morphology. The lungs, hilar nodes, and liver were infiltrated by a diffuse large cell lymphoma admixed with the leukemic cells. By immunohistologic staining these anaplastic lymphoma cells were IgM+/IgD-/lambda+ B cells expressing the same Id noted earlier on the CLL cells. The immunoglobulin gene rearrangement pattern on Southern blot analysis was also the same in leukemic blood cells and in the tissues involved by the lymphoma. Thus, the combination of antiidiotype and immunoglobulin gene analyses in this patient with Richter's syndrome revealed that a CLL clone, seemingly “frozen” in differentiation, was actually undergoing isotype switching, differentiation into plasma cells, and evolution into a rapidly growing and fetal lymphoma.

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.

Anaplastic Large Cell Lymphoma Arising in Bone

2000 ◽  
Vol 124 (9) ◽  
pp. 1339-1343
Author(s):  
Mark A. Lones ◽  
Warren Sanger ◽  
Sherrie L. Perkins ◽  
L. Jeffrey Medeiros
Keyword(s):  
T Cell ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Correct Diagnosis ◽  
Cell Lineage ◽  
Antigen Expression ◽  
Large Cell ◽  
Null Cell ◽  
Anaplastic Lymphoma ◽  
Large Cell Lymphoma

Abstract Anaplastic large cell lymphoma (ALCL) represents approximately 2% of all non-Hodgkin lymphomas according to the recent Non-Hodgkin Lymphoma Classification Project. As defined in the revised European-American classification of lymphoid neoplasms (REAL), ALCL is a neoplasm of T-cell or null-cell lineage; 20% to 60% of cases are associated with the t(2;5)(p23;q35) translocation. ALCL commonly involves nodal as well as a wide variety of extranodal sites, although primary or secondary involvement of bone is rare. We describe the case of a 71-year-old man with stage IE T-cell ALCL, monomorphic variant, arising in the left anterior fifth rib and involving adjacent soft tissue without other sites of disease. The monomorphic histologic features hindered the initial recognition of this neoplasm as ALCL. However, strong uniform CD30 antigen expression and subsequent demonstration of the t(2;5)(p23;q35) translocation and anaplastic lymphoma kinase (ALK) immunoreactivity led to the correct diagnosis. We identified only 5 reported cases of T-cell and null-cell ALCL arising in bone and only 2 of these cases involved a single bone site. All 5 previously reported cases were ALCL of the classic type. We report a case of ALCL that is unique to our knowledge. This case of monomorphic ALCL was localized to bone and tumor cells contained the t(2;5)(p23;q35) translocation.

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