Pediatric ALK+ anaplastic large cell lymphoma with t(3;8)(q26.2;q24) translocation and c‐myc rearrangement terminating in a leukemic phase

Abstract

Pediatric ALK-positive anaplastic large cell lymphoma (ALK+ ALCL) is usually associated with a favorable prognosis. ALK+ ALCL associated with a leukemic phase is uncommon, but has been associated with an aggressive clinical course and unfavorable prognosis. Overexpression of c-myc has been shown to be a consistent finding in ALK+, but not ALK-negative ALCL (ALKÀ ALCL), and the c-myc gene is considered a downstream target of deregulated ALK signaling. We describe a pediatric ALK+ ALCL with a leukemic phase at relapse. Similar to other rare cases described in the literature, it followed an aggressive clinical course despite multiple regimens of chemotherapy and bone marrow transplantation. Lymphoma cells showed aberrant ALK expression and c-myc overexpression. In addition to the characteristic t(2;5)(p23;q35) translocation, a t(3;8)(q26.2;q24) translocation was also present, and c-myc

A novel patient-derived tumorgraft model with TRAF1-ALK anaplastic large-cell lymphoma translocation

“…Although many ALK+ ALCL patients reach clinical remission, few refractory {Savage, 2008 #1044} and rare aggressive forms, carrying translocations or copy number gains of MYC {Monaco, 2007 #939}, have been described {Grewal, 2007 #790;Monaco, 2007 #939;Liang, 2013 #1195;Moritake, 2011 #941}.…”

“…The loss of TP53 , PRDM1/Blimp1 {Boi, 2013 #1207} and TP63 {Vasmatzis, 2012 #1132} and deregulated expression of MYC {Monaco, 2007 #939} might pinpoint at diagnosis refractory/relapse or even aggressive forms of ALCL. In our PDT model, the emergency of subclones carrying defects of PRDM1/Blimp1 and MYC support the hypothesis that these lesions may have a relevant pathogenetic role and might occur as additional event along tumorigenesis contributing to more aggressive phenotype.…”

“…Although the long-term clinical outcome for the majority of ALK+ ALCL patients is relatively favorable {Savage, 2008 #1044;Schmitz, 2010 #1194}, some patients can have a highly aggressive disease. Clinical development can include rapid nodal dissemination, extranodal involvement or even frank leukemic presentation {Monaco, 2007 #939;Liang, 2013 #1195}. Moreover, 20–30% of ALK+ ALCL patients relapse and eventually require high dose chemotherapies and bone marrow transplantation {Savage, 2008 #1044;Schmitz, 2010 #1194;Ferreri, 2012 #1193}.…”

“…Conversely, aggressive ALK+ cases have a large spectrum of chromosomal defects, frequently involving chromosome 8q, suggesting that the deregulated expression of MYC might leads to unfavorable clinical outcome {Grewal, 2007 #790;Monaco, 2007 #939;Liang, 2013 #1195;Moritake, 2011 #941}.…”

Essential role of IRF4 and MYC signaling for survival of anaplastic large cell lymphoma

“…Translocations affecting MYC are infrequent in these lymphomas and seem to be associated with an aggressive clinical course. [39][40][41] In contrast, a recent study using array comparative genomic hybridization on primary ALCL samples reported recurrent MYC gains. 42 In addition, other MYC upregulating mechanisms may be used by ALCL.…”