AACR: Gene Expression in Good, Poor CLL Prognosis

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AACR Abstract Number: 431

Differential gene expression in chronic lymphocytic leukemia

subgroups with good prognosis versus poor prognosis

Avadhut D. Joshi, D. Dickinson, Javed Iqbal, Eudy,

Shantaram S. Joshi. University of Nebraska Medical Center, Omaha, NE.

B–cell chronic lymphocytic leukemia (B-CLL) is characterized by the

monoclonal expansion of CD5+/CD23+B cells in G0/G1 phase of the cell

cycle. Clinical course of B-CLL is very heterogenous with some

patients presenting indolent course while others exhibit an

aggressive disease.

An early prediction of clinical outcome would be very helpful in

developing an effective treatment strategy for CLL. In this regard,

gene expression profile of CLL cells might give the expression

patterns that are associated with prognosis. Therefore, in this study

we have analyzed leukemic cells from 32 B-CLL patients for their gene

expression profile using Clonetech AtlasTM Human Apoptosis cDNA

arrays and our own 10K oligonucleotide DNA microarray analyses.

The gene expression patterns of CLL cells from patients who had poor

prognosis based on lymphadenopathy, time to treatment, relapse (n =

15) were compared to patients who had good prognosis (n= 17). For

these analyses, unsupervised cluster analyses, supervised cluster

analyses and Mann-Whittney Test were used.

We selected a few genes that had significantly different expression

levels (P<0.05) in both these groups. These analyses showed that the

over-expression of genes like CDC2-related protein kinase (CHED), MAP

Kinase 3 (MAPK3), MAPK/ERK kinase 3 (MEKK3) were associated with poor

prognosis patients. CDC2 is associated with G2/M phase transition and

cell proliferation.

Several members of the MAP kinase pathway are known to be involved in

activation, proliferation, differentiation and apoptosis of B

lymphocytes. GAS-1 is a putative tumor suppressor gene. It blocks

entry to S phase and prevents cycling of normal and transformed

cells. Furthermore, these analyses of CLL cells showed that under

expression of GAS1 is associated with patients with poor prognosis.

The differential expression of certain genes that were identified in

DNA microarray analyses were confirmed using quantitative real-time

polymerase chain reaction. Thus, DNA microarray analyses of CLLs from

patient with aggressive disease versus non-aggressive disease

revealed that certain cell cycle associated and cell signaling

associated genes are differentially expressed.

These results also indicate that gene profiling of CLL cells at the

time of initial diagnosis might lead to effective treatment. In

addition, these results also suggest that some of the over-expressed

genes associated with poor prognosis can be targeted to eliminate

residual CLL cells which are often resistant to conventional therapy.

(This study was supported by the Elsa U. Pardee Foundation, Midlands

MI).

Presenter: Avadhut D. Joshi

Affiliation: University of Nebraska Medical Center, Omaha, NE; E-

mail: adjoshi@...

Copyright © 2004 American Association for Cancer Research. All rights

reserved. Citation information: Proceedings of the AACR, Volume 45,

March 2004.