Continuous absence of metaphase-defined cytogenetic abnormalities, especially of chromosome 13 and hypodiploidy, ensures long-term survival in multiple myeloma treated with Total Therapy I: interpretation in the context of global gene expression

Blood ◽  
2003 ◽  
Vol 101 (10) ◽  
pp. 3849-3856 ◽  
Author(s):  
John Shaughnessy ◽  
Joth Jacobson ◽  
Jeff Sawyer ◽  
Jason McCoy ◽  
Athanasios Fassas ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Multiple Myeloma ◽  
Global Gene Expression ◽  
Cell Cycle Gene ◽  
Term Survival ◽  
Cytogenetic Abnormalities ◽  
Chromosome 13 ◽  
Prognostic Implications ◽  
Total Therapy

Abstract Metaphase cytogenetic abnormalities (CAs), especially of chromosome 13 (CA 13), confer a grave prognosis in multiple myeloma even with tandem autotransplantations as applied in Total Therapy I, which enrolled 231 patients between 1989 and 1994. With a median follow-up of almost 9 years, the prognostic implications of all individual CAs, detected prior to treatment and at relapse, were investigated. Among all CAs and standard prognostic factors examined prior to therapy, only hypodiploidy and CA 13 (hypo–13 CA), alone or in combination, were associated with shortest event-free survival and overall survival (OS). The shortest postrelapse OS was observed with hypo–13 CA, which was newly detected in 18 of all 28 patients presenting with this abnormality at relapse. Superior prognosis was associated with the absence of any CA at both diagnosis and relapse (10-year OS, 40%). The lack of independent prognostic implications of other CAs points to a uniquely aggressive behavior of hypo–13 CA (present in 16% of patients at diagnosis). With the use of microarray data in 146 patients enrolled in Total Therapy II, overexpression of cell cycle genes distinguished CA from no CA, especially in cases of del(13) detected by interphase fluorescence in situ hybridization (FISH). FISH 13, resulting in a haploinsufficiency of RB1 and other genes mapping to chromosome 13, as well as activation of IGF1R, appears to have an amplifying effect on cell cycle gene expression, thus providing a molecular explanation for the dire outcome of patients with CA 13 compared with those with other CAs.

Status of Chromosome 13 in Multiple Myeloma: Integrated Approach Using SNP Mapping Array and Gene Expression Array.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1563-1563
Author(s):  
Paola E. Leone ◽  
Brian A. Walker ◽  
David Gonzalez ◽  
Matthew Jenner ◽  
Fiona M. Ross ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Multiple Myeloma ◽  
Snp Array ◽  
Regulatory Genes ◽  
Expression Array ◽  
Array Data ◽  
Chromosome 13 ◽  
Expression Levels ◽  
Cell Cycle Regulatory Genes

Abstract Deletions on chromosome 13 are thought to be one of the most important prognostic features in Multiple Myeloma (MM). The biology underlying this is, however, uncertain. Chromosome 13 abnormalities have been evaluated conventionally by FISH using probes for 13q14, covering the retinoblastoma gene (RB1) region. Typically, for recurrent regions of loss of heterozygosity (LOH) it is possible to map a minimally deleted region within which an important gene may be located. This should be the case with 13q−, or alternatively there may be linkage with another genetic lesion, which could be contributing to the poor prognosis. Following the implementation of high-density single-nucleotide polymorphism (SNP) array, it is now possible to genotype the whole human genome with a mapping resolution of less than 50 Kb. Thus, the SNP array approach offers an opportunity to analyze both copy number abnormalities and LOH simultaneously. The aim of this study was to determine the numerical alterations, LOH and changes in the gene expression profile of the chromosome 13 in MM, and its possible association with other genetic events. For this purpose, we analyzed 17 patients included on the Myeloma IX trial with deletion of 13q14 compared with 22 samples without deletion, using Affymetrix 50K SNP arrays and Affymetrix U133 Plus 2 expression array. IGH translocations and 13q deletion were determined by FISH. dChipSNP and WGSA programs were used to analyze the data. With respect to 13q14, there was 100% correlation between FISH and SNP array results. 16 out of 17 cases with deletion of the RB1 gene by FISH analysis showed loss of 13q arm by SNP array, demonstrating that loss of the whole chromosome 13 is responsible for 13q deletions found in MM in >90% of cases, with only one case showing a defined region of deletion of chromosome 13 (13q14.11–13q21.2). Using gene expression arrays we could not define a specific pattern characteristic of expression loss in genes at 13q. Lower RB1 expression levels were not only restricted to cases with del(13). However, samples containing IGH translocations (t(11;14) and t(4;14)) without del(13) showed up to 4 times more RB1 expression, suggesting that MM evolution in cases containing IGH translocations is independent of RB1 expression. Interestingly, the hyperdiploid cases with and without del(13) expressed similar level of RB1. We also investigated whether other key cell cycle regulatory genes were associated with del(13); in particular, 4 cases showed 9p21 LOH by SNP array and no different gene expression levels, which suggest that LOH does not seem to be a mechanism of lost of expression of CDKN2A, CDKN2B and p14/ARF. We could not find any significant correlation with del(13) and expression of cell cycle regulatory genes, apart from 8/17 samples with del(13) that had low expression of p53 gene, including 6 t(4;14) cases and 2 t(11;14) cases. Also, 2 cases without monosomy 13 (1 with t(4;14) and 1 with t(11;14)), showed low p53 expression levels. However, SNP array data did not show any deletion at 17p in 38 cases, with the exception of a case with monosomy 13 and t(11;14) in which SNP array data showed loss at 17pter-17q21.2 and FISH detected p53 deletion. Further investigation between the association of p53 and del(13) are ongoing and maybe useful in defining the biology of this poor subgroup of patients.

Up-Front Thalidomide-Dexamethasone (THAL) and Double Autologous Transplantation (Double TX) for Multiple Myeloma: Comparison with Double TX without Added Thalidomide and Prognostic Implications of Chromosome 13 Deletion and Translocation t(4;14).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3081-3081 ◽  
Author(s):  
Michele Cavo ◽  
Nicoletta Testoni ◽  
Carolina Terragna ◽  
Elena Zamagni ◽  
Paola Tacchetti ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Autologous Transplantation ◽  
Lower Probability ◽  
Fish Analysis ◽  
Primary Therapy ◽  
Cytogenetic Abnormalities ◽  
Chromosome 13 ◽  
Prognostic Implications ◽  
Intent To Treat

Abstract Aim of the present sudy was to evaluate the benefit of novel agents combined with conventional therapies in multiple myeloma (MM), with particular emphasis on patients (pts) carrying adverse cytogenetic abnormalities. For this purpose, we analyzed a series of 142 pts who received thalidomide-dexamethasone (thal-dex) and double autologous transplantation (double Tx). By study design, thal-dex was administered from the outset until the second autologous Tx. On an intent-to-treat basis, stringently defined (immumofixation negative) complete remission (CR) rate following double Tx and thal-dex was 54%. This value was significantly higher (P=0.0009) compared to the 33% observed in a comparable series of 129 pts who received double Tx without thal-dex. In comparison with these latter patients, addition of thal-dex to double Tx significantly prolonged PFS (median: 31 vs 42 months; P=0.04) and did not adversely affect survival after post-transplant relapse (P=0.7). All 142 pts included in the study were investigated at baseline for the presence of chromosome 13 deletion [del(13)] by FISH analysis and of t(4;14) using a RT-PCR assay. An analysis on an intent-to-treat basis performed according to the presence or absence of these cytogenetic abnormalities revealed that the probability to respond (more than 90% reduction in M protein concentration) to primary therapy with thal-dex for 94 pts who carried both del(13) and t(4;14) was significantly lower compared to that of 69 pts with del(13) alone (12% vs 41%, respectively; P=0.012) and of 18 pts with t(4;14) alone (12% vs 50%, respectively; P=0.006). The lower probability of response to first-line thal-dex therapy conferred by the presence of both del(13) and t(4;14) was completely offset by subsequent application of double Tx and thal-dex. Indeed, on an intent-to-treat basis, the probability to attain a very good partial response or CR for pts with both del(13) and t(4;14) positivity was 68% compared to 80% for pts with both del(13) and t(4;14) negativity (P=0.1). With a median follow-up of 24 months, the 3-year projected probabilities of OS and PFS were 80% and 59%, respectively (intent-to-treat). The presence or absence of t(4;14) had no significant impact on the 3-year projected probability of OS (80.12% vs 80.42%, respectively; P=0.3). Furthermore, an analysis of pts who actually received thal-dex and double Tx showed that curves of OS and EFS were almost superimposable among pts who carried or lacked both del(13) and t(4;14). Indeed, the 3-year projected probability of OS for pts with both these cytogenetic abnormalities was 92% compared to 88% for pts who were negative for both del(13) and t(4;14); (P=0.7); the corresponding figures for EFS were 70% vs 77%, respectively (P=0.9). These results suggest that thal-dex combined with double Tx may overcome the unfavourable prognosis conferred by del(13) and t(4;14). A longer follow-up is required before definite conclusions can be drawn.

ANKHD1 Silencing Induces S-Phase Arrest and Modulates Cell Cycle Gene Expression in Human Myeloma Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1828-1828
Author(s):  
Anamika Dhyani ◽  
Adriana S S Duarte ◽  
Patricia Favaro ◽  
Sara T Olalla Saad
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Multiple Myeloma ◽  
Cell Lines ◽  
Lentiviral Vector ◽  
Myeloma Cell ◽  
S Phase ◽  
Cell Cycle Gene ◽  
Myeloma Cells ◽  
Protein Levels

Abstract Abstract 1828 ANKHD1 is a multiple ankyrin repeats containing protein with a single KH domain. It is a large protein (∼ 280 kDa) derived from an 8 kb transcript. The ANKHD1 gene, present in human chromosome 5q31.3 as a single copy is ubiquitously expressed in normal human tissues and reported to be highly expressed in cancers, such as acute leukemia. Previous study showed higher expression of ANKHD1 in bone marrow plasma cells (CD138+) from Multiple Myeloma patients as compared to control (1) and it is also over expressed in multiple myeloma cell lines such as MM1S, MM1R, U266 and RPMI 8266 at both mRNA and protein level (2). However, the functional role of ANKHD1 in myeloma cells is unknown. In the present study, by silencing ANKHD1 gene expression in glucocorticoid resistant (U266) and sensitive (MM1S) myeloma cell lines, we studied its effect on cell cycle, proliferation and apoptosis. For gene silencing, specific shRNA-expressing lentiviral vector targeting the ANKHD1 gene and as negative control, sequence specific to Lac z gene were used. Cell growth was measured using the MTT colorimetric assay, whereas for apoptosis and cell cycle analysis Flow cytometry was used. Western blot and RTPCR were used for studying gene expression and protein levels, respectively. The results showed that lentiviral vector containing coding sequences for shRNA significantly downregulated ANKHD1 gene expression in Multiple Myeloma cells at the mRNA and the protein levels (p<0.05). Furthermore, we found that the cell cycle was arrested at S phase and the cell proliferation was significantly inhibited in both cell lines studied (p<0.05). However, ANKHD1 suppression did not induce apoptosis in myeloma cells, as evidenced by annexin V binding assay and flow cytometric detection of sub-G1 DNA content. To address the mechanism of the antiproliferative effect of ANKHD1 silencing, we examined the effect of ANKHD1 inhibition on cell cycle-related gene expression and proteins. ANKHD1 suppression caused downregulation of CDKN1B (p27), CCNB1 (cyclin B1), CDC25, CCNE1 (cyclin E1) and WEE 1 gene expression. There was no significant change in CCNA2 (Cyclin A2), CDC20 expression at mRNA levels. On the other hand, expression of CDKN1A (p21),which inhibits cyclin dependent kinases (CDKs) and plays role in preventing proliferation, was highly upregulated in both the cell lines. At protein levels, expression of Cdk2,Cdk4, p27 (CDKN1B) and E2F1 was decreased in both the cell lines with almost complete inhibition of expression in U266 cells. Taken together, the above results suggest that accumulation of cells in S phase (S phase arrest) can be due to inhibition of CDKs which binds with cyclins and are responsible for progression of cell cycle. Further, this inhibition of CDKs could be associated to increased induction of (CDKN1A) p21 in both cell lines. In conclusion, the present study demonstrates that the suppression of ANKHD1 potently inhibits proliferation and promotes cell cycle arrest without affecting rate of apoptosis in both glucocorticoid resistant as well as sensitive multiple myeloma cells. Also, as ANKHD1 suppression prevents S to G2/M progression, ANKHD1 protein might have role in cell cycle control by modulating cell cycle gene expression in intra S phase check point. The mechanisms modulating expression of these genes are under investigation. Further studies with combination of drugs that induce apoptosis and suppression of ANKHD1 may be an effective strategy for treatment of cancers, and therefore needed to be explored. Disclosures: No relevant conflicts of interest to declare.

Ethanol alters cell cycle gene expression in human embryonic stem cells

2016 ◽  
Vol 01 (03) ◽  
pp. 201-208 ◽  
Author(s):  
Malini Krishnamoorthy ◽  
Brian Gerwe ◽  
Jamie Heimburg-Molinaro ◽  
Rachel Nash ◽  
Jagan Arumugham ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Human Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Cell Cycle Gene ◽  
Cell Cycle Gene Expression

scholarly journals Repurposing of KLF5 activates a cell cycle signature during the progression from a precursor state to oesophageal adenocarcinoma

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Connor Rogerson ◽  
Samuel Ogden ◽  
Edward Britton ◽  
Yeng Ang ◽  
Andrew D Sharrocks ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Prognostic Significance ◽  
Gene Expression Signature ◽  
Chromatin Accessibility ◽  
Oesophageal Adenocarcinoma ◽  
Cell Cycle Gene ◽  
Molecular Events ◽  
Common Causes ◽  
A Cell

Oesophageal adenocarcinoma (OAC) is one of the most common causes of cancer deaths. Barrett’s oesophagus (BO) is the only known precancerous precursor to OAC, but our understanding about the molecular events leading to OAC development is limited. Here, we have integrated gene expression and chromatin accessibility profiles of human biopsies and identified a strong cell cycle gene expression signature in OAC compared to BO. Through analysing associated chromatin accessibility changes, we have implicated the transcription factor KLF5 in the transition from BO to OAC. Importantly, we show that KLF5 expression is unchanged during this transition, but instead, KLF5 is redistributed across chromatin to directly regulate cell cycle genes specifically in OAC cells. This new KLF5 target gene programme has potential prognostic significance as high levels correlate with poorer patient survival. Thus, the repurposing of KLF5 for novel regulatory activity in OAC provides new insights into the mechanisms behind disease progression.

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