MLL translocation in two castration-resistant prostate cancer (CRPC) patients.

Abstract

186 Background: The mixed-lineage leukemia (MLL) protein is a histone methyltransferase that regulates multiple genetic elements. Chromosomal rearrangements of the MLL gene result in expression of MLL-fusion proteins that occur in a subset of acute leukemias and are associated with poor prognosis. The MLL protein complex has been shown to interact with the androgen receptor via the MLL-menin subunit and, in model systems, MLL-menin inhibition blocks CRPC growth. We describe 2 cases of metastatic CRPC with a translocation in the MLL gene. Methods: In our institution, fluorescence in situ hybridization (FISH) testing of bone marrow specimens is routinely performed using the MLL Breakapart probe from Cytocell, Ltd (Cambridge, UK). The probe consisted of an 87 kb segment labeled in red that covered a region telomeric to the MLL locus and a 168 kb segment labeled in green centromeric to MLL. The FISH assay was performed according to manufacturer’s instructions. Results: MLL translocation was found coincidentally in 2 patients. The first was a 50 year old male with CRPC who had progressed on abiraterone and multiple chemotherapy regimens. A bone marrow biopsy was done to evaluate pancytopenia and pathology revealed metastatic prostate cancer marrow infiltration, without any evidence of leukemia or myelodysplasia. FISH studies revealed a rearrangement of the MLL locus using the MLL Breakapart probe. The second patient was a 77 year old male with metastatic CRPC who had also progressed through multiple hormonal and chemotherapy regimens. Bone marrow biopsy was done to evaluate thrombocytopenia and pathology revealed metastatic prostate cancer occupying nearly 100% of the marrow. Cytogenetics revealed complex karyotype and FISH was positive for MLL gene rearrangement by the same assay. There was no evidence of leukemia or myelodysplasia in either case. Conclusions: Translocation of the MLL gene is well documented in leukemia but has not been described in CRPC. Additional studies are warranted regarding the frequency and importance of this potential therapeutic target.