Polycomb response element-binding sites in the MDR of CLL: Potential tumor suppressor regulation

Abstract

<p style="text-align:justify;"> <span style="font-size:12px;">Chronic lymphocytic leukemia [CLL] is the most </span><span style="font-size:10.0pt;"><span style="font-size:12px;">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 </span><span style="font-size:12px;">thogenesis [2] due to loss of tumor suppressors</span><span style="font-size:12px;"> [</span><i><span style="font-size:12px;">DLEU</span></i><span style="font-size:12px;"> and </span><i><span style="font-size:12px;">miR</span></i><span style="font-size:12px;">-15</span><i><span style="font-size:12px;">a</span></i><span style="font-size:12px;">/16-1]</span><i><span style="font-size:12px;">. </span></i><span style="font-size:12px;">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 </span><i><span style="font-size:12px;">DLEU</span></i><span style="font-size:12px;">1</span><i> </i><span style="font-size:12px;">and </span><i><span style="font-size:12px;">HTR</span></i><span style="font-size:12px;">2</span><i><span style="font-size:12px;">A</span></i><i><span style="font-size:12px;">, </span></i><span style="font-size:12px;">consistent with a gene dosage effect, and observed PRE-binding sites on</span><i><span style="font-size:12px;"> DLEU</span></i><span style="font-size:12px;">1. Patients with homozygous deletion of 13q14 had a worse prognosis compared to heterozygotes. Lastly, the </span><i><span style="font-size:12px;">DLEU</span></i><span style="font-size:12px;">1 locus is a possible “second hit” loss for CLL progression.</span></span> </p