Pan-HDAC Inhibitors May Restore PRDM1 Expression in Follicular Lymphoma

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SiRNA BMP7 had a negative effect on cell survival at all time points assessed with both drugs showing that BMP7 plays a role in drug resistance.

<p>Jeko cells were exposed with Bortezomib (5 ng/ml) or Cytarabine (20 µg/ml) 24h or 48h after transfection with a BMP7 siRNA or a nonsilencing siRNA used as a control (see material and methods). BMP7 protein expression was assessed by immunoblotting analyzes. Annexin V- and PI-negative cells (non apoptotic) were quantified 48h and 72h after transfection. BMP7 siRNA markedly increased the fraction of annexin V- and PI-negative cells showing that BMP7 suppression plays a role in Jeko cell chemosensitivity to Bortezomib and Cytarabine.</p

Large-scale nuclear remodeling and transcriptional deregulation occur on both derivative chromosomes after Mantle Cell Lymphoma chromosomal translocation

Recurrent chromosomal translocations are found in many blood and solid cancers. Balanced translocations, frequent in lymphoid malignancies, lead to the formation of two aberrant derivative (der) chromosomes. This event often leads to overexpression of an oncogene. In many cases, the expression of an oncogene is not enough to produce a malignant phenotype; however, most part of the studies focus on the events involving the chromosome where the oncogene is located, but rarely the other der chromosome where other oncogenic alterations may potentially arise. Mantle cell lymphoma (MCL), an aggressive B-cell non-Hodgkin lymphoma, is a perfect example of this. In 85% of the cases, it is characterized by the translocation t(11;14), which leads to the overexpression of cyclin D1 ( CCND1 ) gene which results juxtaposed to the immunoglobulin heavy chain ( IGH ) gene on the der14 chromosome. This feature alone is not sufficient to induce oncogenesis. Here we focused on the der11 chromosome. We demonstrated that expression of 88 genes located in a 15mb region close to the translocation breakpoint on the der11 was deregulated both in the GRANTA-519 MCL cell line and in B-cells from MCL patients. We found that a large segment of der11containing deregulated genes was relocated from its normal position in the nuclear periphery towards the center of the nucleus in close proximity to the nucleolus where the abundant nucleolar protein nucleolin binds a subset of genes located close to the breakpoint and activates their expression. This finding allowed to identify new potential oncogenes involved in MCL and the mechanisms of their upregulation

Gene expression ratios were calculated for each gene in primary refractory (non-responders) and in responders (secondary resistant).

<p>Gene expression ratio is equal to the geometric mean gene expression after treatment divided by the geometric mean gene expression before treatment. Gene expression ratios greater than one correspond to increased expression after treatment and conversely. Each point on the figure corresponds to a gene expression ratio in responders according to the expression ratio in non-responders. Nine genes classified as relevant (see methods) are symbolized by black dots. BMP7 which was selected for further investigations is symbolized by a red dot. Small grey symbols were used for “Other genes”.</p

A: Expression of mRNAs encoding BMP7 tested by RT-PCR performed on 1: UPN1, 2: Jeko, 3: Rec-1, 4: GRANTA-519 and 5: placenta (positive control).

<p>B: methylation profile of BMP-7 CpG islands in the cell line C: UPN1, Jeko, Rec-1 and GRANTA-519 cells were cultured in serum-free media in the presence or absence of 200 ng/ml of BMP-7 for 7 days. BMP-7 had no effect on Jeko, GRANTA-519 and Rec-1 cell survival and on annexin V-positive cells compared to serum-free media alone.</p