Association Analysis of TP53 rs1042522, MDM2 rs2279744, rs3730485, MDM4 rs4245739 Variants and Acute Myeloid Leukemia Susceptibility, Risk Stratification Scores, and Clinical Features: An Exploratory Study

This study aimed to explore the associations between the TP53 rs1042522 (TP53 Arg72Pro), MDM2 rs2279744 (MDM2 309T>G), rs3730485 (MDM2 del1518), MDM4 rs4245739 (MDM4 34091 C>A) variants and odds of developing acute myeloid leukemia (AML) in a cohort of 809 adult subjects, consisting of 406 healthy controls and 403 AML patients. Model-based multifactor dimensionality reduction (MB-MDR) framework was used to identify the interactions of the mentioned variants and their association with AML risk. Associations of the mentioned variants with clinical features of AML, somatic mutations, and response to treatment were also evaluated. Significant associations between TP53 rs1042522 and MDM4 rs4245739 variants and AML susceptibility were noticed. MB-MDR and logistic regression analysis revealed an interaction between MDM2 rs2279744 and TP53 rs1042522, between MDM4 rs4245739 and MDM2 rs3730485, as well as significant associations with AML susceptibility. Several associations between the mentioned variants and clinical features of AML and somatic mutations were also noticed. Individually, the variant genotypes of TP53 rs1042522 and MDM4 rs4245739 were associated with AML susceptibility, but their interaction with MDM2 rs2279744 and rs3730485 modulated the risk for AML. The variant genotypes of TP53 rs1042522 were associated with adverse molecular and cytogenetic risk and also with NPM1 mutations.

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Circulating Endothelial Cells Are an Indicator of Response to Treatment in Acute Myeloid Leukemia Patients.

Blood ◽

10.1182/blood.v106.11.2776.2776 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2776-2776

Author(s):

Agnieszka Wierzbowska ◽

Tadeusz Robak ◽

Anna Krawczynska ◽

Agata Wrzesien-Kus ◽

Agnieszka Pluta ◽

...

Keyword(s):

Endothelial Cells ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Circulating Endothelial Cells ◽

Response To Treatment ◽

Control Group ◽

Healthy Controls ◽

Endothelial Progenitor ◽

Activation Markers ◽

Acute Myeloid

Abstract Introduction. The circulating endothelial cells (CEC) are proposed to be a noninvasive marker of angiogenesis. The number of CEC in peripheral blood of patients (pts) with acute myeloid leukemia (AML) has not been investigated so far. Patients and Methods. We evaluated the count of resting (rCEC) and activated (aCEC) CEC and circulating endothelial progenitor cells (CEPC) as well as apoptotic CEC (CECAnnV+) in 62 AML pts at the time of diagnosis and 30 healthy controls. Additionally in 26 pts measurements were performed at the time of response evaluation and in 15 pts also 24 h after the first and last dose of chemotherapy. The levels of CEC were correlated with known prognostic factors and response to treatment. CEC were evaluated by the four colour flow cytometry using a panel of previously described monoclonal antibodies and an appropriate analysis gate. CEPC were defined as negative for hematopoietic marker CD45 and positive for endothelial cells markers CD34, CD31 and the endothelial progenitor marker CD133. Resting CEC were defined as CD45−, CD133−, CD31+, CD34+, CD146+ and negative for activation markers (CD105, CD106). CD105 or CD106 positive mature endothelial cells were classified as activated CEC. Apoptotic CEC were CD146 and Annexin V positive. Results. In untreated AML pts we observed 10-fold higher CEC level (median 29,3/μL) than in the control group (2,95/μL) p<0,0001. The numbers of aCEC (12,7/μL), rCEC (12,3/μL) and CEPC (1,7/μL) were significantly higher in AML pts at diagnosis when compared to healthy controls (aCEC 0,9/μL, rCEC 1,6/μL and 0,1/μL; p<0,0001). CECAnnV+ count was also 10-fold higher in AML (1,5/μL) than in controls (0,15/μL; p<0,0001). Both CEC and CECAnnV+ counts did not correlate with WBC, hemoglobin and platelets count as well as percentage of blasts in bone marrow and absolute blast count. The positive correlations between CEC number and CEPC count (r=0,435; p<0,001), CECAnnV+ count (r=0,502; p<0,01) as well as LDH activity (r=0,328; p<0,02) were found. The significant decrease of aCEC and rCEC numbers 24 hours after the first dose of chemotherapy was noted in patients who achieved complete remission (CR)(p<0,04) but not in pts refractory to treatment. Moreover aCEC, rCEC, CEPC and CECAnnV+ counts determined at the time of response’s evaluation were significantly lower then at the time of diagnosis in pts who achieved CR (p<0,01) and did not differ in refractory AML. There was no difference between levels of both viable and apoptotic CEC in AML pts in CR and in the control group (p>0,05). Conclusions. The CEC and CECAnnV+ levels are significantly higher in AML patients than in healthy subjects and correlate with response to treatment. Further investigation should be undertaken to better determine their prognostic and therapeutic value.

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The prospective prognostic value of the immune checkpoint BTLA expression in adult acute myeloid leukemia patients

Egyptian Journal of Medical Human Genetics ◽

10.1186/s43042-021-00198-1 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Sara M. Radwan ◽

Nooran S. Elleboudy ◽

Nermeen A. Nabih ◽

Amal El-kholy ◽

Amany M. Kamal

Keyword(s):

Acute Myeloid Leukemia ◽

Immune Checkpoint ◽

Myeloid Leukemia ◽

Immune Surveillance ◽

Response To Treatment ◽

Healthy Controls ◽

Survival Times ◽

Over Expression ◽

Kaplan Meier ◽

Acute Myeloid

Abstract Background One of the crucial functions of the immune system is to prevent tumorigenesis, yet cancer occurs when malignant cells manage to evade immune surveillance via multiple strategies. Accordingly, this study aimed at assessing the potential significance of the novel immune checkpoint B and T lymphocyte attenuator (BTLA) as a prognostic marker in acute myeloid leukemia (AML), in addition to how it relates to response to treatment and patients’ survival. Thus, mRNA expression of BTLA was investigated on peripheral blood in 60 AML patients and 15 healthy controls. Results BTLA expression was found to be significantly elevated (p = 0.024) in the tested AML cases in comparison with healthy controls. Moreover, BTLA was over-expressed in the CD13, CD33, and HLA-DR positive cases as compared to their negative counterparts (p = 0.003; p < 0.001, and p = 0.001, respectively), and cases showing BTLA over-expression had significantly poorer overall survival times (p = 0.001) as confirmed by Kaplan–Meier survival analysis. Conclusion These observations suggest that BTLA over-expression may be associated with reduced immunity against tumors and could be recommended as a promising biomarker for unfavorable prognosis in AML.

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Types, Clinical Features and Survival Outcomes of Patients with Acute Myeloid Leukemia in Thailand: A 3-year Prospective Multicenter Study from Thai Acute Leukemia Study Group (TALSG)

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/j.clml.2021.03.004 ◽

2021 ◽

Author(s):

Chinadol Wanitpongpun ◽

Eakkapol Utchariyaprasit ◽

Weerapat Owattanapanich ◽

Adisak Tantiworawit ◽

Ekarat Rattarittamrong ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Acute Leukemia ◽

Clinical Features ◽

Multicenter Study ◽

Myeloid Leukemia ◽

Survival Outcomes ◽

Study Group ◽

Prospective Multicenter Study ◽

Acute Myeloid

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Dysregulation of CCAAT/enhancer binding protein-alpha (CEBPA) expression in the bone marrow of acute myeloid leukemia patients

Egyptian Journal of Medical Human Genetics ◽

10.1186/s43042-021-00154-z ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Naglaa M. Hassan ◽

Fadwa Said ◽

Roxan E. Shafik ◽

Mona S. Abdellateif

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Binding Protein ◽

Response To Treatment ◽

Pathological Features ◽

Poor Prognostic Factor ◽

Enhancer Binding Protein ◽

Ccaat Enhancer Binding Protein ◽

Acute Myeloid

Abstract Background Acute myeloid leukemia (AML) is a heterogeneous malignant disease characterized by accumulation of different types of mutations commonly the CCAAT/enhancer binding protein-alpha (CEBPA). However, the dysregulations of CEBPA expression in AML is still a debatable issue. The aim of the current study was to assess CEBPA gene expression in bone marrow (BM) aspiration specimens of 91 AML patients, compared to 20 control donors of bone marrow transplantation (BMT), using RT-PCR. Data were correlated with patients’ clinico-pathological features, response to treatment, progression-free survival (PFS), and overall survival (OS) rates. Results There was overexpression of CEBPA gene in AML patients compared to normal control [1.7 (0.04–25.6) versus 0.17 (0–4.78), respectively, P < 0.001]. Upregulation of CEBPA expression associated significantly with increased BM hypercellularity, total leucocyte counts, peripheral blood blast cell count, and poor PFS (P < 0.001, 0.002, 0.001, and 0.013, respectively). There was no significant association between CEBPA expression and any other relevant clinico-pathological features or OS rates (P = 0.610) of the patients. ROC analysis for biological relevance of CEBPA expression with AML showed that sensitivity and specificity of CEBPA expression at a cut-off value of 0.28 are 92.3% and 78.6%, respectively (P < 0.001). All patients who had CEBPA overexpression and mutant FLT3 showed BM hypercellularity, adverse cytogenetic risk, increased TLC, and PB blast cells count (P = 0.007, P < 0.001, 0.016, and 0.002, respectively). Conclusion CEBPA overexpression could be used as a genetic biological marker for AML diagnosis, as well as a poor prognostic factor for disease progression. It has no impact on OS rates of the patients.

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Increased Oxidative Stress in Acute Myeloid Leukemia Patients after Red Blood Cell Transfusion, but Not Platelet Transfusion, Results Mainly from the Oxidative/Nitrative Protein Damage: An Exploratory Study

Journal of Clinical Medicine ◽

10.3390/jcm10071349 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1349

Author(s):

Kamila Czubak-Prowizor ◽

Jacek Trelinski ◽

Paulina Stelmach ◽

Piotr Stelmach ◽

Agnieszka Madon ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Myeloid Leukemia ◽

Exploratory Study ◽

Myeloid Leukemia ◽

Thiobarbituric Acid ◽

Red Blood Cell Transfusion ◽

Packed Red Blood Cells ◽

Chronic Oxidative Stress ◽

Total Antioxidant ◽

Acute Myeloid

Chronic oxidative stress (OS) can be an important factor of acute myeloid leukemia (AML) progression; however, there are no data on the extent/consequence of OS after transfusion of packed red blood cells (pRBCs) and platelet concentrates (PCs), which are commonly used in the treatment of leukemia-associated anemia and thrombocytopenia. We aimed to investigate the effects of pRBC/PC transfusion on the OS markers, i.e., thiol and carbonyl (CO) groups, 3-nitrotyrosine (3-NT), thiobarbituric acid reactive substances (TBARS), advanced glycation end products (AGE), total antioxidant capacity (TAC), SOD, GST, and LDH, in the blood plasma of AML patients, before and 24 h post-transfusion. In this exploratory study, 52 patients were examined, of which 27 were transfused with pRBCs and 25 with PCs. Age-matched healthy subjects were also enrolled as controls. Our results showed the oxidation of thiols, increased 3-NT, AGE levels, and decreased TAC in AML groups versus controls. After pRBC transfusion, CO groups, AGE, and 3-NT significantly increased (by approximately 30, 23, and 35%; p < 0.05, p < 0.05, and p < 0.01, respectively) while thiols reduced (by 18%; p < 0.05). The PC transfusion resulted in the raise of TBARS and AGE (by 45%; p < 0.01 and 31%; p < 0.001), respectively). Other variables showed no significant post-transfusion changes. In conclusion, transfusion of both pRBCs and PCs was associated with an increased OS; however, transfusing the former may have more severe consequences, since it is associated with the irreversible oxidative/nitrative modifications of plasma proteins.

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Dissecting the Immune Landscape of Acute Myeloid Leukemia

Biomedicines ◽

10.3390/biomedicines6040110 ◽

2018 ◽

Vol 6 (4) ◽

pp. 110 ◽

Cited By ~ 12

Author(s):

Jan Davidson-Moncada ◽

Elena Viboch ◽

Sarah Church ◽

Sarah Warren ◽

Sergio Rutella

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Clinical Success ◽

Therapeutic Option ◽

Immune Checkpoint Blockade ◽

Response To Treatment ◽

Variable Response ◽

Molecular Features ◽

Therapeutic Decisions ◽

Acute Myeloid

Acute myeloid leukemia (AML) is a molecularly heterogeneous hematological malignancy with variable response to treatment. Recurring cytogenetic abnormalities and molecular lesions identify AML patient subgroups with different survival probabilities; however, 50–70% of AML cases harbor either normal or risk-indeterminate karyotypes. The discovery of better biomarkers of clinical success and failure is therefore necessary to inform tailored therapeutic decisions. Harnessing the immune system against cancer with programmed death-1 (PD-1)-directed immune checkpoint blockade (ICB) and other immunotherapy agents is an effective therapeutic option for several advanced malignancies. However, durable responses have been observed in only a minority of patients, highlighting the need to gain insights into the molecular features that predict response and to also develop more effective and rational combination therapies that address mechanisms of immune evasion and resistance. We will review the state of knowledge of the immune landscape of AML and identify the broad opportunity to further explore this incompletely characterized space. Multiplexed, spatially-resolved immunohistochemistry, flow cytometry/mass cytometry, proteomic and transcriptomic approaches are advancing our understanding of the complexity of AML-immune interactions and are expected to support the design and expedite the delivery of personalized immunotherapy clinical trials.

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Alternative splicing redefines landscape of commonly mutated genes in acute myeloid leukemia

10.1101/2020.05.21.107557 ◽

2020 ◽

Cited By ~ 1

Author(s):

Osvaldo D. Rivera ◽

Michael J. Mallory ◽

Mathieu Quesnel-Vallières ◽

David C. Schultz ◽

Martin Carroll ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Alternative Splicing ◽

Myeloid Leukemia ◽

Gene Disruption ◽

Somatic Mutations ◽

Aberrant Splicing ◽

Gene Dysregulation ◽

Number Of Patients ◽

Acute Myeloid ◽

Classical Mutation

AbstractMost genes associated with Acute Myeloid Leukemia (AML) are mutated in less than 10% of patients, suggesting alternative mechanisms for gene disruption contribute to this disease. Here we find a set of splicing events that disrupt the expression of a subset of AML-associated genes, including EZH2 and ZRSR2, independent of known somatic mutations. Most strikingly, in at least one cohort, aberrant splicing triples the number of patients with a reduction in functional EZH2 as compared to that predicted by somatic mutation of EZH2 alone. Together, these results demonstrate that classical mutation analysis underestimates the burden of functional gene disruption in AML and highlights the importance of assessing the contribution of alternative splicing to gene dysregulation in human disease.

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Clinical features and outcomes of hypocellular acute myeloid leukemia in adults

Medicine ◽

10.1097/md.0000000000024185 ◽

2021 ◽

Vol 100 (1) ◽

pp. e24185

Author(s):

Ik-Chan Song ◽

Deog-Yeon Jo ◽

Hyeoung-Joon Kim ◽

Yoo-Hong Min ◽

Dae Sik Hong ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Clinical Features ◽

Myeloid Leukemia ◽

Acute Myeloid

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A Predictor Combining Clinical and Genetic Factors for AML1-ETO Leukemia Patients

Frontiers in Oncology ◽

10.3389/fonc.2021.783114 ◽

2022 ◽

Vol 11 ◽

Author(s):

Min Yang ◽

Bide Zhao ◽

Jinghan Wang ◽

Yi Zhang ◽

Chao Hu ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Somatic Mutations ◽

Genetic Factors ◽

Risk Model ◽

Core Binding Factor ◽

Kit Mutation ◽

Binding Factor ◽

Prognostic Prediction ◽

Acute Myeloid

Core Binding Factor (CBF)-AML is one of the most common somatic mutations in acute myeloid leukemia (AML). t(8;21)/AML1-ETO-positive acute myeloid leukemia accounts for 5-10% of all AMLs. In this study, we consecutively included 254 AML1-ETO patients diagnosed and treated at our institute from December 2009 to March 2020, and evaluated molecular mutations by 185-gene NGS platform to explore genetic co-occurrences with clinical outcomes. Our results showed that high KIT VAF(≥15%) correlated with shortened overall survival compared to other cases with no KIT mutation (3-year OS rate 26.6% vs 59.0% vs 69.6%, HR 1.50, 95%CI 0.78-2.89, P=0.0005). However, no difference was found in patients’ OS whether they have KIT mutation in two or three sites. Additionally, we constructed a risk model by combining clinical and molecular factors; this model was validated in other independent cohorts. In summary, our study showed that c-kit other than any other mutations would influence the OS in AML1-ETO patients. A proposed predictor combining both clinical and genetic factors is applicable to prognostic prediction in AML1-ETO patients.

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