Stem Cell Gene Mutation and MTHFR C677T Variants Increased“Risk” in Acute Myeloid Leukemia Patients

2012 ◽  
Vol 01 (03) ◽  
Author(s):  
Ajit K Saxena
2016 ◽  
Vol 214 (2) ◽  
pp. 359-380 ◽  
Author(s):  
Carsten Riether ◽  
Christian M. Schürch ◽  
Elias D. Bührer ◽  
Magdalena Hinterbrandner ◽  
Anne-Laure Huguenin ◽  
...  

Aberrant proliferation, symmetric self-renewal, increased survival, and defective differentiation of malignant blasts are key oncogenic drivers in acute myeloid leukemia (AML). Stem cell gene signatures predict poor prognosis in AML patients; however, with few exceptions, these deregulated molecular pathways cannot be targeted therapeutically. In this study, we demonstrate that the TNF superfamily ligand–receptor pair CD70/CD27 is expressed on AML blasts and AML stem/progenitor cells. CD70/CD27 signaling in AML cells activates stem cell gene expression programs, including the Wnt pathway, and promotes symmetric cell divisions and proliferation. Soluble CD27, reflecting the extent of CD70/CD27 interactions in vivo, was significantly elevated in the sera of newly diagnosed AML patients and is a strong independent negative prognostic biomarker for overall survival. Blocking the CD70/CD27 interaction by mAb induced asymmetric cell divisions and differentiation in AML blasts and AML stem/progenitor cells, inhibited cell growth and colony formation, and significantly prolonged survival in murine AML xenografts. Importantly, hematopoietic stem/progenitor cells from healthy BM donors express neither CD70 nor CD27 and were unaffected by blocking mAb treatment. Therefore, targeting CD70/CD27 signaling represents a promising therapeutic strategy for AML.


Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3305-3305
Author(s):  
Sameh Ayari ◽  
Mohamad Mohty ◽  
Karin Bilger ◽  
Gaelle Guillerm ◽  
Denis Guyotat ◽  
...  

Abstract Abstract 3305 Poster Board III-193 Patients with breast carcinoma who received Radio and/or chemotherapy, have an increased risk for developing therapy-related myelodysplastic syndromes/acute myeloid leukemia (1-5%). Such secondary AMLs have often poor prognosis when treated with conventional chemotherapy. This retrospective series assessed the outcome of 29 female patients who were reported to the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire Registry, and who were treated with allo-SCT for secondary MDS/AML developing after initial therapy for breast cancer. The median age of patients at time of breast cancer treatment was 51 (range, 31-62) years. The median age at time of allo-SCT was 53 (range 31-63) years. Diagnosis included 21 AML and 8 MDS. Cytogenetics: four patients had CBF abnormalities, 10 had 11q23 abnormalities, 5 had an intermediate caryotype and 3 had unfavourable one. At time of allo-SCT, 21 patients were in complete remission (CR), while 8 had a refractory/relapsed disease. PBSCs were used as stem cell source in 18 patients, while 9 patients received classical bone marrow and one patient received an unrelated umbilical cord blood. Patients received a median of 5.2 ×10e6/Kg CD34+ cells. A matched related donor was used in 23 cases (82%) and an unrelated donor in 5 cases (18%). Conditioning regimen was myeloablative (Cy-TBI or Bu-Cy) in 7 cases (24%) and reduced-intensity in 22 cases (76%). Twenty four patients engrafted with a median time of 18 (range, 9-32) days for ANC>500/μL. Seven (24%) patients experienced grade 2-4 acute GVHD. Also, 7 patients (24%) experienced chronic GVHD (5 extensive and 2 limited). With a median follow-up of 24 (range, 3-129) months, 16 patients (55%) were still alive. Disease progression accounted for 6 deaths while transplant related causes (infection n=4, GVHD n=1, MOF n=1, cardiac failure n=1) occurred in 7 cases. The Kaplan-Meier estimates of overall and disease-free survival at 2 years were at 54 and 38% respectively. These results highlight the poor outcome of secondary leukemia occurring after therapy for breast cancer, even with the use of allo-SCT. Innovative maintenance approaches such as early use of hypomethylating or immunomodulatory agents after allo-SCT aiming to decrease the relapse are warranted. Disclosures No relevant conflicts of interest to declare.


2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Shahira Kamal Anis Botros ◽  
Nesrine El Gharbawi ◽  
Gehan Shahin ◽  
Hend Al Lithy ◽  
Mahmoud El Sherbiny

Abstract Background It has been postulated that the interaction between environmental risk factors and genetic susceptibility is a possible cause for the development of acute myeloid leukemia (AML). Cytochrome P450 (CYP) detoxification enzymes are responsible for the elimination of oxidative stress. Genetic polymorphisms in these enzymes may cause AML due to enhanced accumulation of reactive oxygen species. To study the association between CYP3A4 (A290G) and CYP2B6 (G516T) gene polymorphisms and the predisposition and prognosis of AML, 50 upfront AML patients and 50 healthy individuals were genotyped for CYP2B6 (G516T) and CYP3A4 (A290G) single-nucleotide polymorphisms (SNPs) using polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) technique. The polymorphisms were evaluated in relation to the response to chemotherapy and survival. Results CYP2B6 gene mutation carries a threefold risk of developing AML (odds ratio [OR], 3.0; 95% confidence interval [CI], 1.3–6.9), whereas CYP3A4 gene mutation carries approximately fourfold risk (OR, 3.8; 95% CI, 1.4–10.1). The presence of combined gene mutation conferred about 15-fold increased risk of developing AML compared with the presence of a single gene mutation (OR, 14.8; 95% CI, 1.8–124.2). CYP3A4 gene mutation is associated with worse overall survival (P = 0.030). Conclusion CYP enzyme gene polymorphisms are associated with the development of AML. Elimination of oxidative stress in genetically susceptible individuals may decrease the risk of AML and may improve survival.


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