Cyclin D1 Overexpression in Hairy Cell Leukemia (HCL) Is Common and Not Related to Structural CCND1 Gene Rearrangements or Gene Amplification.
Justin L Seningen, David S Viswanatha, Rhett P Ketterling, Ryan A Knudson, James D Hoyer. Mayo Clinic, Rochester, MN
Background: HCL is a distinct chronic B-cell lymphoproliferative disorder characterized by splenic and bone marrow (BM) infiltration and excellent responses to cladribine monotherapy. Relatively little is understood regarding recurrent genetic abnormalities in HCL. Overexpression of the G1 cell cycle positive regulator cyclin D1 has been identified in a significant subset of HCL, the mechanism for which has not been clearly elucidated. A review of literature for HCL did not disclose a definitive study examining the possibility of CCND1 gene rearrangement or amplification in the context of cyclin D1 expression in HCL. To better understand the mechanism of cyclin D1 deregulation in HCL, we evaluated the CCND1 locus in cases of HCL and correlated our findings with relevant immunohistochemical (IHC) studies.
Design: Thirty-one cases of previously-diagnosed HCL with paraffin-embedded splenic tissue were available for review. IHC was performed using antibodies to cyclin D1, TRAP, and Annexin 1. Fluorescence in situ hybridization analysis was performed on 5 micron cut slides using a dual fusion/dual color (D-FISH) strategy to detect genomic rearrangements of the CCND1 locus and the IGH@ locus. The entire tissue was scanned for potential fusion signals or extra signals, and a minimum of 200 nuclei were scored by FISH. Splenic tissue was chosen due to suboptimal hybridization of FISH probes on decalcified BM biopsies.
Results: Twelve of the 31 cases of HCL splenic tissue produced no signals on D-FISH, most likely related to sample age (taken prior to 1992). No cases demonstrated fusion or extra signals for CCND1 or IGH@ by D-FISH. Twenty-three cases (74%) were positive for cyclin D1, 31 (100%) for Annexin, and 31 (100%) for TRAP.
Conclusions: The majority of HCL cases (74%) overexpress cyclin D1 protein to a variable degree, but the mechanism of deregulation is not attributable to detectable rearrangement or amplification of the CCND1 gene. Given the oncogenic properties of cyclin D1 overexpression, additional investigations regarding the molecular mechanisms underlying this process in HCL are of interest. Recent data indicate that in mantle cell lymphoma, cyclin D1 overexpression may be aberrantly regulated by the SOX11 transcription factor; we are exploring this possibility in HCL.
Wednesday, March 2, 2011 9:30 AM
Poster Session V # 170, Wednesday Morning