Overexpression of BAALC and MN1 Predict Worse Outcome in De Novo AML with Partial Tandem Duplication of MLL.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1002-1002
Author(s):  
Tung-Liang Lin ◽  
Lee-Yung Shih ◽  
Der-Cherng Liang ◽  
Chein-Fuang Huang ◽  
Chia-Hui Chang ◽  
...  
Keyword(s):  
Tandem Duplication ◽  
Target Genes ◽  
De Novo ◽  
High Expression ◽  
Expression Levels ◽  
Partial Tandem Duplication ◽  
De Novo Aml ◽  
Normal Controls ◽  
Low Expression ◽  
Erg Genes

Abstract Abstract 1002 Poster Board I-24 Background and purpose: Overexpression of BAALC, MN1, or ERG gene has been described to have adverse impact on the outcome of acute myeloid leukemia (AML) with normal karyotype. The majority of patients with partial tandem duplication of MLL gene (MLL-PTD) had normal karyotypes. The prognostic relevance of overexpression of these genes in MLL-PTD AML was not clear. Aims: We aimed to (1) measure the mRNA expression levels of FLT3, BAALC, FHIT, MN1, and ERG genes in AML patients with MLL-PTD (2) compare the expression levels of these genes with normal controls, and (3) determine their prognostic significance. Patients and methods: Bone marrow samples from 93 de novo AML patients with MLL-PTD at diagnosis were analyzed. MLL-PTD was screened by Southern blot analysis or reverse transcriptase polymerase chain reaction (RT-PCR) then confirmed by real-time quantitative PCR (RQ-PCR). RQ-PCR assay with TaqMan probe was performed to measure the expression of FLT3, BAALC, FHIT, MN1, and ERG genes in MLL-PTD AML as well as in 34 normal controls for comparison. The expression levels of target genes were calculated as the copy number of each gene normalized to the copy number of ABL control gene (NCN). Positive and negative controls as well as standard curve constructs were included in each assay. Mutational analysis was performed by DNA/cDNA PCR followed by GeneScan analysis for detection of internal tandem duplication of FLT3 gene (FLT3/ITD). The expression levels of each target genes were dichotomized at the median value to low and high expression groups. The event-free and overall survivals (EFS and OS) were compared between the 2 groups. Results: The expression levels of mRNAs for FLT3, BAALC, FHIT, MN1, and ERG genes at diagnosis in MLL-PTD AML and 34 normal controls are shown in Table. MLL-PTD patients had significantly higher expression levels of FLT3, BAALC, MN1, and ERG compared to normal controls. The expression of FHIT was also higher than that of controls, but did not reach statistic significance. FLT3/ITD was present in 26 of 52 patients (50%). The expression levels of the above genes were not different between patients with FLT3/ITD and those without. The median age of the entire cohort was 56 years. The median EFS and OS of the 52 patients who received standard induction chemotherapy were 5.8 and 11.4 months, respectively. The complete remission (CR) rate was higher in the low expression group than that of high expression group for BAALC (P = 0.011). The CR rate was not significantly different between low and high expression groups for FLT3, FHIT, MN1, or ERG, and between FLT3/ITD(+) and (-) groups. There were no significant difference in EFS or OS between patients with FLT3/ITD and those without. Patients with high expression of BAALC had a significantly shorter survival than those with low expression group; the median EFS was 10.3 mons (95% CI: 5.9-14.7 mons) vs. 0 mon, P = 0.044 and the median OS was 16.4 mons (95% CI: 8.3-25.5 mons) vs. 10.9 mons (95% CI: 6.5-15.3 mons), P = 0.031. Patients with high expression of MN1 also had a poor outcome compared with low expression group; the median EFS was 10.9 mons (95% CI: 0-28.3 mons) vs. 4.1 mons (95% CI: 0-11.7mons), P = 0.002 and the median OS was 29.7 mons (95% CI: 0-70.7mons) vs.11.0 mons (95% CI: 10.7-11.3 mons), P = 0.024. The EFS and OS were not significantly different between low and high expression groups for FLT3, BAALC, FHIT, and ERG. Conclusions: Our results showed that MLL-PTD was associated with overexpression of FLT3, BAALC, MN1, and ERG. The patients with lower expression level of BAALC had a higher CR rate and patients with overexpression of BAALC or MN1 had poor EFS and OS. FLT3/ITD had no prognostic impact. Supported by grants NSC97-2314-B-182 -011-MY3, NSC96-2314-B-195-006-MY3, and MMH-E-96009. Disclosures: No relevant conflicts of interest to declare.

High Transcription Levels Of S100A8 and S100A9 In Acute Myeloid Leukemia Are Predictors For Poor Overall Survival

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2610-2610 ◽  
Author(s):  
Shao-yan Hu ◽  
Ming-ying Zhang ◽  
Shui-yan Wu ◽  
Dong Wu ◽  
Neetika Ashwani ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
De Novo ◽  
Risk Group ◽  
High Expression ◽  
Intermediate Risk ◽  
Newly Diagnosed ◽  
Transcription Level ◽  
Expression Levels ◽  
De Novo Aml ◽  
Low Expression

Abstract S100A8 and S100A9 are two members of the S100 calcium-binding protein family, preferentially form functional heterodimers of S100A8/S100A9, and have been increasingly recognized as biomarkers in malignancies. Recent proteomic studies revealed that S100A8 and S100A9 played pivotal roles in hematologic malignancies and elevated expression of S100A8/S100A9 implicated in glucocorticoid resistance in MLL-rearranged infant acute lymphoblastic leukemia (ALL). In addition, S100A8 proteomic expression in leukemic cells was reported to predict survival in AML patients. However, information on the gene expression level of S100A8 and S100A9 and their clinical correlation in acute myeloid leukemia (AML) is lacking. Using the real-time quantitative RT-PCR, we analyze the transcription levels of S100A8 and S100A9 in AML patient leukemic specimens underwent pre-planned induction chemotherapy. A total of 189 patient cases at different stages of AML (excluding acute promyelocytic leukemia [APL]), including 91 newly diagnosed AML, 64 patient remission marrow specimens and 34 patient specimens as well as 20 controls without leukemia were included in the study collected from the period between 2007 and 2011. Among the cohort of 91 newly diagnosed AML, the over all median OS was 20 months, and the median follow-up for survivors was 24 months (range: 17 to 60 months). There were significant positive correlations of transcription levels between S100A8 and S100A9 in AML patients from different stages. The expression levels of S100A8 and S100A9 in newly diagnosed and relapsed AML patients revealed no significant difference, but were both lower than those in complete remission and control group. Patients with high transcription level of S100A8 and S100A9 were predominantly in AML with myelo-monocytic differentiation (M4, M5) whereas those with low transcription level of S100A8 and S100A9 often showed more immature cytomorphology (M0, M1), erythrocytic or megakaryocytic differentiation. The subgroup of patient with high transcription level of S100A8 could be a predictor for inferior overall survival (OS) (P = 0.0012). High levels of transcription for both S100A8 and S100A9 in de novo AML patients could predict shorter OS than those with low levels after adjustment on their ages at diagnosis (P = 0.003). In a multivariate analysis for OS, high S100A8 transcription was a significant prognostic factor (P =0.001) after analysis adjustment for age (P = 0.019), bone marrow blast percentage (P = 0.04) and cytogenetic classification (P = 0.05) at diagnosis. Using a combination of S100A8 transcription level and cytogenetic risk classification, survival analysis gave result that the new stratification was highly correlated with the OS (P < 0.0001). With significantly different OS, patients from the intermediate-risk group can be divided into two subgroups (IH = cytogenetically intermediate-risk with S100A8 high transcription and IL = cytogenetically intermediate-risk with S100A8 low transcription). Patients from group IL emerged with a probability of OS similar to the cytogenetically favorable-risk group, whereas the survival curve of IH subgroup was close to the unfavorable-risk group. (Figure)FigureRisk stratification of de novo AML patients by a combination of age and cytogenetic characteristics with S100A8 expression levels. 1H = cytogenetically favorable-risk with S100A8 high expression, 1L = cytogenetically favorable-risk with S100A8 low expression, 2H = cytogenetically intermediate-risk with S100A8 high expression, 2L = cytogenetically intermediate-risk with S100A8 low expression, 3H = cytogenetically unfavorable-risk with S100A8 high expression, 3L = cytogenetically unfavorable-risk with S100A8 low expression.Figure. Risk stratification of de novo AML patients by a combination of age and cytogenetic characteristics with S100A8 expression levels. 1H = cytogenetically favorable-risk with S100A8 high expression, 1L = cytogenetically favorable-risk with S100A8 low expression, 2H = cytogenetically intermediate-risk with S100A8 high expression, 2L = cytogenetically intermediate-risk with S100A8 low expression, 3H = cytogenetically unfavorable-risk with S100A8 high expression, 3L = cytogenetically unfavorable-risk with S100A8 low expression. In conclusion, the transcription levels of S100A8 and S100A9 were significantly associated with development and prognosis of AML. Both S100A8 and S100A9 expression levels provided useful clinical information, and more importantly, S100A8 expression level significantly correlates with prognosis in addition to well-known cytogenetic risk factors, and could potentially further refine current stratification of de novo AML patients. Disclosures: No relevant conflicts of interest to declare.

High Expression Levels of Iaps Predict Poor Overall Survival in Childhood De Novo Acute Myeloid Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4396-4396
Author(s):  
Ingo Tamm ◽  
Stephan Richter ◽  
Doreen Oltersdorf ◽  
Ursula Creutzig ◽  
Jochen Harbott ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
High Expression ◽  
Prognostic Impact ◽  
Poor Overall Survival ◽  
Expression Levels ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Apoptosis-related proteins are important molecules for predicting chemotherapy response and prognosis in adult acute myeloid leukemia (AML). However, data on the expression and prognostic impact of these molecules in childhood AML are rare. Using flow cytometry and western blot analysis, we therefore investigated 45 leukemic cell samples of children with de novo AML enrolled and treated within the German AML-BFM93 study for the expression of apoptosis-regulating proteins (CD95, Bcl-2, Bax, Bcl-xL, Procaspase-3, XIAP, cIAP-1, Survivin). XIAP (p&lt;0.002) but no other apoptosis regulators showed maturation-dependent expression differences as determined by FAB morphology with the highest expression levels observed within the immature M0/1 subtypes. XIAP (p&lt;0.01) and Bcl-xL (p&lt;0.01) expression was lower in patients with favorable than intermediate/poor cytogenetics. After a mean follow-up of 34 months, a shorter overall survival was associated with high expression levels of XIAP {30 (n=10) vs. 41 months (n=34); p&lt;0.05} and Survivin {27 (n=10) vs. 41 months (n=34); p&lt;0.05}. We conclude that apoptosis-related molecules are associated with maturation stage, cytogenetic risk groups and therapy outcome in childhood de novo AML. The observed association of XIAP with immature FAB types, intermediate/poor cytogenetics and poor overall survival should be confirmed within prospective pediatric AML trials.

Different Patterns of Cooperating Mutations between De Novo AML Patients with MLL-Partial Tandem Duplication and MLL Translocations.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2363-2363
Author(s):  
Lee-Yung Shih ◽  
Der-Cherng Liang ◽  
Chein-Fuang Huang ◽  
Ya-Tzu Chang ◽  
Yu-Shu Shih ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Tandem Duplication ◽  
De Novo ◽  
Direct Sequencing ◽  
Ras Signaling ◽  
Missense Mutations ◽  
Ras Pathway ◽  
Ras Signaling Pathway ◽  
Partial Tandem Duplication ◽  
De Novo Aml

Abstract Two-hit model of leukemogenesis has been proposed for AML. In AML with MLL rearrangements (MLL-R), MLL gene is fused to a variety of partner genes through reciprocal chromosomal translocations (MLL/t11q23), or is rearranged to generate a partial tandem duplication (MLL-PTD). The cooperating mutations of AML with MLL-R have not been systematically analyzed. We aimed to determine the cooperating mutations, including receptor tyrosine kinase (RTK) /Ras signaling pathway, NPM1 and myeloid transcription factors in de novo AML with MLL-R. MLL-R was screened by Southern blot analysis. RT-PCR was used to detect common MLL fusion transcripts. cDNA panhandle PCR was used to identify the infrequent or unknown MLL partner genes. Mutational analysis was peformed by DNA/cDNA PCR-GeneScan analysis for FLT3/ITD, by PCR-RFLP followed by direct sequencing for FLT3/TKD, by DNA/cDNA PCR and direct sequencing for N-Ras, K-Ras, c-KIT, c-FMS, PTPN11, NPM1, AML1 and CEBPα. Of the 131 patients with MLL-R, 77 had MLL-PTD and 54 had MLL/t11q23. None of the 131 patients with MLL-R had c-FMS mutations and c-KIT mutation was present in only one patient with MLL/t11q23. NPM1 mutations occurred in one with MLL-PTD and 2 with MLL/t11q23. The frequencies of other cooperating mutations are shown in Table 1. Taken together, cooperating mutations involving RTK/Ras pathway, NPM1, and/or myeloid transcription factors occurred in 71.4% (55/77) of patients with MLL-PTD and 59.3% (32/54) of patients with MLL/t11q23. In MLL-PTD group, coexistence of two mutations occurred in 23 patients. In MLL/t11q23 group, 6 patients had two mutations. Of the 18 patients with MLL-PTD and AML1 mutations, 8 mutations were located in the Runt homology domain (RHD) and 10 in the non-RHD, 15 were frameshift or nonsense mutations and 3 were missense mutations. Fourteen patients with MLL-PTD and AML1 mutations also had mutations of RTK/Ras singling pathway. Three patients with MLL/t11q23 and AML1 mutations, one in the RHD and 2 in the non-RHD, all were missense mutations. Of the 5 patients with MLL-PTD and CEBPα mutations, 3 harbored FLT3/ITD. Patients with MLL-PTD had a significantly higher frequency of cooperating mutations with myeloid transcription factors than patients with MLL/t11q23 (20/77 vs. 3/54, P=0.002), whereas there was no difference in the frequency of mutations involving RTK/Ras pathway between MLL-PTD and MLL/t11q23 groups (51/77 vs. 29/54, P=0.202). Our results showed that patients with de novo AML and MLL-R had a high frequency of cooperating mutations with RTK/Ras signaling pathway, NPM1 or myeloid transcription factors, and the mutation patterns were different between MLL-PTD and MLL/t11q23 groups. Table 1. Comparison of cooperating mutations between MLL-PTD and MLL/t11q23 groups FLT3/ITD FLT3/TKD N-Ras K-Ras PTPN11 AML1 CEBPα MLL-PTD 35/77 11/77 5/77 0/77 3/77 18/77 5/77 MLL/t11q23 2/54 7/54 9/54 13/54 1/53 3/54 0/54 P value <0.0001 1.000 0.085 <0.0001 0.648 0.007 0.077

scholarly journals The Prognostic Impact of the Diagnostic CD34+/CD38- Cell Burden and Expression of the Stem Cell Marker GPR56 after Stem Cell Transplantation Depends on the AML Origin

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 323-323
Author(s):  
Madlen Jentzsch ◽  
Marius Bill ◽  
Juliane Grimm ◽  
Dominic Brauer ◽  
Julia Schulz ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Solid Tumors ◽  
Cell Transplantation ◽  
Research Funding ◽  
De Novo ◽  
Prognostic Impact ◽  
Expression Levels ◽  
Rheumatologic Diseases ◽  
De Novo Aml

Introduction: Acute myeloid leukemia (AML) developing secondary after other hematologic diseases, or therapy related after cytotoxic treatment for solid tumors or rheumatologic diseases (s/tAML) is clinically, genetically & prognostically distinct from de novo diseases. Data indicate that s/tAML patients (pts) have inferior outcome compared to de novo cases after chemotherapy & therefore often require consolidation therapy using allogeneic stem cell transplantation (HSCT). Leukemic stem cells (LSC) initiate & maintain AML. They are also believed to exist within the CD34+/CD38- &/or high GPR56 expressing bone marrow (BM) population, which have been shown to impact adversely on outcome. The prognostic impact of LSC markers in de novovs s/tAML after HSCT with non-myeloablative conditioning intensity - where the therapeutic approach also relies on immunological graft-versus-leukemia effects - is unknown. Methods: We analyzed 379 AML pts who received an allogeneic peripheral blood HSCT in complete remission (CR, 82%) or CR with incomplete peripheral recovery (CRi, 18%) between 1999 & 2018 after non-myeloablative (3x30 mg/m2 Fludarabine & 2 Gy total body irradiation) conditioning. At diagnosis, cytogenetic & flow cytometric analyses were performed centrally. For pts with pre-treatment BM available the mutation status of CEBPA, NPM1 & presence of FLT3-ITD by fragment analyses as well as expression levels of GPR56 by qPCR were assessed. Using a next-generation targeted amplicon sequencing approach we analyzed a panel comprising 54 recurrently mutated (mut) genes in myeloid malignancies on the MiSeq platform (Illumina). Median follow up after HSCT was 3.7 years. Results: 229 pts (60%) had de novo & 150 pts (40%) had AML secondary to myelodysplastic syndrome (MDS, n=82), myeloproliferative neoplasm (MPN, n=22) or MDS/MPN (n=10), or therapy related after Non-Hodgkin lymphoma (n=9), solid tumors (n=25) or rheumatologic diseases (n=2). At diagnosis, s/tAML pts had lower white blood counts (P=.03), lower blasts in BM (P&lt;.001) or blood (P=.007) & a higher BM CD34+/CD38- cell burden (P=.01) & GPR56 expression (P=.04). They also had worse European LeukemiaNet risk (P=.007), were less likely to have a normal karyotype by trend (P=.06), to have a core binding factor AML (P=.02), to be NPM1mut (P=.003), DNMT3Amut (P=.03) & to harbor a FLT3-ITD (P=.002) but more likely to be JAK2mut (P&lt;.001). Comparing pts with s/tAML vsde novo AML, there was no significant different cumulative incidence of relapse (CIR, P=.85) or overall survival (OS, P=.29). Next, we evaluated the prognostic impact of the LSC-associated populations in pts with de novo or s/tAML separately. In pts with de novo AML, we observed a significantly higher CIR & shorter OS for pts harboring a high CD34+/CD38- cell burden (high vs low, 6% cut, P=.006 [Fig. 1A] & P=.003) & a higher CIR but not significantly different OS for pts with a low GPR56 expression (high vs low, median cut, P=.03 [Fig. 1B] & P=.95). Combining both parameters, we observed a stepwise higher CIR & shorter OS for pts with low expression of both variables vs pts with a low CD34+/CD38- cell burden but high GPR56 expression vs pts with a high CD34+/CD38-cell burden (P=.003 [Fig. 1C] & P=.05). In contrast, in pts with s/tAML, there was no prognostic significance of the CD34+/CD38- cell burden (CIR P=.38 [Fig. 1D] & OS P=.95), the GPR56 expression (CIR P=.64 [Fig. 1E] & OS P=.82) & both markers combined (CIR P=.57 [Fig. 1F] & OS P=.98). Also in multivariate analyses, the combination of both markers significantly impacted CIR (Hazard ratio 2.49, P&lt;.001 after adjustment for donor type) & was the only significant factor for OS (Odds Ratio 0.68, P=.04) in de novo AML but not in s/tAML. Conclusion: While there was no significantly different CIR or OS in s/tAML compared to de novo AML pts undergoing non-myeloablative HSCT we observed a significant impact on outcome for the known LSC-associated prognosticators CD34+/CD38- cell burden & GPR56 expression levels at diagnosis only in de novo AML pts. Different underlying disease biology & possibly different LSC-associated populations may be relevant for disease reoccurrence in s/tAML. Figure Disclosures Jentzsch: Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria. Niederwieser:Daichii: Speakers Bureau; Cellectis: Consultancy. Platzbecker:Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Schwind:Daiichi Sankyo: Honoraria; Novartis: Honoraria, Research Funding.

FLT3 Internal Tandem Duplications in Adults with De Novo Acute Myeloid Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4430-4430
Author(s):  
Sandra G. Xavier ◽  
Rocío Hassan ◽  
Nelma C.D. Clementino ◽  
Daniel G. Tabak ◽  
Nelson Spector ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Tandem Duplication ◽  
De Novo ◽  
Univariate Analysis ◽  
Internal Tandem Duplication ◽  
Hematopoietic Stem ◽  
Proliferation And Differentiation ◽  
Polymerase Chain ◽  
De Novo Aml ◽  
Tandem Duplications

Abstract FLT3 is a receptor tyrosine kinase involved in the proliferation and differentiation of hematopoietic stem cells. Recently, internal tandem duplication (ITD) mutations of the FLT3 gene have been described in patients with AML and associated with a poor prognosis. The aim of this study was to analyze the prevalence of FLT3-ITD in a series of 90 adults with de novo AML and correlate the presence of this mutation with biological characteristics and clinical response. We analyzed diagnostic peripheral blood or bone marrow specimens from 43 women and 47 men, with a median age of 38 years (16–83). Polymerase chain reaction was performed on genomic DNA using previously published primers for exons 11 and 12. An FLT3-ITD was found in 22/89 patients (25%). It was present in 37% (9/24) of the patients with acute promyelocytic leukemia (APL) and in only 20% (13/65) of the patients with non-M3-AML (p=0.07). The FLT3-ITD was not detected in patients with M6 (n=1) and M7-AML (n=3), nor in patients with the AML1-ETO (n=2) or with the CBFb-MYH11 (n=4) fusion genes. The median WBC counts were higher in FLT3-ITD patients than in those without the mutation (37 X 109/L vs. 27 X 109/L, p=0.43). In APL, FLT3-ITD was found in 5 out of 6 patients with the short PML-RARa isoform, but in only 4 out of 18 patients with the non-short isoform (p=0.01). Univariate analysis showed an association between the presence of FLT3-ITD and both a lower complete remission (CR) rate (41% vs. 64%; p=0.05) and a shorter overall survival (14% vs. 34%; p=0.03). However, FLT3-ITD was not associated with the CR rate (p=0.18) or the OS (p=0.07) in the multivariate analysis. The clinical significance of FLT3-ITD in adult AML remains uncertain, and further investigation is clearly warranted.

Action of SDF-1/CXCR4 axis in liver metastasis of colorectal cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 530-530 ◽  
Author(s):  
Shinichiro Yamada ◽  
Mitsuo Shimada ◽  
Toru Utsunomiya ◽  
Satoru Imura ◽  
Yuji Morine ◽  
...  
Keyword(s):  
Liver Metastasis ◽  
Colorectal Liver Metastasis ◽  
Normal Liver ◽  
High Expression ◽  
Expression Level ◽  
Expression Levels ◽  
High Expression Group ◽  
Cxcr4 Axis ◽  
Low Expression ◽  
Liver Tissues

530 Background: It has recently been suggested that the SDF-1/CXCR4 axis is involved in tumor progression, angiogenesis, metastasis, and survival in various cancer. In this study, we investigate the possible role of SDF-1/CXCR4 axis in colorectal liver metastasis. Methods: Both primary colorectal tumors and liver metastatic tumors were obtained from 12 patients with colorectal liver metastasis. Expression levels of CXCR4 and SDF-1 were determined using RT-PCR. In 4 patients with benign liver disease, the expression level of SDF-1 in normal liver tissues was also determined. We divided the 12 patients into two groups; high expression group (n=6) and low expression group (n=6) according to each expression level of SDF-1 and CXCR4, and compared the clinicopathological factors between the two groups. Results: 1. CXCR4 expression levels in primary tumor: The frequency of the peritoneal dissemination in the CXCR4 high expression group was higher than in the low expression group (p=0.07). Moreover, overall survival rate in the CXCR4 high expression group was significantly lower than that in the low expression group (3 year-survival rate: 67% vs. 100%, p<0.05). 2. CXCR4 in metastatic tumor tissues and SDF-1 in non-tumor liver tissues: The expression level of SDF-1 in non-tumor liver tissues was significantly higher than that in normal liver tissues (p<0.01). A significant correlation between the CXCR4 expression levels in metastatic tumor tissues and SDF-1 expression levels of non-tumor liver tissues (p<0.05). The number of metastatic liver tumors in the SDF-1 high expression group tended to be larger than that in the low expression group (p=0.12). Conclusions: The present data suggest that there is a significant association of the SDF-1/CXCR4 axis with enhanced liver metastasis and poor prognosis of the patients with colorectal liver metastasis. Furthermore, an enhanced expression of SDF-1 in non-tumor liver tissues may have an important role in the formation of liver metastasis.

scholarly journals Epigenetic Allelic States of a Maize Transcriptional Regulatory Locus Exhibit Overdominant Gene Action

Genetics ◽  
1998 ◽  
Vol 150 (2) ◽  
pp. 891-897 ◽  
Author(s):  
Jay B Hollick ◽  
Vicki L Chandler
Keyword(s):  
Gene Action ◽  
High Expression ◽  
Regulatory Mechanisms ◽  
Epigenetic Changes ◽  
Anthocyanin Pigment ◽  
Pigment Synthesis ◽  
Expression Levels ◽  
Sexually Transmitted ◽  
Transcriptional Regulatory ◽  
Low Expression

Abstract Using alleles of the maize purple plant locus (pl), which encodes a transcriptional regulator of anthocyanin pigment synthesis, we describe a case of single-locus heterosis, or overdominance, where the heterozygote displays a phenotype that is greater than either homozygote. The Pl-Rhoades (Pl-Rh) allele is subject to epigenetic changes in gene expression, resulting in quantitatively distinct expression states. Allelic states with low-expression levels, designated Pl′-mahogany (Pl′-mah), are dominant to the high-expression state of Pl-Rh. Pl′-mah states retain low-expression levels in subsequent generations when homozygous or heterozygous with Pl-Rh. However, Pl′-mah alleles frequently exhibit higher expression levels when heterozygous with other pl alleles; illustrating an overdominant allelic relationship. Higher expression levels are also observed when Pl′-mah is hemizygous. These results suggest that persistent allelic interactions between Pl′-mah and Pl-Rh are required to maintain the low-expression state and that other pl alleles are missing sequences required for this interaction. The Pl-Rh state can be sexually transmitted from Pl′-mah/pl heterozygotes, but not from Pl′-mah hemizygotes, suggesting that fixation of the high-expression state may involve synapsis. The existence of such allele-dependent regulatory mechanisms implicates a novel importance of allele polymorphisms in the genesis and maintenance of genetic variation.

scholarly journals High Expression of SPAG1 Is Associated with a Worse Clinical Outcome in Intermediate Risk Acute Myeloid Leukemia That Can be Partially Overcome By Hematopoietic Stem Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2804-2804
Author(s):  
Guillaume Richard-Carpentier ◽  
Miriam Marquis ◽  
Guy Sauvageau ◽  
Josee Hebert
Keyword(s):  
Myeloid Leukemia ◽  
Significant Interaction ◽  
De Novo ◽  
High Rate ◽  
High Expression ◽  
Prognostic Impact ◽  
Intermediate Risk ◽  
Hematopoietic Stem ◽  
P Values ◽  
De Novo Aml

Abstract Introduction: Acute myeloid leukemia (AML) is a heterogeneous disease with variable responses to therapy and clinical outcomes. Cytogenetics and molecular analyses help to stratify patients and to select therapy, especially regarding indication of hematopoietic stem cell transplant (HSCT) after achieving complete remission (CR). Patients in the intermediate cytogenetic risk category (~40%) represent a clinical dilemma regarding consolidation because of the high rate of relapse with chemotherapy alone and high rate of morbidity/mortality with HSCT. Consequently, we aimed to identify new prognostic markers to refine the risk stratification of this patients' subgroup and to identify which patients are most likely to benefit from HSCT. Methods: We analyzed RNA sequencing data of 263 specimens from patients with de novo AML treated with curative intent including 165 patients with intermediate risk cytogenetics. Data from 24 586 genes were normalized as RPKM values with logarithmic transformation and standardization. Cox proportional hazard models were used to assess the prognostic impact of gene expression (GE) on overall survival (OS) and relapse-free survival (RFS). We performed univariate analyses (UVA) and multivariate analyses (MVA) adjusted for age and white blood cell count (WBC) at diagnosis, mutations in NPM1, FLT3, CEBPA, RUNX1, ASXL1, TP53 and DNMT3A and HSCT as a time-dependent (TD) covariate. Interaction between GE and TD-HSCT was tested in MVA for OS and RFS. Genes with a significant interaction between GE and TD-HSCT (p < 0.10) were retained for further analyses. GE of candidate markers were dichotomized using a bioinformatic method assessing hazard ratios (HR) and p values for all potential cut-offs to identify the most optimal threshold. The markers were finally reassessed as dichotomic variables for association with covariates, CR rates, RFS and OS. All statistical tests were two-sided with p values < 0.05 considered significant. Results: We identified SPAG1 (Sperm Associated Antigen 1) as the gene with the highest HR for OS and RFS in the intermediate cytogenetic risk group. SPAG1 expression was dichotomized on the median RPKM value in the global cohort of 263 de novo AML specimens (RPKM cut-off 2.06). Using this cut-off, 79 patients had low expression of SPAG1 and 86 patients had high expression of SPAG1 in the intermediate cytogenetic risk cohort. Median age, sex, WBC at diagnosis and HSCT in CR1 rates were similar between the two groups. Patients with high expression of SPAG1 had a higher frequency of FLT3-ITD (51.2% vs 32.9%, p = 0.02) and DNMT3A mutations (51.2% vs 32.9%, p = 0.02). SPAG1-high patients were enriched in the NPM1/FLT3-ITD/DNMT3A triple positive mutation population (SPAG1-high 24/33 vs SPAG1-low 9/33, OR 3.00, p = 0.01). The frequencies of all other analyzed mutations were similar between both groups. CR rates did not differ between the two groups (SPAG1-high 77.9% vs SPAG1-low 79.7%, p = 0.77). In UVA with censorship at time of HSCT, SPAG1-high patients had worse OS (5-year estimates 14.2% vs 28.1%, HR 1.75, 95% CI 1.16-2.63, p < 0.01) and RFS (5-year estimates 9.3% vs 27.1%, HR 1.90, 95% CI 1.20-3.01, p < 0.01) (Figure 1). In MVA with censorship at time of HSCT, high expression of SPAG1 remained significantly associated with OS (HR 1.78, 95% CI 1.12-2.83, p = 0.01) and RFS (HR 2.34, 95% CI 1.38-3.96, p < 0.01). Furthermore, there was a significant interaction between SPAG1 GE and TD-HSCT (p = 0.09) in the RFS model. Importantly, SPAG1 had a lower prognostic impact for RFS in the model including TD-HSCT (HR 1.65, 95% CI 1.07-2.55, p = 0.02) compared with the model in which survival was censored at time of HSCT (HR 2.34, p < 0.01). High SPAG1 expression was also associated with worse OS in the TCGA AML dataset which is enriched in intermediate cytogenetic risk samples (p < 0.001). Conclusion: In patients with intermediate cytogenetic risk AML, high expression of SPAG1 is independently associated with worse OS and RFS. The prognostic impact of SPAG1 expression on RFS is lower when adjusted for TD-HSCT indicating that the adverse prognosis conferred by high expression of this gene may be partially overcome by HSCT in CR1. Consequently, SPAG1 expression might help identify AML patients with intermediate cytogenetic risk who are most likely to benefit from HSCT in CR1. These results need to be validated in other independent cohorts and prospective studies before implementation into clinics. Disclosures Sauvageau: ExCellThera: Employment, Equity Ownership.

FLT3, NPM1 and MLL Mutations Help Risk Stratification in Pediatric Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1574-1574
Author(s):  
Shuhong Shen ◽  
Yin Liu ◽  
JingYan Tang ◽  
Long-Jun Gu
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Myeloid Leukemia ◽  
Tandem Duplication ◽  
De Novo ◽  
Genetic Alterations ◽  
Npm1 Mutation ◽  
De Novo Aml ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract Abstract 1574 Poster Board I-600 Introduction Acute myeloid leukemia (AML) is a heterogeneous disease which harbors various genetic alterations. Among theses genetic events, Mutations of FLT3, NPM1, MLL and other genes often predict prognosis, particularly in cases cytogenetic normal (CN-AML). Could these be criteria for risk stratification in Pediatric AML ? Patients and Methods 155 cases of de novo AML were diagnosed routinely according to morphology, immunology, cytogenetics, and molecular biology examination on bone marrow (BM) aspirates between Jan. 2002 and Dec. 2008. All patients received chemotherapy according to the AML-XH-99 protocol, which consist of Daunorubicin, Cytosine arabinoside, Etoposide, Homoharringtonine. For acute promyelocytic leukemia, all-trans retinoic acid and Arsenic trioxide were also included. Meanwhile, total RNA of leukemic cells form all diagnostic BM samples were extracted, and then reverse transcribed. MLL partial tandem duplication (MLL/PTD) fusion transcripts were screened by real-time quantitative polymerase chain reaction. FLT3 internal tandem duplication (FLT3/ITD), FLT3 tyrosine kinase domain mutation (FLT3/TKD) and NPM1 mutation were examined by High resolution melting analysis. Results Of the 155 children with de novo AML, 121(78.1%) had received chemotherapy for more than one week with data available for analysis. Among them, 55(45.5%) was cytogenetically normal (CN-AML). In this total cohort of patients 49(27.09%) had FLT3/ITD (32.70% in CN-AML), 14 (9.03%) had FLT3/TKD (7.30% in CN-AML), 62 (40%) had NPM1 mutation (49% in CN-AML), and additional 8 (5.16%) had MLL/PTD (5.50% in CN-AML). In this cohort of patients 98 (63.22%) had at least one mutation. The clinical outcomes were listed in table 1. Generally, patients with FLT3 mutation (ITD or TKD mutation) usually have worse results after chemotherapy, as reported previously by other researchers. Meanwhile, NPM1 mutations usually predict better prognosis in our cohort of AML patients. MLL/PTD always predicts the worst outcome in AML as other MLL rearrangements in leukemia. Among CN-AML patients, 5-year EFS and OS were similar to whole cohort of patients according to those mutations. Cox regression analysis in a univariate model revealed that the presence of FLT3/ITD and NPM1 was significant prognostic factor of EFS, (P<0.05). We therefore proposed a molecular-risk classification of pediatric AML patients based on the data we got in this study. For the newly classified groups of low, medium and high risk groups, EFS rate was 62.03%±8.42%, 45.42%±4.52%, and 14.85%±2.99%, respectively, P=0.00. CRD for the 3 groups was 27.69±21.34 months, 22.62±19.64 months, 13.26±11.95 months, respectively, p=.022. Our results indicate that combinations of these couple of molecular events may be the useful tool for further classify AML in children. Disclosures No relevant conflicts of interest to declare.

A Distinct Signature of Natural Killer Cell KIR Gene Frequencies In Secondary AML Compared with De Novo AML and Normal Controls

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1697-1697
Author(s):  
Kate Stringaris ◽  
A. John Barrett ◽  
Robert Hills ◽  
David C Linch ◽  
Rosemary Gale ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
De Novo ◽  
Gene Frequencies ◽  
Secondary Aml ◽  
Kir Genes ◽  
De Novo Aml ◽  
Normal Controls ◽  
Kir Gene

Abstract Abstract 1697 There is increasing evidence for the role of KIR genetics in predicting outcome of haematological malignancies. We recently showed that donor (but not recipient) KIR genes 2DS1, 3DS1 and 2DL5a are associated with significantly less relapse in AML patients following matched sibling allogeneic stem cell transplantation. Interestingly, this effect was not seen in patients with AML secondary to MDS but only in de novo AML.1 To explore whether outcome of non-transplant treatment for AML might be affected by KIR genetics we performed KIR genotyping on the DNA sample archive from the Medical Research Council UK AML 10 and 15 trials. All patients underwent four courses of chemotherapy according to MRC protocols. KIR genotyping was performed using Qiagen SSP PCR KIR genotyping kits as previously described.1 We measured KIR gene frequencies in AML samples obtained at diagnosis from 469 de novo AML, and 38 secondary AML and compared the gene distribution with that of a normal control population of 246 individuals. To allow for multiple comparisons, significance was set at p<0.01. The KIR gene frequencies of de novo AML did not differ significantly from those of the normal population but frequency of KIR 2DS2 was significantly lower in secondary AML compared to de novo AML (26% vs. 51% for KIR 2DS2, p=0.004 vs. 44% (111/246) for normal controls). There was some evidence that KIR 2DL2, which shows linkage disequilibrium with KIR 2DS2, was also reduced in secondary AML (32% v 54%, p=0.009). Rates of KIR 2DS2 and KIR 2DL2 were lower in both secondary groups: therapy-related AML (t-AML) and antecedent haematological disorders. Interestingly, patients with t-AML had lower rates of KIR HaploB than those without t-AML (27% v 67%, p=0.005). However, analyses of the AML cohort adjusted for known prognostic factors showed no significant prognostic effect of any single KIR group, or KIR B haplotype. These results suggest that inheritance of KIR 2DS2 may be protective for the development of secondary AML and that individuals lacking haplotype B KIR genes are more prone to develop t-AML. These observations raise the possibility that KIR gene inheritance determines the efficiency of immunosurveillance of AML by NK cells.Figure 1.Distribution of the variably inherited KIR genes in secondary AML compared to de novo AML and normal controlsFigure 1. Distribution of the variably inherited KIR genes in secondary AML compared to de novo AML and normal controls 1. Donor KIR Genes 2DL5A, 2DS1 and 3DS1 Are Associated with a Reduced Rate of Leukemia Relapse After HLA-Identical Sibling Stem Cell Transplantation for Acute Myeloid Leukemia but Not Other Hematologic Malignancies. Stringaris K, Adams S, Uribe M, Eniafe R, Wu CO, Savani BN, Barrett AJ. Biol Blood Marrow Transplant. 2010 Mar 16. [Epub ahead of print] Disclosures: Linch: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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