Detection of a TRAF1-ALK fusion in an anaplastic large cell lymphoma patient with chemotherapy and ALK inhibitor-resistant disease

Abstract

BackgroundThe anaplastic lymphoma kinase (ALK) gene encodes a receptor tyrosine kinase, which was first identified as the fusion partner of the nucleophosmin (NPM1) gene in the recurrent t(2;5)(p23;q35) found in a subset of anaplastic large cell lymphoma (ALCL). Several distinct, non-NPM1, ALK fusions have subsequently been described in lymphomas and other tumor types. All of these fusions result in the constitutive expression and activation of ALK and ALK signaling pathways, ultimately leading to the malignant phenotype.Case reportA non-NPM1 fusion partner of ALK was identified in a 32-year-old Caucasian male ALCL patient whose disease was refractory to standard chemotherapy and autologous stem cell transplantation, and exhibited a poor response to a first-generation ALK inhibitor. Non-allele-specific ALK RT-qPCR revealed ALK overexpression and 5′ RACE PCR revealed that the patient’s lymphoma expressed a TRAF1-ALK fusion.ConclusionsWe report the case of an ALCL patient whose tumor harbored the newly recognized TRAF1-ALK fusion and describe the clinical outcome after treatment with an ALK inhibitor. The short survival of our patient may reflect a propensity toward aggressive behavior in lymphomas that express this ALK fusion.

Genetic Alterations of TRAF Proteins in Human Cancers

“…There is only one fusion of the TRAF1 gene detected in human cancers, the TRAF1-ALK fusion that has been detected in five patients with anaplastic large cell lymphoma (ALCL) ( 16 – 19 ). All five cases contain the identical in frame fusion of TRAF1 and ALK that generates a chimeric protein linking the N-terminal 1–294 aa of TRAF1 to the entire intracellular domain of ALK (1,058–1,620 aa), including its kinase domain ( 16 – 19 ).…”

“…There is only one fusion of the TRAF1 gene detected in human cancers, the TRAF1-ALK fusion that has been detected in five patients with anaplastic large cell lymphoma (ALCL) ( 16 – 19 ). All five cases contain the identical in frame fusion of TRAF1 and ALK that generates a chimeric protein linking the N-terminal 1–294 aa of TRAF1 to the entire intracellular domain of ALK (1,058–1,620 aa), including its kinase domain ( 16 – 19 ). Interestingly, expression of the TRAF1-ALK fusion protein leads to constitutive activation of the ALK and NF-κB pathways as demonstrated by the elevated levels of phosphorylated ALK (pALK) and STAT3 (pSTAT3) as well as nuclear p50 NF-κB1 and p52 NF-κB2 in ALCL cells ( 18 ).…”

TRAF1-ALK fusion indicates poor prognosis to ALK tyrosine kinase inhibitors in relapsed/refractory ALK-positive anaplastic large-cell lymphoma patients

“…Thus, it was hypothesized that the TRAF1-ALK fusion pattern has different sensitivities to TKIs. Exons 7 and 8 of the TRAFI gene fused to exon 20 of the ALK gene identi ed in our patients has not been reported, while exons 5 and 6 of the TRAF1 gene fusion were reported recently [29][30][31] . In general, different kinds of fusion genes may be involved in distinct pathways or mechanisms that in uence the outcomes of patients.…”

“…The patient was successfully treated with high-dose chemotherapy and ASCT. Another case report presented a 32-year-old male patient who failed autologous transplantation and crizotinib treatment 30 . Similar to our patients, an improvement was observed 3 months after starting crizotinib, but he failed subsequent treatment, indicating that TKI activity is short in these patients.…”

Anaplastic large cell lymphoma: pathology, genetics, and clinical aspects

“…[200][201][202][203][204][205][206] In a pediatric phase I trial evaluating crizotinib for refractory solid tumors or ALCL, seven of nine (78%) patients with ALK-positive ALCL achieved CR. 207 Gambacorti-Passerini et al reported nine adult patients with refractory ALK-positive ALCL treated with crizotinib.…”