RANBP2/ALK Rearrangement Is a New Rare but Recurrent Fusion Gene in Childhood Myeloid Disorders.

The ALK gene which is typically rearranged in anaplastic large cell lymphoma (ALCL) and inflammatory myofibroblastic tumor (IMT) is located in the band 2p23. An involvement of this band was detected in 6 patients (0.35%) when we checked the cytogenetic database of our laboratory with approximately 1500 successfully analyzed karyotypes of childhood AML and MDS. Patient 1 had a t(2;4)(p23;q27) and patient 2 showed a del(2)(p23). In both cases, the 2p23 abnormality was part of a complex karyotype that included several non-specific alterations. Among the remaining four children, three (pts. 3–5) showed an inv(2)(p23q13) and patient 6 a t(2;2)(p23;q13). We performed a hybridization using the LSI ALK Dual Color Break Apart Rearrangement Probe (Vysis, Downers Grove, IL) onto all six patients. Whereas in the nuclei of pts 1, 2, 3 two normal fusion signals were found, a split hybridization signal showed the ALK involvement in the inv(2) and the t(2;2) of patients 4, 5 and 6. The latter case was further analyzed using chromosome arm-specific painting probes and this approach also confirmed the translocation. For the identification of the partner gene we used the primers for RANBP2/ALK which were described for IMT. In all patients with ALK involvement a PCR product was found and the sequencing identified identical breakpoints within the ALK and RANBP2 gene. In addition, a FISH and RT-PCR screening was performed in 20 children with AML or MDS, but no ALK involvement could be detected. All 3 ALK rearranged patients were originally diagnosed as myeloid disease (AML/MDS), but showed different unspecific morphological features. To the best of our knowledge this is the first description of an inv(2)(p23q13) and a t(2;2)(p23;q13) and the first report of an RANBP2/ALK rearrangement in childhood AML/MDS. Further studies will help to elucidate the role of this rearrangement in pediatric leukemia.