Identification of a novel fusion, SQSTM1-ALK, in ALK-positive large B-cell lymphoma.
ALK-positive large B-cell lymphoma is a rare subtype of lymphoma, and most cases follow an aggressive clinical course with a poor prognosis. We examined an ALK-positive large B-cell lymphoma case showing an anti-ALK immunohistochemistry pattern distinct from those of 2 known ALK fusions, CLTC-ALK and NPM-ALK, for the presence of a novel ALK fusion; this led to the identification of SQSTM1-ALK. SQSTM1 is an ubiquitin binding protein that is associated with oxidative stress, cell signaling, and autophagy. We showed transforming activities of SQSTM1-ALK with a focus formation assay and an in vivo tumorigenicity assay using 3T3 fibroblasts infected with a recombinant retrovirus encoding SQSTM1-ALK. ALK-inhibitor therapies are promising for treating ALK-positive large B-cell lymphoma, 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.
Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research. 3-8-31 Ariake, Koto, Tokyo 135-8550, Japan. kentakeuchi-tky@umin.net
Kengo
K
Takeuchi
Manabu
M
Soda
Yuki
Y
Togashi
Yasunori
Y
Ota
Yasunobu
Y
Sekiguchi
Satoko
S
Hatano
Reimi
R
Asaka
Masaaki
M
Noguchi
Hiroyuki
H
Mano
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use; D002472:Cell Transformation, Viral; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000627:therapeutic use; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007279:Injections, Subcutaneous; D016403:Lymphoma, Large B-Cell, Diffuse / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011239:Prednisolone / Q000008:administration & dosage / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D012190:Retroviridae; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000235:genetics; D014750:Vincristine / Q000008:administration & dosage / Q000627:therapeutic use
D048868:Adaptor Proteins, Signal Transducing; D015514:Oncogene Proteins, Fusion; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011239:Prednisolone; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases