TITLE:
Polycomb response element-binding sites in the MDR of CLL: Potential tumor suppressor regulation
AUTHORS:
Christine E. Cutucache, Javeed Iqbal, Philip J. Bierman, Robert Gregory Bociek, Dennis D. Weisenburger, Shantaram S. Joshi
KEYWORDS:
Chronic Lymphocytic Leukemia; Gene Expression; 13q14; Nullisomy; DLEU; Tolerogenic
JOURNAL NAME:
Advances in Bioscience and Biotechnology,
Vol.4 No.1A,
January
31,
2013
ABSTRACT: Chronic lymphocytic leukemia
[CLL] is the most common adult leukemia and is
heterogeneous in clinical presentation. CLL cases present with various chromosomal
aberrations, including 11q23, 14q32, 17p, and trisomy 12, with the most common
abnormality being deletion of 13q14 [1]. Although monoallelic deletion of 13q14
is common, there is a subset of patients who have complete nullisomy at 13q14,
a locus that has been hypothesized to contribute to CLL pa thogenesis [2] due to loss of tumor suppressors [DLEU and miR-15a/16-1]. We
hypothesized that deletion of both copies of 13q14 would lead to uncontrollable
proliferation of CLL cells and a poor prognosis. We examined our 13q14
nullisomy for survival, treatment-free survival, lymphocyte doubling time, and
the presence of lymphadenopathy. Furthermore, we compared the gene expression
profiles between patients with 13q14 monosomy, nullisomy, or normal karyotype.
Our results suggest that patients with 13q nullisomy have a higher incidence of
bulky lymphadenopathy [16.6% compared to 10% of monosomy patients], a higher
frequency of lymphocyte doubling time [27.7% compared to 7.4% of monosomy patients],
and a higher rate of needing treatment [50% compared to 18.5% of monosomy
patients]. We observed deletion of DLEU1 and HTR2A, consistent with a gene dosage effect,
and observed PRE-binding sites on DLEU1.
Patients with homozygous deletion of 13q14 had a worse prognosis compared to heterozygotes.
Lastly, the DLEU1 locus is a possible
“second hit” loss for CLL progression.