scholarly journals PROGNOSTIC VALUE OF BRAIN AND ACUTE LEUKEMIA CYTOPLASMIC GENE EXPRESSION IN EGYPTIAN CHILDREN WITH ACUTE MYELOID LEUKEMIA

2015 ◽  
Vol 7 ◽  
pp. e2015033 ◽  
Author(s):  
Adel Abd elhaleim Hagag
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Acute Leukemia ◽  
Myeloid Leukemia ◽  
Egyptian Children ◽  
Significant Difference ◽  
The Impact ◽  
Acute Myeloid

Abstract      Background: Acute myeloid leukemia (AML) accounts for 25%-35% of the acute leukemia in children. BAALC (Brain and Acute Leukemia, Cytoplasmic gene) is a recently identified gene on chromosome 8q22.3 that has prognostic significance in AML.  The aim of this work was to study the impact of BAALC gene expression on prognosis of AML in Egyptian children. Patients and methods: This study was conducted on 40 patients of newly diagnosed AML who were subjected to the following: Full history taking, clinical examination, laboratory investigations including: complete blood count, LDH, bone marrow aspiration, cytochemistry and immunophenotyping, assessment of BAALC Gene by real time PCR in bone marrow aspirate mononuclear cells before the start of chemotherapy. Results: BAALC gene expression showed positive expression in 24 cases (60%) and negative expression in 16 cases (40%). Patients who showed positive BAALC gene expression included 10 patients achieved complete remission, 8 patients died and 6 relapsed patients, while patients who showed negative expression include 12 patients achieved complete remission, 1 relapsed patient and 3 patients died. There was significant association between BAALC gene expression and FAB classification of patients of AML patientsas positive BAALC expression is predominantly seen in FAB subtypes M1 and M2 compared with negative BAALC gene expression that was found more in M3 and M4 (8 cases with M1, 12 cases with M2, 1 case with M3 and 3 cases with M4 in positive BAALC expression versus 2 cases with M1, 3 cases with M2, 4 cases with M3 and 7 cases with M4 in BAALC gene negative expression group with significant difference regarding FAB subtypes). As regard age, sex, splenomegaly, lymphadenopathy, pallor, purpura, platelets count, WBCs count, and percentage of blast cells in BM, the present study showed no significant association with BAALC. Conclusion: BAALC expression is an important prognostic factor in AML patients and its incorporation into novel risk-adapted therapeutic strategies will improve the currently disappointing cure rate of this group of patients.

Cdx4 Upregulates Hox Gene Expression and Generates Acute Myeloid Leukemia Alone and in Cooperation with Meis1a in a Murine Model.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 10-10
Author(s):  
Dimple Bansal ◽  
Claudia Scholl ◽  
Stefan Frohling ◽  
Elizabeth Mcdowell ◽  
Benjamin H. Lee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Acute Leukemia ◽  
Myeloid Leukemia ◽  
Hox Genes ◽  
Function Analysis ◽  
Marrow Transplant ◽  
Hox Gene ◽  
Acute Myeloid

Abstract HOX genes have emerged as critical effectors of leukemogenesis, but the mechanisms that regulate their expression in leukemia are not well understood. Recent data suggest that the caudal homeobox transcription factors CDX1, 2 and 4, developmental regulators of HOX gene expression, may contribute to HOX gene dysregulation in leukemia. We report here that CDX4 is normally expressed in early hematopoietic progenitors, and is aberrantly expressed in~25% of AML patient samples. Cdx4 regulates Hox gene expression in the adult murine hematopoietic system, and upregulates Hox genes that are implicated in leukemogenesis. Furthermore, bone marrow progenitors that are retrovirally engineered to express Cdx4 serially replate in methylcellulose cultures, grow in liquid culture and generate a partially penetrant, long-latency acute myeloid leukemia (AML) in bone marrow transplant recipients. Co-expression of the Hox co-factor Meis1a accelerates the Cdx4 AML phenotype and renders it fully penetrant. Structure -function analysis demonstrates that leukemic transformation requires intact Cdx4 transactivation and DNA-binding domains, but not the Pbx co-factor interaction motif. Taken together, these data indicate that Cdx4 regulates Hox gene expression in adult hematopoiesis and may serve as an upstream regulator of Hox gene expression in the induction of acute leukemia. Inasmuch as many human leukemias show dysregulated expression of a spectrum of HOX family members, these collective findings also suggest a central role for CDX4 expression in the genesis of acute leukemia.

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.

scholarly journals Predicting Complete Remission of Acute Myeloid Leukemia: Machine Learning Applied to Gene Expression

2019 ◽  
Vol 18 ◽  
pp. 117693511983554 ◽  
Author(s):  
Ophir Gal ◽  
Noam Auslander ◽  
Yu Fan ◽  
Daoud Meerzaman
Keyword(s):  
Gene Expression ◽  
Machine Learning ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Statistical Significance ◽  
Expression Patterns ◽  
Pathway Enrichment Analysis ◽  
Data Set ◽  
Acute Myeloid

Machine learning (ML) is a useful tool for advancing our understanding of the patterns and significance of biomedical data. Given the growing trend on the application of ML techniques in precision medicine, here we present an ML technique which predicts the likelihood of complete remission (CR) in patients diagnosed with acute myeloid leukemia (AML). In this study, we explored the question of whether ML algorithms designed to analyze gene-expression patterns obtained through RNA sequencing (RNA-seq) can be used to accurately predict the likelihood of CR in pediatric AML patients who have received induction therapy. We employed tests of statistical significance to determine which genes were differentially expressed in the samples derived from patients who achieved CR after 2 courses of treatment and the samples taken from patients who did not benefit. We tuned classifier hyperparameters to optimize performance and used multiple methods to guide our feature selection as well as our assessment of algorithm performance. To identify the model which performed best within the context of this study, we plotted receiver operating characteristic (ROC) curves. Using the top 75 genes from the k-nearest neighbors algorithm (K-NN) model ( K = 27) yielded the best area-under-the-curve (AUC) score that we obtained: 0.84. When we finally tested the previously unseen test data set, the top 50 genes yielded the best AUC = 0.81. Pathway enrichment analysis for these 50 genes showed that the guanosine diphosphate fucose (GDP-fucose) biosynthesis pathway is the most significant with an adjusted P value = .0092, which may suggest the vital role of N-glycosylation in AML.

Childhood acute myeloid leukemia: outcome in a single center using chemotherapy and consolidation with busulfan/cyclophosphamide for bone marrow transplantation.

1994 ◽  
Vol 12 (10) ◽  
pp. 2138-2145 ◽  
Author(s):  
P J Shaw ◽  
M E Bergin ◽  
M A Burgess ◽  
L Dalla Pozza ◽  
S J Kellie ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Bone Marrow Transplantation ◽  
Survival Rate ◽  
Complete Remission ◽  
Relapse Rate ◽  
Marrow Transplantation ◽  
Myeloid Leukemia ◽  
Free Survival ◽  
Acute Myeloid

PURPOSE To report the impact of bone marrow transplantation (BMT) with busulfan/cyclophosphamide (BuCy) as end consolidation in a cohort of consecutively diagnosed children with acute myeloid leukemia (AML). PATIENTS AND METHODS Between May 1987 and November 1992, 43 patients were diagnosed with AML. Tissue typing at diagnosis determined whether patients would proceed to autologous or allogeneic BMT as end consolidation after six cycles of chemotherapy. Conditioning for BMT was with BuCy, followed by allogeneic or unpurged autologous marrow infusion. RESULTS Of 37 patients who received chemotherapy, 35 achieved remission (95%) after one to six courses of treatment and 34 (92%) were transplanted. Five relapsed before BMT, four were subsequently transplanted in second complete remission (CR2) (n = 3) or untreated first relapse (n = 1), and one failed to respond to further therapy. All other patients proceeded to BMT in first complete remission (CR1). Eleven patients received allografts: one relapsed and one died of graft-versus-host disease (GvHD), for a leukemia-free survival rate of 90% at a median of 41 months after BMT (range, 3 to 60). For 23 autografts, there were two toxic deaths and eight relapses, with a leukemia-free survival rate of 61% at a median of 11 months after BMT (range, 0 to 66). The high relapse rate following autologous BMT led us to escalate the dose of Bu from 16 mg/kg to 600 mg/m2 using a single daily dose of Bu. CONCLUSION With modern supportive therapy, most newly diagnosed children with AML will enter remission and are eligible for intensification therapy. BuCy is well tolerated in children, which allowed us to escalate the dose of Bu in recent patients. Further follow-up is needed to determine whether this has an impact on the relapse rate following autologous BMT.

The impact of therapy-related acute myeloid leukemia (AML) on outcome in 2853 adult patients with newly diagnosed AML

Blood ◽  
2011 ◽  
Vol 117 (7) ◽  
pp. 2137-2145 ◽  
Author(s):  
Sabine Kayser ◽  
Konstanze Döhner ◽  
Jürgen Krauter ◽  
Claus-Henning Köhne ◽  
Heinz A. Horst ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Topoisomerase Ii ◽  
De Novo ◽  
Negative Impact ◽  
Primary Malignancy ◽  
De Novo Aml ◽  
The Impact ◽  
Acute Myeloid

Abstract To study the characteristics and clinical impact of therapy-related acute myeloid leukemia (t-AML). 200 patients (7.0%) had t-AML and 2653 de novo AML (93%). Patients with t-AML were older (P < .0001) and they had lower white blood counts (P = .003) compared with de novo AML patients; t-AML patients had abnormal cytogenetics more frequently, with overrepresentation of 11q23 translocations as well as adverse cytogenetics, including complex and monosomal karyotypes, and with underrepresentation of intermediate-risk karyotypes (P < .0001); t-AML patients had NPM1 mutations (P < .0001) and FLT3 internal tandem duplications (P = .0005) less frequently. Younger age at diagnosis of primary malignancy and treatment with intercalating agents as well as topoisomerase II inhibitors were associated with shorter latency periods to the occurrence of t-AML. In multivariable analyses, t-AML was an adverse prognostic factor for death in complete remission but not relapse in younger intensively treated patients (P < .0001 and P = .39, respectively), relapse but not death in complete remission in older, less intensively treated patients (P = .02 and P = .22, respectively) and overall survival in younger intensively treated patients (P = .01). In more intensively treated younger adults, treatment-related toxicity had a major negative impact on outcome, possibly reflecting cumulative toxicity of cancer treatment.

scholarly journals Kinetics of bone marrow blasts during induction and achievement of complete remission in acute myeloid leukemia

Haematologica ◽  
2008 ◽  
Vol 93 (8) ◽  
pp. 1263-1265 ◽  
Author(s):  
M. Yanada ◽  
G. Borthakur ◽  
F. Ravandi ◽  
C. Bueso-Ramos ◽  
H. Kantarjian ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Kinetics Of ◽  
Bone Marrow Blasts ◽  
Acute Myeloid

Expression of Angiopoietins and Their Receptor Tie2 in the Bone Marrow of Patients with Acute Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1894-1894
Author(s):  
Christoph Schliemann ◽  
Ralf Bieker ◽  
Teresa Padro ◽  
Torsten Kessler ◽  
Heike Hintelmann ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Critical Role ◽  
Angiogenic Factor ◽  
Term Survival ◽  
Bone Marrow Biopsies ◽  
Cox Regression Analysis ◽  
The Impact ◽  
Acute Myeloid

Abstract Angiopoietin-1 (Ang-1) and its natural antagonist Angiopoietin-2 (Ang-2), both ligands for the receptor tyrosine kinase Tie2, are known to play an essential role in normal and pathological angiogenesis. However, the importance of angiopoietin signaling in the pathophysiology of hematologic neoplasias such as acute myeloid leukemia (AML) remains to be elucidated. We investigated the expression of Ang-1, Ang-2 and Tie2 by immunohistochemical analyses in bone marrow biopsies of 64 adult patients with newly diagnosed AML and correlated angiogenic factor expression with clinicopathological variables and long-term survival. Expression of Ang-2 was significantly increased in the bone marrow of AML patients (median [interquartile ranges]: 4.7 [3.3 – 5.7] AU [arbitrary units]) as compared with 16 control patients (1.5 [1.5 – 1.8] AU; P < 0.0001). In contrast, Ang-1 expression levels in AML patients did not differ from those found in controls. Thus, we observed a reversal of the Ang-1 and Ang-2 expression balance in the neoplastic bone marrow (Ang-2:Ang-1 ratio: 1.73) as compared with normal bone marrow (0.51; P < 0.0001). Furthermore, the angiopoietin receptor Tie2 was significantly overexpressed in leukemic blasts (3.8 [2.8 – 4.9] AU vs. 1.8 [1.6 – 2.3] AU; P < 0.0001). Patients expressing high levels of Ang-2 showed significantly longer overall survival (OS) than those with low Ang-2 levels (52.7 vs. 14.7 months; P = 0.039). The impact of Ang-2 expression on OS was especially evident in AML patients simultaneously expressing low levels of Ang-1 (P = 0.0298). Multivariate Cox regression analysis revealed karyotype and Ang-2 expression as independent prognostic factors for OS (hazard ratio [CI]: 3.06 [1.39 – 6.70] and 0.31 [0.14 – 0.69], respectively; P < 0.01). In conclusion, these data provide evidence that the alteration of angiopoietin balance in favor of Ang-2 may play a critical role in the pathophysiology of AML. Furthermore, high pre-therapeutic bone marrow Ang-2 levels indicate a favorable prognosis in polychemotherapy treated AML by a yet unknown mechanism.

Constitutive Activation of SHP2 Protein Tyrosine Phosphatase Cooperates with HoxA10 Overexpression for Progression to Acute Myeloid Leukemia in a Murine Model

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 752-752
Author(s):  
Hao Wang ◽  
Stephan Lindsey ◽  
Iwona Konieczna ◽  
Elizabeth Horvath ◽  
Ling Bei ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Protein Tyrosine Phosphatase ◽  
Myeloid Leukemia ◽  
Tyrosine Phosphatase ◽  
Post Translational Modification ◽  
Protein Tyrosine ◽  
Acute Myeloid ◽  
Myeloid Progenitors

Abstract HOX genes encode highly conserved homeodomain (HD) transcription factors and are arranged in four groups (A–D). During definitive hematopoiesis, HOX gene expression is activated 3′ to 5′ through each group. Therefore, HOX1-4 are actively transcribed in hematopoietic stem cells and HOX7-11 in committed progenitors. Under normal conditions, HoxA7-11 expression decreases during CD34+ to CD34− maturation. Abnormal Hox expression is characteristic of several poor prognosis subtypes of Acute Myeloid Leukemia (AML) including AML with translocations or duplications of the MLL gene. In such leukemias, expression of HoxB3, B4 and A7-11 is sustained in CD34−CD38+ cells. In murine bone marrow transplantation experiments, expression of MLL fusion proteins, HoxA9 or HoxA10 induces a myeloproliferative disorder (MPD) characterized by increased neutrophils (PMN). Over time, the mice progress to AML with circulating myeloid blasts. These results suggest overexpression of HoxA9 or HoxA10 is adequate for MPD, but differentiation block (AML) requires additional lesions. We found that HoxA9 and HoxA10 proteins not only decrease in expression during the CD34+ to CD34− transition, but also are tyrosine phosphorylated. In additional studies, we found that HoxA10 tyrosine phosphorylation state is relevant for differentiation stage-specific target gene expression during myelopoiesis. HoxA10 represses genes encoding phagocyte effector proteins in undifferentiated myeloid cells. During myelopoiesis, phosphorylation of conserved HD-HoxA10 tyrosines decreases binding to these genes, permitting phenotypic and functional differentiation. HoxA10 activates transcription of the gene encoding Mkp2 (Dusp4) in myeloid progenitors. Decrease in HoxA10-binding to this gene as differentiation proceeds decreases transcription and renders the cells susceptible to Jnk induced apoptosis. Therefore, we hypothesized that genetic lesions which influence post translational modification might cooperate with HoxA10 overexpression to lead from MPD to AML. In myeloid progenitors, HoxA10 is maintained in a non-phosphorylated state by SHP2 protein tyrosine phosphatase. SHP2 activity decreases as differentiation proceeds. Activating mutations in SHP2 have been described in AML. We found that such activated SHP2 mutants dephosphorylate HoxA10 through out ex vivo myelopoiesis. Therefore, we investigated cooperation between these two leukemia associated abnormalities in vivo. Mice were transplanted with bone marrow overexpressing HoxA10 (or empty vector control) with or without activated SHP2 (E76K). To control for SHP2 overexpression, other mice were transplanted with bone marrow overexpressing HoxA10 and wild type SHP2. Mice transplanted with bone marrow overexpressing HoxA10 (±SHP2) developed MPD which evolved to AML over 4 mos, consistent with previous observations. However, mice transplanted with bone marrow overexpressing HoxA10 and E76K SHP2 developed AML within 4 wks. This rapid development of AML correlated with abnormalities in expression of myeloid specific HoxA10 target genes. These studies indicate the importance of HoxA10 post translational modification for physiologically relevant function and identify cooperating lesions which may be significant for disease progression in human AML.

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