Identification of a novel fusion, SQSTM1-ALK, in ALK-positive large B-cell lymphoma

Takeuchi, Kengo; Soda, Manabu; Togashi, Yosuke; Ota, Yasunori; Sekiguchi, Y.; Hatano, Satoko; Asaka, Reimi; Noguchi, Masaaki; Mano, Hiroyuki

doi:10.3324/haematol.2010.033514

Cited by 89 publications

(59 citation statements)

References 23 publications

(16 reference statements)

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“…2D). The coiled-coil domain is shared in all ALK fusion partners (except for NPM, MSN, and SQSTM1), with which the ALK fusion proteins homodimerize leading to constitutive activation of ALK kinase domains (8,19). As expected, in the present study, the oncogenicity of PPFIBP1-ALK was clearly confirmed with an in vitro focus formation assay and an in vivo tumorigenicity assay.…”

Section: Discussionsupporting

confidence: 69%

“…1-10), ALK has further been found to generate fusions in inflammatory myofibroblastic tumor (IMT; TPM3, TPM4, CLTC, CARS, RANBP2, ATIC, or SEC31L1; refs. [10][11][12][13][14][15], ALK-positive large B-cell lymphoma (CLTC, NPM, SEC31L1, or SQSTM1; [16][17][18][19], lung cancer (EML4 or KIF5B; refs. 20,21), and ALK-positive histiocytosis (TPM3; ref.…”

Section: Introductionmentioning

confidence: 99%

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Pulmonary Inflammatory Myofibroblastic Tumor Expressing a Novel Fusion, PPFIBP1–ALK: Reappraisal of Anti-ALK Immunohistochemistry as a Tool for Novel ALK Fusion Identification

Takeuchi

Soda

Togashi

et al. 2011

Clinical Cancer Research

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Purpose: The anaplastic lymphoma kinase (ALK) inhibitor crizotinib has been used in patients with lung cancer or inflammatory myofibroblastic tumor (IMT), both types harboring ALK fusions. However, detection of some ALK fusions is problematic with conventional anti-ALK immunohistochemistry because of their low expression. By using sensitive immunohistochemistry, therefore, we reassessed "ALK-negative" IMT cases defined with conventional immunohistochemistry (approximately 50% of all examined cases).Experimental Design: Two cases of ALK-negative IMT defined with conventional anti-ALK immunohistochemistry were further analyzed with sensitive immunohistochemistry [the intercalated antibodyenhanced polymer (iAEP) method].Results: The two "ALK-negative" IMTs were found positive for anti-ALK immunohistochemistry with the iAEP method. 5 0 -rapid amplification of cDNA ends identified a novel partner of ALK fusion, proteintyrosine phosphatase, receptor-type, F polypeptide-interacting protein-binding protein 1 (PPFIBP1) in one case. The presence of PPFIBP1-ALK fusion was confirmed with reverse transcriptase PCR, genomic PCR, and FISH. We confirmed the transforming activities of PPFIBP1-ALK with a focus formation assay and an in vivo tumorigenicity assay by using 3T3 fibroblasts infected with a recombinant retrovirus encoding PPFIBP1-ALK. Surprisingly, the fusion was also detected by FISH in the other case. Conclusions: Sensitive immunohistochemical methods such as iAEP will broaden the potential value of immunohistochemistry. The current ALK positivity rate in IMT should be reassessed with a more highly sensitive method such as iAEP to accurately identify those patients who might benefit from ALK-inhibitor therapies. Novel ALK fusions are being identified in various tumors in addition to IMT, and thus a reassessment of other "ALK-negative" cancers may be required in the forthcoming era of ALK-inhibitor therapy.

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Section: Discussionsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Pulmonary Inflammatory Myofibroblastic Tumor Expressing a Novel Fusion, PPFIBP1–ALK: Reappraisal of Anti-ALK Immunohistochemistry as a Tool for Novel ALK Fusion Identification

Takeuchi

Soda

Togashi

et al. 2011

Clinical Cancer Research

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“…24,25 Activated ALK, usually in the form of highly expressed chimeric oncoproteins, is the main oncogenic driver of these neoplasms, which are hence sensitive to therapeutic inhibition with ALK-specific small molecule inhibitors. 26 Epithelioid fibrous histiocytoma is a benign tumor, which virtually always pursues an indolent clinical course; however, the extremely rare occurrence of metastasis of morphologically benign fibrous histiocytoma has been described in one case showing epithelioid morphology.…”

Section: Discussionmentioning

confidence: 99%

ALK rearrangement and overexpression in epithelioid fibrous histiocytoma

et al. 2015

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Epithelioid benign fibrous histiocytoma, also known as 'epithelioid cell histiocytoma,' has traditionally been considered a morphologic variant of cutaneous fibrous histiocytoma (dermatofibroma). In addition to its characteristic epithelioid cytomorphology, several phenotypic differences suggest that epithelioid fibrous histiocytoma may differ biologically from other variants. Recently, ALK rearrangement was described in two cases of epithelioid fibrous histiocytoma and separately in two cases reported as 'atypical' fibrous histiocytoma (with epithelioid features), with corresponding ALK expression detectable by immunohistochemistry. The goals of this study were to determine the frequency of ALK expression by immunohistochemistry in epithelioid fibrous histiocytoma, to determine its value for the diagnosis of epithelioid fibrous histiocytoma among variants and other histologic mimics, and to evaluate ALK gene rearrangement in epithelioid fibrous histiocytoma. ALK protein expression was evaluated in whole tissue sections from 33 epithelioid fibrous histiocytomas, 41 other cases of fibrous histiocytoma (11 conventional and 10 each cellular, atypical, and aneurysmal types), 10 cutaneous syncytial myoepitheliomas, and 5 atypical fibroxanthomas, using a mouse anti-ALK monoclonal antibody. Fluorescence in situ hybridization (FISH) was performed using break-apart probes. In total, 29/33 (88%) cases of epithelioid fibrous histiocytoma showed diffuse cytoplasmic ALK expression. Staining was moderate to strong in intensity in all cases except one, which showed diffuse weak expression. All other tumor types were negative for ALK expression. FISH demonstrated ALK rearrangement in all ALK-immunoreactive cases evaluated (n = 13), and not in one ALK expression-negative epithelioid fibrous histiocytoma successfully examined. In conclusion, the majority of epithelioid fibrous histiocytomas demonstrate ALK expression and ALK gene rearrangement. ALK expression is not seen in other variants of fibrous histiocytoma, providing a useful diagnostic tool to distinguish epithelioid fibrous histiocytoma from most histologic mimics. The expression of ALK suggests that epithelioid fibrous histiocytoma is a biologically distinct tumor type, unrelated to conventional fibrous histiocytoma and histologic variants. Modern Pathology (2015) 28, 904-912;

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“…The nucleophosmin (NPM)anaplastic lymphoma kinase (ALK) fusion protein was first identified as a neoplastic agent in patients with anaplastic large cell lymphoma (ALCL) [Shiota and Mori, 1996;Shiota et al 1995;Morris et al 1994], with the NPMALK protein resulting from the translocation t(2,5)(p23:q35), between the ALK gene on chromosome 2 and the NPM gene on chromosome 5 [Lamant et al 1996;Shiota and Mori, 1996]. ALK has since been linked with many different fusion partners in different tumor types, including TRK-fused gene (TFG), tropomyosin (TPM)3, TPM4, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), and moesin (MSN) in ALCL; TPM3, TPM4, cysteinyl tRNA synthetase (CARS), Ranbinding protein 2 (RANBP2), and clathrin heavy chain gene (CLTC) in inflammatory myofibroblastic tumor; a variety of ALKamplifying point mutations in neuroblastoma; TPM4 in esophageal squamous tumor; SQSTM1ALK fusion, CLTC, and NPM in diffuse large B-cell lymphoma; and echinoderm microtubule-associated protein-like 4 (EML4) and kinesin family member 5B (KIF5B) in NSCLC [Takeuchi et al 2011[Takeuchi et al , 2009Palmer et al 2009;Webb et al 2009;Mossé et al 2008;Coffin et al 2007;Rikova et al 2007;Soda et al 2007;Jazii et al 2006;Li et al 2004;Ma et al 2003;Onciu et al 2003;Gascoyne et al 2003;Drexler et al 2000]. A further solid tumor ALK fusion (VCLALK in renal cell carcinoma) has also recently been reported [Debelenko et al 2011].…”

Section: Introductionmentioning

confidence: 99%

The potential for crizotinib in non-small cell lung cancer: a perspective review

Bang

2011

Ther Adv Med Oncol

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Tyrosine kinases have a crucial role as key regulators of signaling pathways that influence cell differentiation and growth. Dysregulation of tyrosine kinase-mediated signaling is understood to be an important oncogenic driver. Genetic rearrangements involving the tyrosine kinase anaplastic lymphoma kinase (ALK) gene occur in non-small cell lung cancer (NSCLC), anaplastic large cell lymphomoas, inflammatory myofibroblastic tumors, and other cancers. Cells with abnormal ALK signaling are sensitive to ALK inhibitors such as crizotinib. This review will highlight the discovery of the fusion between echinoderm microtubuleassociated protein-like 4 (EML4) and ALK as an oncogenic driver, recognition of other ALK gene rearrangements in NSCLC, and the confirmation that crizotinib is an effective treatment for patients with ALK-positive NSCLC. Work is underway to further define the role for crizotinib in the treatment of ALK-positive lung cancer and other cancers and to investigate the molecular mechanisms for resistance to ALK inhibition with crizotinib.

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Identification of a novel fusion, SQSTM1-ALK, in ALK-positive large B-cell lymphoma

Abstract: especially for refractory cases. SQSTM1-ALK may be a rare fusion, but our data provide novel biological insights and serve as a key for the accurate diagnosis of this rare lymphoma.

Cited by 89 publications

References 23 publications

Pulmonary Inflammatory Myofibroblastic Tumor Expressing a Novel Fusion, PPFIBP1–ALK: Reappraisal of Anti-ALK Immunohistochemistry as a Tool for Novel ALK Fusion Identification

Pulmonary Inflammatory Myofibroblastic Tumor Expressing a Novel Fusion, PPFIBP1–ALK: Reappraisal of Anti-ALK Immunohistochemistry as a Tool for Novel ALK Fusion Identification

ALK rearrangement and overexpression in epithelioid fibrous histiocytoma

The potential for crizotinib in non-small cell lung cancer: a perspective review

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