Influence of Maternal Folic Acid Supplementation on Hematopoietic Factors in Offspring.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4276-4276
Author(s):  
Kimberly J. Johnson ◽  
David A. Largaespada ◽  
Tucker W. LeBien ◽  
Raha Allaei ◽  
Julie A. Ross
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Folic Acid ◽  
Lymphoblastic Leukemia ◽  
Surface Marker ◽  
Control Group ◽  
Offspring Survival ◽  
Childhood All ◽  
Significant Difference ◽  
B Lineage

Abstract Observational studies of childhood acute lymphoblastic leukemia (ALL) have generally supported a protective role for maternal intake of foods or vitamins rich in folic acid during pregnancy. Using C57BL/6J mice, we evaluated the effect of dietary folic acid intake in the perigestational period on surface marker and gene expression in B-lineage cells as a potential model to further elucidate the role of maternal diet in the etiology of childhood ALL. Thirty-six female mice were randomized to one of three folic-acid varied diets (low=0.3, control=2.0, high=8.0 mg/kg) one month prior to mating and maintained on the diet until pup weaning at three weeks. Reproductive characteristics and offspring red blood cell (RBC) folate were recorded, and bone marrow lymphocytes were isolated for surface marker characterization by flow cytometry. For gene expression analyses, CD19 positive B-lineage bone marrow cells were purified from three pups per dietary group using anti-CD19 microbeads. Gene expression levels were interrogated using the Agilent mouse whole genome microarray. No statistically significant differences were found among dietary groups with respect to mating success, litter size, estimated 21 day offspring weights, or the percentage of male offspring. However, there were significant differences among the 3 diets in offspring survival to the end of the experiment (39%, 84%, and 30% for the 0.3, 2.0, and 8.0 mg/kg groups, respectively). Pup RBC folate values were positively correlated with dietary folic acid dose with mean values of 428, 615, and 724 ng/ml, respectively. Mice were euthanized at 3 weeks. There was no significant difference in the expression of CD19, IgM, or kappa light chains on bone marrow lymphocytes in the offspring among dietary groups. ANOVA analysis, using Genedata Expressionist Pro software, showed differential expression of 267 genes using a Benjamini and Hochburg false discovery rate cutoff of 10%. Three main patterns of gene expression between pups of different dietary groups were identified through unsupervised hierarchical clustering analysis; 152 and 86 genes were up- and down-regulated, respectively, in both the high and the low folic acid groups relative to the control group. Twenty-seven genes showed increasing expression with increasing dietary folic acid dose. In conclusion, dietary folic acid given to dams prior to conception through weaning had a significant effect on offspring survival and gene expression. Additional analyses are underway to determine the relevance of genes found to be differentially expressed with respect to risk of B-cell lineage leukemias followed by validation of relevant gene candidates through quantitative RT-PCR. These data will be used to help inform future etiologic studies of childhood ALL.

scholarly journals PROGNOSTIC IMPACT OF NEUROPILIN-1 EXPRESSION IN EGYPTIAN CHILDREN WITH B-LINEAGE ACUTE LYMPHOBLASTIC LEUKEMIA

2014 ◽  
Vol 7 ◽  
pp. e2015009 ◽  
Author(s):  
Adel Abd elhaleim Hagag ◽  
Nahla A Nosair
Keyword(s):  
Bone Marrow ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Serum Lactate Dehydrogenase ◽  
Control Group ◽  
Prognostic Impact ◽  
Neuropilin 1 ◽  
Egyptian Children ◽  
Significant Difference ◽  
B Lineage

Abstract:Background: Neuropilins are transmembrane glycoproteins that act as receptors for vascular endothelial growth factors and are involved in the process of tumor angiogenesis. Objective: The aim of this work was to study the prognostic value of neuropilin-1 (NRP-1) expression in children with B-lineage ALL. Subjects and methods: This study was conducted on fifty children with newly diagnosed B-lineage ALL who were admitted in Oncology Unit, Pediatric Department, Tanta University Hospitals in the period from August 2010 to March 2014 including 32 males and 18 females with their ages ranged from 3-17 years and mean value of 9 ± 3.5 years. Twenty healthy age and sex matched children serving as a control group was also included in this study. Patients were subjected to history taking, clinical examination and laboratory investigations including; complete blood count, serum LDH levels, bone marrow aspiration, cytochemistry, immunophenotyping and estimation of nuropilin-1 expression on blast cells by flow cytometry. Results: The present study revealed highly significant differences in NRP-1 expression between patients with B-lineage ALL and controls. The highest levels of NRP-1 expression were noted in pre-B ALL (74.04%) followed by early pre-B (23.55%) and lastly mature B-ALL (12.06%) with significant difference between the three subtypes. NRP-1 expression was significantly associated with higher white blood cells count, bone marrow blasts percentage and serum lactate dehydrogenase levels at diagnosis and there were significantly higher levels of NRP-1 expression on BM blasts at diagnosis in patients who subsequently relapsed or died later on during the period of follow up compared to those who achieved and maintained complete remission. Also, patients with higher NRP-1 expression had significantly shorter overall survival (OS) and disease free survival (DFS) than patients with low NRP-1 expression. Conclusion: Our findings suggest that neuropilin-1 has bad prognostic impact in children with B-lineage ALL and so we can recommend the incorporation of NRP-1 as a prognostic marker in children with B-lineage ALL to offer a chance for intensive therapeutic intervention in patients designated as having poor prognosis.

Folate Pathway Gene Expression Differs in Genetic Subtypes of Acute Lymphoblastic Leukemia and Influences Methotrexate Pharmacodynamics.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 452-452
Author(s):  
Leo Kager ◽  
Meyling H. Cheok ◽  
Wenjian Yang ◽  
Gianluigi Zaza ◽  
Ching-Hon Pui ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cells ◽  
Cancer Resistance ◽  
Childhood All ◽  
Pathway Gene ◽  
Folate Pathway ◽  
B Lineage ◽  
Lower Expression

Abstract Methotrexate (MTX) is an essential treatment component for acute lymphoblastic leukemia (ALL). The ability of leukemia cells to accumulate MTX in its polyglutamylated form (MTXPG) is recognized as an important determinant of its antileukemic effect. We measured in vivo MTXPG accumulation in leukemia cells from 101 children with ALL, and established that blasts of B-lineage ALL with either the TEL-AML1 (n=24 patients, median 911, range 338 to 5906 pmol/109 blasts) or E2A-PBX1 gene fusion (n=5, median 553, range 364 to 800 pmol/109 blasts) or T-lineage ALL (n=14, median 572, range 284 to 1468 pmol/109 blasts) accumulate significantly lower MTXPG, compared to those of other B-lineage ALL (BNHD, n=39, median 2210, range 186 to 9722 pmol/109 blasts) or hyperdiploid ALL (BHD, n=19, median 4375, range 377 to 9206 pmol/109 blasts) (E2A-PBX1 versus BHD, p=0.008; E2A-PBX1 vs. BNHD, p=0.010; TEL-AML1 vs. BHD, p<0.001; TEL-AML1 vs. BNHD, p=0.004; T-ALL vs. BHD and BNHD, p<0.001; p-values are from pair-wise comparisons using Wilcoxon rank sum test, adjusted for multiple testing using Holm’s method). To elucidate mechanisms underlying these differences in MTXPG accumulation, we used oligonucleotide microarrays (Affymetrix® HG-U133A) to analyze expression of 32 folate pathway genes (53 probe sets) in diagnostic bone marrow blasts from 197 children with ALL. This revealed ALL subtype-specific patterns of folate metabolism gene expression and identified differences in gene expression that discriminated the MTXPG accumulation phenotype in ALL cells. We found significantly lower expression of the reduced folate carrier (SLC19A1, MTX uptake transporter) in E2A-PBX1 ALL; significantly higher expression of breast cancer resistance protein (ABCG2, MTX efflux transporter) in TEL-AML1 ALL; and lower expression of FPGS (catalyzes formation of MTXPG) in T-ALL; consistent with lower MTXPG accumulation in these ALL subtypes. These findings reveal distinct mechanisms of subtype-specific differences in MTXPG accumulation and point to new strategies to overcome this potential cause of treatment failure in childhood ALL.

A Plateau after 30 Months of Follow-Up in B -Lineage Childhood Acute Lymphoblastic Leukemia (ALL) with t(1;19)(q23;p13)/E2A-PBX1?.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1441-1441
Author(s):  
André Baruchel ◽  
Sylvie Chevret ◽  
Anne Auvrignon ◽  
Paola Ballerini ◽  
Gérard Michel ◽  
...  
Keyword(s):  
Median Time ◽  
Burkitt Lymphoma ◽  
Lymphoblastic Leukemia ◽  
Fusion Transcript ◽  
Wilcoxon Test ◽  
Response To Treatment ◽  
Control Group ◽  
Childhood All ◽  
Secondary Tumor ◽  
B Lineage

Abstract Late events are observed in B-lineage ALL with no plateau seen if a sufficient observation period is provided. The prognosis of childhood ALL associated to the t(1;19)(q23;p13)/E2A-PBX1 translocation has improved over the two last decades. The purpose of this study is to define the kinetics of relapse in a large cohort of children and to raise the possibility of a plateau in that entity. We identified 110 children treated for a B-lineage ALL harbouring a t(1;19(q23;p13) and/or E2A-PBX1 fusion transcript from 1987 to 2004 in the FRALLE protocols (FRALLE 83: n= 3, FRALLE 87–89: n=18, FRALLE 92 (phase II): n=10, FRALLE 93: n=48, FRALLE 2000 (still opened: n=31). Analysed features included: male sex (50, 45%), age (median: 6.9y; Q1–Q3: 3.5–12), CNS disease (4, 3.5%), leucocytosis (median: 21.4 G/L; Q1–Q3: 10.8–53.4), D8 poor prednisone response (PPR) (5/79, 6%), M1 D21 marrow response (103, 94%), and CR (108, 98%). For an accurate comparison, the subgroup of pts with t(1;19) included in the FRALLE 93 protocol (n=48) was compared to the 1,147 children aged more than 1 y with B- lineage ALL treated in the same protocol. Significant differences in the t(1;19) cohort were: excess of girls (65% vs. 46%; p= .01), and older age (median: 7 vs. 4.7; p= .01)). No differences in early response to treatment (D8, D21, D35) were seen. All the 110 patients received chemotherapy only, except 3 who received an autologous BMT for D8 PPR as recommended by the FRALLE 93 protocol. At a median FU of 65 months, 18 events have been recorded including 17 relapses (bone marrow: 13, CNS: 4) and 1 secondary tumor (abdominal Burkitt lymphoma) giving a 5 y and 10 y EFS of 78.7%. If “modern era” only is considered (> 1992), 5 y and 10 y EFS is 85.5%. Relapses occurred at a median time of 422 days (range: 72–899) in the whole t(1;19) cohort. In those from FRALLE 93, the median time to relapse (MTTR) was 280 days, that is significantly lower than the one observed in the control group defined above (MTTR = 894 days, Wilcoxon test, p = .01). Conclusions: We confirm that a high cure rate is now associated to that subgroup of childhood ALL. The main finding is that no event except from the secondary Burkitt lymphoma (1705 d) was registered after 30 months from diagnosis in that cohort of 110 children with t(1;19)/E2A-PBX1 translocation associated ALL. It is then conceivable to announce cure at 36 months in that subgroup with an extremely low possibility of mistake, thus much earlier and with more confidence than in the other B-lineage ALL.

Pentoxifylline During Steroid Window At Induction To Remission Increases Apoptosis In Childhood Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2623-2623
Author(s):  
Oscar Gonzalez-Ramella ◽  
Jimenez-Lopez Xochiquetzatl ◽  
Sergio Gallegos-Castorena ◽  
Pablo Ortiz-Lazareno ◽  
Jose Manuel Lerma-Diaz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Cancer Cells ◽  
Lymphoblastic Leukemia ◽  
Remission Induction ◽  
Control Group ◽  
Induction Phase ◽  
Study Group ◽  
Significant Difference

Abstract Introduction Acute lymphoblastic leukemia (ALL) is the most common cancer diagnostic in children, and it represents the second death cause in this population. Despite advances in the treatment of childhood ALL, there are small portion of patients whom still succumb to this disease. A reduced apoptosis in cells plays an important role in carcinogenesis. This phenomenon is an important component in the cytotoxicity induced by anticancer drugs. A currently challenge is the chemotherapy resistance of tumor cells, inhibiting the apoptosis induced by chemotherapy. Pentoxifylline, (PTX) has been studied for its role on increase of apoptosis on cancer cells by different pathways. Our group has reported its efficacy in vitro and ex vivo in increasing apoptosis induced by chemotherapy drugs such as adriamycin and cisplatin in fresh leukemic human cells, lymphoma murine models and cervical cancer cells. We conducted a phase 1 controlled randomized trial to evaluate the efficacy of adding PTX to the steroid window during the remission induction phase in new diagnosed children with ALL. Methods We included all children from both sexes from 9 months to 17 years old during October 2011 to December 2012. Patients were divided into 3 groups, the first one as a non-malignant control group (NL group) included children with a non-hematology disease in which bone marrow aspiration (BMA) was mandatory in order to reach the diagnosis. The second one, the ALL control group whom received prednisone (PRD group) for the steroid window at 40mg/m2/day PO from day -7 to day 0; and then the third one (PTX group), the study group which included children receiving the steroid phase with PRD as early described, plus PTX at 10mg/kg/day IV divided in 3 doses, at the same days as recommended in our treatment protocol (Total Therapy XV). For all 3 groups a BMA was performed at diagnosis, for PRD group as well as PTX group, a second BMA was also collected at day 0. Apoptosis was evaluated by means of Annexin V Apoptosis Detection Kit FITC/PI (eBioscience¨, San Diego, CA, USA) in 1×106 bone marrow mononuclear cells. We measured minimal residual disease (MRD) by flow cytometry at day 14 to demonstrate complete remission in leukemic patients. Statically analysis was performed by U Man Whitney. Results We enrolled 32 patients: 10 in NL group; 11 in PRD group; and 11 in PTX group. The median age of all groups was 6 years (range 9 months-17 years). In PRD group, patient 1 abandoned treatment after administration of day 0, nevertheless the second BMA sample was collected. Patient number 7 died at day 4 due to complications from tumor lysis syndrome. Consequently, in these patients we were not able to measure MRD and BM aspiration at day 14. Except one patient in PRD group, all achieved complete remission at day 14. We did not find any significant difference between NL group and PRD and PTX groups before intervention (U=32 p=0.7; U=28.5 p=0.48 respectively). There was no significant difference between treatment groups before intervention (U= 37 p=0.79). However, after treatment we found an important difference between PRD and PTX groups, we observed an increase in apoptosis in PTX group in comparison with PRD group (U=17.5 p=0.04). There were no adverse effects during treatment. Conclusions The present study is the first one that shows the efficacy of PTX in increasing apoptosis induced by PRD in new ALL diagnosed children, whom have not received any treatment yet. This might be helpful, not only in patients with relapse, but to increase the overall cure rate in ALL. Further studies are needed to prove this hypothesis. With this objective, our study group is already planning a second trial were PTX will be given during all remission induction phase. Experimental reports strongly suggest that PTX induces inhibition of the transcription factor NF-ĸB, by inhibiting survival gens and facilitating apoptosis. To prove it, we are currently processing these patients' samples to know their genetic expression. Disclosures: No relevant conflicts of interest to declare.

Long-term evaluation of a CNS prophylaxis trial--treatment comparisons and outcome after CNS relapse in childhood ALL: a report from the Childrens Cancer Study Group.

1987 ◽  
Vol 5 (10) ◽  
pp. 1646-1654 ◽  
Author(s):  
J A Ortega ◽  
M E Nesbit ◽  
H N Sather ◽  
L L Robison ◽  
G J D'Angio ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Current Status ◽  
Intrathecal Methotrexate ◽  
Childhood All ◽  
Cns Disease ◽  
Cns Prophylaxis ◽  
Cns Relapse ◽  
Significant Difference

The current status of children with acute lymphoblastic leukemia (ALL) who had developed CNS disease while being treated on protocol CCG-101 was investigated. Seven hundred thirty-six eligible patients were entered into the study between June 1972 and July 1974. All children who were greater than 18 months of age were eligible for randomization to a CNS prophylaxis trial for which one regimen gave only a short course of intrathecal methotrexate (IT MTX) as prophylaxis. All other regimens included radiation therapy as prophylaxis. Current follow-up (median, greater than 10 years) shows no significant difference by standard life-table analysis for ultimate survival, although a substantial excess of CNS episodes occurred on the IT MTX regimen. Of the 675 patients who completed induction therapy and achieved remission in the study, 100 (14.8%) developed CNS disease as the first evidence of relapse. Fifty-five of these 100 had no subsequent CNS episodes. Only 17 of these 55 patients are surviving without further relapses since the CNS episode. The median time to isolated CNS relapse was 457 days. Time to the initial CNS relapse was found to be the most important factor for predicting outcome. Thirty-five of the 55 patients with isolated relapse subsequently relapsed in the bone marrow, and of these, 32 have died. Twenty patients of the 100 with CNS disease as the first evidence of relapse developed two episodes of CNS involvement and 17 of these 20 patients subsequently relapsed in the bone marrow; only one patient survived. Twenty-five patients of the 100 have shown a pattern of chronic CNS disease with multiple CNS relapses. The overall disease-free survival for the 100 patients who developed one or more relapse was only 16%. These data demonstrate that the occurrence of a CNS relapse is an indicator of poor subsequent outcome. Comparison of results of groups receiving different CNS prophylaxis required careful consideration of the entire pattern of relapses and mortality.

Two Decades of Progresses in Adolescents with Acute Lymphoblastic Leukemia (ALL) Treated in the FRALLE Protocols: Adolescence Is No More a Bad Prognostic Feature If an Intensive Chemotherapy Is Applied.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1852-1852
Author(s):  
Andre Baruchel ◽  
Marie-Françoise Auclerc ◽  
Yves Perel ◽  
Françoise Mechinaud ◽  
Anne Auvrignon ◽  
...  
Keyword(s):  
Young Adults ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Intensive Chemotherapy ◽  
Pilot Phase ◽  
Adult Type ◽  
Childhood All ◽  
Significant Difference ◽  
Prognostic Feature ◽  
B Lineage

Abstract Adolescence has been claimed since the seventies to be associated to a a bad prognosis in childhood ALL. Out of 4658 patients with ALL, 258 adolescents (15–20 year old)(5.5%) were treated in the successive FRALLE 83, FRALLE 87–89, FRALLE 92 (pilot phase), FRALLE 93 and FRALLE 2000 protocols. The main characteristics were: a sex ratio of 1.8 (M/F), a B-lineage in 71% of the cases vs T lineage in 29%, and a median WBC of 12 G/L (9–1000). Translocation and fusion transcripts were searched for in 120 evaluable BCP-ALL: t(9;22)/BCR-ABL, 8 pts (6%); t(1;19)/E2A-PBX1, 12 pts (10%); t(4;11)/MLL-AF4, 4 pts (3%). Out of 75 evaluable pts t(12;21)/TEL-AML1 was found in only 4 pts (3%). 242 out of 258 adolescents were in CR at the end of induction therapy(EOI)(94%) without any significant difference according to the era. Nevertheless a major difference in the 3y and 5y EFS was found: Number of pts CR at EOI (%) 3y EFS (%) 5y EFS (%) 10y EFS (%) *: p=.04; **: p=.04 Eighties (F83, F87–89) 100 93 42 +/− 5 35 +/− 5 35 +/− 5 Nineties (F92, F93) 84 93 71 +/−5* 67 +/− 5** 67 +/− 5 2000– (F2000) 74 96 86 +/−5* 86 +/− 10** NYA The main modification introduced in the nineties was the adoption of a double delayed intensification for the good early responders. Autologous BMT or allogenic BMT were indicated in bad early responders (D8 poor prednisone response, D21 marrow M3 response) and/or unfavourable cytogenetics. The better results of the 2000 protocol can mainly be explained by the further intensification of chemotherapy between induction and delayed Intensification 1 and before delayed Intensification 2. These better results were obtained despite decreasing the indications of BMT (6 performed vs 20 in the nineties) and of CNS irradiation (100% in the nineties vs 35% in the current era, including the TBI for BMTs). Conclusions:excellent results can now be achieved in adolescents with ALLthis study emphasizes again the need to treat adolescents with ALL according to pediatric intensive protocols and not “adult-type” protocols, as we recently suggested (Boissel et al, J Clin Oncol 2003).Whether this could also be applied to young adults remains to be demonstrated but seems appealing.

Evaluation of FOXP1 gene expression in pediatric B-cell precursor acute lymphoblastic leukemia patients at remission induction therapy

2020 ◽  
Author(s):  
Gholamhossein Tamaddon ◽  
Mehran Bahraini ◽  
Alieh Fazeli
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Cell Line ◽  
Lymphoblastic Leukemia ◽  
Remission Induction ◽  
Control Group ◽  
Cell Precursor ◽  
New Diagnosis

Background: Transcription factors (TFs) play a key role in the development, therapy, and relapse of B-cell malignancies, such as B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Given the essential function of Forkhead box protein P1 (FOXP1) transcription factor in the early development of B-cells, this study was designed to evaluate FOXP1 gene expression levels in pediatric BCP-ALL patients and NALM6 cell-line. Materials and Methods: This case-control study was done on the NALM6 cell-line and bone marrow specimens of 23 pediatric BCP-ALL patients (median age: 7.5 years; range: 2.0 – 15.0 years) at different clinical stages including new diagnosis, 15th day after the treatment, and relapse. Also, 10 healthy children were included as the control group. FOXP1 gene expression was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). The correlation analysis was performed between the FOXP1 gene expression and patients’ demographic and laboratory characteristics. Results: The results showed that FOXP1 gene expression was significantly downregulated in the NALM-6 cell-line (median=0.05, P<0.001) and patients at new diagnosis (median=0.06, p<0.0001), and relapse (median=0.001, p<0.0001) phases, compared to the control group (median=0.08). FOXP1 gene expression on the 15th day of the treatment was significantly higher than its level at the new diagnosis stage (p<0.001). Moreover, FOXP1 gene was significantly downregulated in the relapse phase compared to the new diagnosis. Patients whose number of bone marrow blasts on the 15th day of the treatment was below 5% had higher FOXP1 gene expression at the diagnosis phase (Spearman’s correlation, P<0.05, r=-0.485) and higher ratio of diagnosis/day 15 (p<0.001, Mann-Whitney U test). Conclusions: FOXP1 levels could be a potential biomarker of therapy response in remission induction therapy for pediatric BCP-ALL patients.

Unrelated Allogeneic Stem Cell Transplantation with Myeloablative Conditioning in Adults with Acute Lymphoblastic Leukemia in Remission: Peripheral Blood or Bone Marrow?.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 174-174 ◽  
Author(s):  
Nadezda Basara ◽  
Myriam Labopin ◽  
Tapani Ruutu ◽  
Axel Zander ◽  
Oliver Ottmann ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Peripheral Blood ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Peripheral Blood Stem Cells ◽  
Significant Difference ◽  
B Lineage ◽  
Group B

Abstract With the objective to compare outcomes of peripheral blood stem cells (PBSC) and bone marrow (BM) in patients with ALL in remission, we have studied 388 adults with ALL given an unrelated BMT and 337 PBSCT reported to EBMT from 1998 to 2004. The donors were HLA identical (HLA-A and -B low resolution and HLA-DRB1 allelic typing). Median age was 27 years for BM (range 16–63, male 60%) and 30 years for PBSC (range 16–63, male 62%), respectively. Fifty nine and 68% of patients were transplanted in first complete remission (CR1) in the BM and PBSC groups. Female donor to male recipient constellation was 18% in the BM and 15% in the PBSC group. Total Body Irradiation (TBI)-based preparative regimens were given in 85% and 88% of patients in the BM and PBSC group respectively. GvHD-prophylaxis consisted of cyclosporine A (CsA) (6% and 4%), CsA and methotrexate (77% and 58%) or in vivo T-cell depletion (17% and 38% in BM and PBSC group). With the median follow-up of 19 and 13 months, the incidence of GvHD grade II–IV was 37% in the BM group and 39% in the PBSC group (p=0.39). Probabilities of LFS, NRM and relapse were calculated using the Kaplan-Meier estimate. LFS was 45+/−3% vs 36+/−3% (p=0.03) nonrelapse related mortality (NRM) was 30+/−3% and 34+/−4 (p=0.39) while incidence of relapse (RI) was 24+/−4% and 30+/−5% (p=0.13), in the BM and PBSC groups respectively. Three years LFS for the patients transplanted in CR1 was 48% (BM) and 42% (PBSC, p=0.48). In a multivariate analysis adjusting for differences in patients with CR1 in both groups showed not statistically difference for RI, NRM and LFS. However, 3-years LFS for patients transplanted in CR2 was significantly higher in the BM (n=159) compared to the PBSC group (n=106) (40% and 27%, p&lt;0.04). The RI was significantly lower in BM compared to PBSC (33% vs 54%, p&lt;0.01) without there being a detectable difference in NRM at 3 years (40% vs 40%, p= 0.59). This finding led us to look in more details CR2 group of ALL patients. There was no statistically difference between patients receiving BM or PBSC regarding the incidence of Ph’+ or t(4;11) (20% vs 37% in BM and PBSC group), B-lineage (80% vs 76%, respectively) and T-lineage ALL (20% vs 24%, respectively), but patients were older in the PBSC group at the time of transplant (24y vs 27y, p= 0.02) and they received more in vivo T-cell depleted transplants by using antithymocyte globulin (p=0.02). The interval from diagnosis to transplant was longer in BM group (977d vs 687 d in BM and PBSC group, p=0.02). Three years LFS with an interval from diagnosis to Tx &gt; 30 months was not different in BM and PBSC group (48% vs 42%, p=0.65). However, there was a significant difference in LFS in BM group (32%) in comparison to PBSC group (17%) if an interval from diagnosis to Tx &lt;30 mo (p=0.001). The incidence of chronic GvHD in adult ALL in CR2 was 53% and 40% in PBSC and BM, respectively (p=0.09). After statistical adjustments for differences between the two groups, the interval from diagnosis to Tx &lt;30 mo was a risk factor for LFS. In addition, TBI-based conditioning and the interval from diagnosis to Tx &lt;30 mo were risk factors for RI. In conclusion, UD-SCT with either BM or PBSC as a graft source is an effective treatment for adult ALL patients in CR1 and CR2 when the interval between diagnosis and transplant is superior to 30 months. In patients transplanted in CR2 with an interval from diagnosis to Tx&lt;30 months outcomes are worse independent of the cell source used.

scholarly journals Reductive regulation of BECN1 gene in adult Egyptian patients with do novo AML

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Manal Fawzy Ghozlan ◽  
Botheina Ahmed Thabet Farweez ◽  
Nesma Ahmed Safwat ◽  
Noha Bassiouny Hassan ◽  
Walaa Ali Elsalakawy
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Peripheral Blood ◽  
De Novo ◽  
Quantitative Polymerase Chain Reaction ◽  
Control Group ◽  
Significant Difference ◽  
Egyptian Patients ◽  
Blast Cells ◽  
De Novo Aml

Abstract Background Acute myeloid leukaemia (AML) is a clonal haematopoietic disease characterized by the proliferation of immature blast cells in the bone marrow and peripheral blood. Autophagy is an inherent cellular route by which waste macromolecules are engulfed within autophagosomes prior to their fusion with cytoplasmic lysosomes for degradation. The BECN1 gene encodes the Beclin-1 protein, which regulates autophagy. Few reports have investigated BECN1 gene expression and its value in AML patients. Results This randomized case-control study included 50 newly diagnosed AML patients, in addition to 20 subjects as a control group. BECN1 gene expression was assessed using real-time quantitative polymerase chain reaction (qRT-PCR). The median level of BECN1 gene expression in AML patients was 0.41 (IQR 0.29–1.03) in comparison to 1.12 (IQR 0.93–1.26) in the control group (P = 0.000). Seventy-two percent of AML patients showed reduced BECN1 gene expression, which was highly significantly associated with intermediate and adverse cytogenetic risk. Reduced BECN1 gene expression was associated with older age, higher total leukocyte counts, the presence of peripheral blood blast cells, a higher percentage of bone marrow blast cells, and higher expression of CD34 and CD117. FLT3-ITD mutation was detected in 14 patients (38.9%), all of whom showed reduced BECN1 gene expression (P = 0.006). BECN1 gene expression was also reduced in non-responder AML patients, with a highly statistically significant difference (P = 0.002). Conclusion A reduction in BECN1 gene expression might indicate a poor prognosis in adult Egyptian patients with de novo AML. Decreased BECN1 gene expression is associated with a higher risk of resistance to treatment. Targeting autophagy pathways may help in the treatment of AML patients.

Expression of BECN1 gene in Acute Myeloid Leukemia: Association with Hematological and Clinical Parameters

QJM ◽  
2021 ◽  
Vol 114 (Supplement_1) ◽  
Author(s):  
Mohamed Moustafa Ahmed ◽  
Manal Fawzy Ghozlan ◽  
Walaa Ali Mohamed ◽  
Nesma Ahmed Safwat ◽  
Noha Bassiouny Hassan
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Control Group ◽  
Fish Analysis ◽  
Newly Diagnosed ◽  
Significant Difference ◽  
Acute Myeloid

Abstract Background In acute myeloid leukemia (AML), there is copy number loss in autophagic genes such as BECN1. Accordingly, decreased autophagy and the development of AML are related. BECN1 is a critical mediator that influences the onset and progress of autophagy. Objective To investigate the expression status of BECN1 gene in newly diagnosed adult AML patients and its association with various hematological parameters and clinical outcomes. Methods Case control study to study BECN1 gene expression variability between 50 newly diagnosed adult AML patients and 20 healthy age and sex matched controls, with follow up of the patients to detect its effect on induction therapy. All AML patients underwent full history taking, through clinical examination, laboratory investigations such as complete blood count (CBC) with examination of peripheral blood and bone marrow Leishman stained films, immunophenotyping, cytogenetic analysis (karyotyping/FISH analysis) and BECN1 gene expression analysis using real-time quantitative polymerase chain reaction (qRT-PCR). Results In our study, a highly significant difference was found as regards reduced expression of BECN1 gene in patients group compared to control group. We also found reduced BECN1 gene expression in both intermediate and adverse risk groups compared to favorable risk group. Reduced expression of BECN1 gene was associated with increasing age and total leukocytic count (TLC), peripheral blood (PB) and bone marrow (BM) blasts, the presence of FLT3-ITD mutation, CD34 and CD117 and in non-responders group. No statistically significant difference was found as regards haemoglobin (Hb) level, platelet (PLT) count and FAB subtypes. Conclusion Autophagy plays an important role in the pathogenesis of AML. Furthermore; the reductive regulation of the BECN1 gene may carry a poor prognosis and is associated with many well established bad prognostic factors especially FLT3-ITD mutation. Targeting autophagy pathways especially its major regulator (BECN1 gene) may become an effective and promising new line of therapy for AML patients.

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