Gene expression profiling defines a high-risk entity of multiple myeloma

Donna D and Donald M Lambert Laboratory of Myeloma Genetics at the Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences 05/2007; 32(2):191-203.
Source: PubMed


Multiple myeloma (MM) is the second most common hematological malignancy and remains incurable. The marked variation in survival of patients with symptomatic myeloma ranging from few months to more than 15 years can be explained by differences in tumor mass, proliferative activity and, more recently, by cytogenetic and molecular genetic characteristics of the myeloma clone. Oligonucleotide microarray-based gene expression analysis was applied to CD138-enriched plasma cells from newly diagnosed patients with symptomatic or progressive multiple myeloma treated with melphalan-based high-dose therapy. Here we discuss recent progress made in the development of molecular-based diagnostics and prognostics for MM from Myeloma Institute for Research and Therapy of University Arkansas for Medical Sciences, where we treat more patients with myeloma than anywhere else in the world. Seven distinct entities of myeloma were elucidated by genomic profiling. Expression extremes of 70 genes from a high-risk signature profile,30% of which were derived from chromosome 1, were strongly linked to disease-related survival. CKS1B located on chromosome 1q21, responsible for promoting cell cycle progression by inducing the degradation of p27Kip1, represented a strong candidate gene related to rapid patient death and was studied in detail. The data suggest that CKS1B influences myeloma cell growth and survival through SKP2j and P27(Kip1) -dependent and independent mechanisms and that therapeutic strategies aimed at abolishing CKS1B function may hold promise for the treatment of high-risk disease for which effective therapies are currently lacking.

1 Read
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: M icroarrays used for measuring chromosomal aberrations in genomic DNA and for defining gene expression patterns have become almost routine. A microarray consists of an arrayed series of microscopic spots each containing either DNA or protein molecules known as feature reporters. Advances in microarray fabrication and in feature detection systems, such as high-resolution scanners and their associated software, lead to high-throughput screening of the genome or the tran-scriptome of a cell or a group of cells in only few days. Despite the potential of high-density microarrays, several problems about data interpretation are still to be solved. In addition, targeted microarrays are shown to be useful tools for rapid and accurate diagnosis of diseases. The aim of this review was to discuss the impact of microarrays on different application levels from the definition of disease biomarkers to pharmaceutical and clinical diagnostics.
    Journal of the Association for Laboratory Automation 10/2010; 15(5):405-13. DOI:10.1016/j.jala.2010.06.011 · 1.50 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To investigate the prevlance of 1q21 amplification in patients with multiple myeloma (MM) and its correlation with the progression and prognosis of the disease. 1q21 amplification was detected in 48 patients with MM using cytoplasmic light chain immunofluorescence with fluorescence in situ hybridization analysis (cIg-FISH) and interphase fluorescence in situ hybridization (I-FISH) analysis combined with CD138 immunomagnetic cell sorting (MACS). 1q21 amplification (≥ 3 red signals) was detected in 26/48(54.2%) cases by cIg-FISH and 31/48 (64.6%) cases by I-FISH combined with CD138 MACS. There was a good consistency between the two methods (P>0.05). The mortality of patients with 1q21 amplification was significantly higher than those without (P< 0.05). No significant difference was detected in terms of sex, age, Durie-Salmon stage, subgroup and international staging system (ISS) stage between patients with 1q21 amplification and those without (P>0.05). The frequency of 1q21 amplification in MM is high. There was also an association between the amplification and poor prognosis. cIg-FISH is consistent with CD138 MACS combined with I-FISH.
    Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 12/2011; 28(6):686-9. DOI:10.3760/cma.j.issn.1003-9406.2011.06.020
  • [Show abstract] [Hide abstract]
    ABSTRACT: Phosphoinositide phosphatases comprise several large enzyme families with over 35 mammalian enzymes identified to date that degrade many phosphoinositide signals. Growth factor or insulin stimulation activates the phosphoinositide 3-kinase that phosphorylates phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P(2)] to form phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P(3)], which is rapidly dephosphorylated either by PTEN (phosphatase and tensin homologue deleted on chromosome 10) to PtdIns(4,5)P(2), or by the 5-phosphatases (inositol polyphosphate 5-phosphatases), generating PtdIns(3,4)P(2). 5-phosphatases also hydrolyze PtdIns(4,5)P(2) forming PtdIns(4)P. Ten mammalian 5-phosphatases have been identified, which regulate hematopoietic cell proliferation, synaptic vesicle recycling, insulin signaling, and embryonic development. Two 5-phosphatase genes, OCRL and INPP5E are mutated in Lowe and Joubert syndrome respectively. SHIP [SH2 (Src homology 2)-domain inositol phosphatase] 2, and SKIP (skeletal muscle- and kidney-enriched inositol phosphatase) negatively regulate insulin signaling and glucose homeostasis. SHIP2 polymorphisms are associated with a predisposition to insulin resistance. SHIP1 controls hematopoietic cell proliferation and is mutated in some leukemias. The inositol polyphosphate 4-phosphatases, INPP4A and INPP4B degrade PtdIns(3,4)P(2) to PtdIns(3)P and regulate neuroexcitatory cell death, or act as a tumor suppressor in breast cancer respectively. The Sac phosphatases degrade multiple phosphoinositides, such as PtdIns(3)P, PtdIns(4)P, PtdIns(5)P and PtdIns(3,5)P(2) to form PtdIns. Mutation in the Sac phosphatase gene, FIG4, leads to a degenerative neuropathy. Therefore the phosphatases, like the lipid kinases, play major roles in regulating cellular functions and their mutation or altered expression leads to many human diseases.
    Sub-cellular biochemistry 01/2012; 58:215-79. DOI:10.1007/978-94-007-3012-0_7
Show more