Relationship Between Cytotoxic T-Lymphocyte-Associated Antigen-4: Programmed Death-1 Genes Polymorphisms and Susceptibility to Pediatric B-Cell Acute Lymphoblastic Leukemia.

Programmed death-1 (PD1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) have a vital role in immune checkpoint pathways. Single nucleotide polymorphisms (SNPs) of PD1 and CTLA4 have been reported to be associated with susceptibility to certain autoimmune diseases and cancers. The potential association between SNPs in these immune checkpoint genes and risk of acute lymphoblastic leukemia (ALL) still unclear. The aim of this study is to clarify the effect of PD1 and CTLA4 SNPs on the risk of developing ALL and the prognosis of the disease. The study was performed on 100 pediatric B-ALL patients and 100 controls. The PD1 and CTLA4 SNPs were examined by RFLP technique. The study revealed that CTLA4 (rs11571316) was associated with high risk of B-ALL developments OR 1.492 (CI: 1157 to 1924) (P=0.002). PD1 (rs36084323) GA genotype was significantly associated with protective effect against nonremission (P=0.007). PD1 (rs36084323) A allele were associated with protective effect against relapse (P=0.008). CTLA4 and PD1 genotypes did not have significant impact on B-ALL patients outcome. The current study displayed for the first time that genetic variations of the CTLA-4, was associated with susceptibility to B-ALL and that PD1 (rs36084323) GA genotype was significantly associated with protective effect against nonremission, while PD1 (rs36084323) A allele was associated with protective effect against relapse.

Prognostic effect of CTLA4/LAG3 Expression by T-Cells Subsets on Acute Myeloid Leukemia Patients.

BACKGROUND: Deregulation of immune checkpoint is an important point in cancer evolution as well as patients outcome. T-cells is an important arm in immunity against cancer. This study aimed to assess CTLA4/LAG3 expression on different T-cell subsets and its effect on disease outcome. METHODS: This study included 81 newly diagnosed Egyptian adult AML patients. For each one of the patients CTLA4/ LAG3 expression on T-cell subsets was identified by flowcytometry before start of induction chemotherapy. RESULTS: Total CD3 count in AML patients was lower than control. LAG3 expression were significantly higher in total CD3, T-cell subsets (CD4, CD8) as compared to healthy control. Moreover, co-expression of LAG3/CTLA4 on T-cell subsets were significantly higher in AML as compared to healthy control . NPM-/ FLT3+ was significantly associated with high LAG3 expression in T-cells subsets as compared to other molecular subtypes. Shorter OS, DFS were significantly associated with higher expression of LAG3 on T-cells subsets as compared to patients harbor low expression. COX regression analysis revealed that high expression of CD3/LAG3, CD4/LAG3, CD8/LAG4, CD3/CTLA4/LAG3 were considered a poor prognostic risk factor. CONCLUSION: High LAG3/CTLA4 expression could predict AML Patients' outcome Conclusion: Our findings indicated that high expression of LAG3/CTL4 on T cells subsets identify a subgroup of AML patients with poor prognosis.

Level of interleukin 17 in inflammatory bowel disease and its relation with disease activity.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder of the gastrointestinal tract (GIT).It results in progressive intestinal epithelium structural and functional damage that necessitates lifetime medication.Thereis imbalance in the production of T helper 1 (Th1), Th2 and Th17 cytokines. This plays a crucial role in the chronic inflammatory process and the defective immune response to pathogenic agents; thus promoting the recurrence of the disease.Our aim of this study was to detect serum IL-17 levels in IBD patients and its relation with disease activity. METHODS: This was a single center case control study, conducted at hepatology and gastroenterology unit, Mansoura specialized Medical Hospital, Egypt.Patients who were included were aged 18-65 years, diagnosed either Ulcerative Colitis (UC)or Crohn's Disease (CD) based on previous colonoscopy.IBD activity was measured for UC using the MAYO score and CD using the CD activity index (CDAI). Fifty five patients were UC, 24 patients were CD, 21 patients were control.Patients who were excluded were under 15 years old, with history of GIT malignancy, or any serious comorbidities. Study protocol was approved by Institution Research Board (IRB) of Mansoura Medical College.All patients were subjected to full history taking, routine physical examination, colonoscopy and laboratory investigations including serum IL-17 levels by ELISA besides CBC, CRP, ESR and fecal calprotectin. RESULTS: Serum IL-17 level was increased significantly among UC; median (min-max) = 72(21-502)pg/ml, in CD 54.5(25-260) versus control 19 (14-35), P < 0.001.However, it was not correlated to the disease activity either Mayo score of UC or CDAI of CD.There was significant correlation to the extent of inflammation in UC affecting the colon (either proctosigmoiditis, left sided colitis or pan colitis), also to the type of CD (either inflammatory, stricturing or fistulizing) by P < 0.05.It was not correlated significantly with any of the IBD activity markers (CRP, ESR, or fecal calprotectin).Yet there was negative significant correlation with Hb level (r =-0.28, p = 0.005).There was not significant association between median serum level of IL-17 & duration of disease (P = 0.6).However, median IL-17 was higher among hospitalized cases than non-hospitalized (73 & 55, pg/ml respectively; p < 0.002). AUC was significantly differentiating between IBD and control group = 0.993 with the best-detected cut off point from curve 32 pg/ml yielding sensitivity of 97.5% and specificity of 95.2%. CONCLUSION: Serum IL-17 increases in colonic inflammation significantly more than in control group, however its increase is not correlated to IBD activity.

Significance of OCT3/4 and SOX2 antigens expression by leukemic blast cells in adult acute leukemia.

OBJECTIVE: This study aimed to address the prognostic impact of SOX2 and OCT3/4 expression on adult acute leukemia patients' outcomes. METHODS: SOX2 and OCT3/4 expression by blast cells were evaluated by flow cytometry in 80 acute leukemia patients and 8 healthy controls. RESULTS: Baseline SOX2 and OCT3/4 expression were significantly higher in both ALL (P = < 0.001, P = 0.005 respectively) and AML patients (P < 0.001, P = 0.003 respectively) as compared to control, and decline at complete remission (CR) and elevated again at relapse. High SOX2 and OCT3/4 levels were significantly correlated with the presence of adverse risk stratification parameters. CONCLUSION: Our findings indicated that both SOX2 and OCT3/4 could serve as biomarkers that could improve risk stratification of acute leukemia patients. Also, both SOX2 and OCT3/4 might be a therapeutic target, especially in resistant acute leukemia.

Cytogenetic Subclone Burden: A New Biomarker Predicting Chronic Lymphocytic Leukemia Patients Outcome.

BACKGROUND: Chronic lymphocytic leukemia is the most prevalent adult leukemia that occurs in older patients and presents a variable course of the disease. Risk stratification of CLL is a matter of continuous improvement. Thus, this study aimed to assess the impact of the quantification of 17p del and 11q del cytogenetic subclones on the outcome of patients with chronic lymphocytic leukemia. PATIENTS AND METHODS: This is a prospective study that involved 100 subjects with CLL. For all included patients; assessment of the cytogenetic subclones burden for 17p del and 11q del using the FISH technique was carried out. RESULTS: CLL patients with a high 17p del (>33%) cytogenetic subclone burden showed significantly shorter lymphocyte doubling time (LDT), time to first treatment (TTFT), and progression free survival (PFS) compared to those with a lower burden. On contrary 11q del subclone(>30%) burden had an insignificant impact on LDT, TTFT and PFS. CONCLUSION: Quantification of 17pdel burden (>vs.≤33%) could be used for refining risk stratification of CLL patients.

Frequency and Prognostic Impact of Aberrant Antigens Expression among Egyptian Adult Acute Leukemia.

OBJECTIVE: Aberrant antigen expression was reported to be due to genetic and epigenetic dysregulation. This study aimed to address aberrant antigen expression and its link to poor prognostic genetic markers in acute leukemia patients. METHODS: This study included 432 newly diagnosed acute leukemia patients (AML, B-ALL). For all included patients blast cells expression for line assignment CD33 CD13 on B-All and CD7 on cytogenetically normal-AML blasts was assessed by flow cytometry in parallel to FLT3 and Philadelphia and philadelphia like chromosome in B-ALL. RESULTS: From the total 432 cases of acute leukemia, the most frequent aberrant antigen expressed in B acute lymphoid leukemia (ALL) was CD33 (23.3%) followed by CD13(16.7%); while the most frequent one in AML was CD7 (16.7%). Aberrant myeloid phenotype in B-ALL was associated with lower mean total leukocytes count (TLC), low platelets count, positive Philadelphia like chromosome, shorter overall survival compared to the B-ALL without. Aberrant lymphoid phenotype (CD7) in AML was associated with a higher platelets count, FLT3 mutation, shorter disease-free and overall survival compared to those patients without. CONCLUSION: CD7 aberrant antigen expression is frequently detected in patients with CN-AML and frequently associated with FLT3 mutation. While in patients with B-ALL the most frequently detected ones are CD33 and CD13 which are frequently associated with Philadelphia like chromosome.

Prognostic Value of Plasma miR-29a Evaluation in Chronic Lymphocytic Leukemia Patients.

OBJECTIVE: Dysregulation of microRNA expression could attenuate the course of chronic lymphocytic leukemia (CLL). Therefore, the aim of our study is to address the association between miR-29a expression and other prognostic markers in CLL patients. METHODS: miR-29a expression was determined by quantitative real-time PCR in the plasma of 158 CLL patients at diagnosis beside 21 healthy controls in a prospective study. RESULTS: The levels of miR-29a expression were found to be significantly higher in CLL patients as compared to healthy controls (P<0.001). Moreover, a significant association between high miR-29a expression and poor prognostic markers (high expression of CD38 and ZAP70, high LDH levels, Stage III Rai stage, unfavorable cytogenetic finding, time to first treatment (TTFT) and patients outcome (P<0.001 for All). Using ROC curve, we have reported that miR-29a expression levels (29a<0.76 vs >0.76) is able to discriminate severity subgroups of CLL patients. CONCLUSION: Up regulation of miR-29a expression at CLL diagnosis was detected. Determination of miR-29a expression concentration levels at diagnosis could be demonstrated as a prognostic biomarker in CLL patients.

Prognostic Value of Serum CD200 Concentrations in Chronic Lymphocytic Leukemia.

BACKGROUND: little is known regarding the prognostic value of soluble CD200 (sCD200)in  chronic lymphocytic leukemia patients. Therefore, the objective of our study is  to address the prognostic value of sCD200 antigen concentration on  CLL patients outcome. METHODS: Determination of  serum sCD200 was done using ELISA kit in 158 CLL patients at diagnosis  before start of therapy beside 21 healthy controls. RESULTS: sCD200 concentration levels was significantly higher in CLL patients as compared to healthy controls.  High sCD200 was associated with poor prognostic markers (high expression of CD38+% and ZAP70+, high LDH, high risk Rai stages, unfavorable cytogenetic finding, time to first treatment (TTT) as well as patients outcome (P<0.001 for All). sCD200 at cut-off value ( 752.5 pg/ml) could predicts TTT with specificity 83.4%. CONCLUSION: Determination of sCD200 concentration levels at diagnosis could be used as a prognostic biomarker in CLL patients.

Implication of Dynamin-2 (DNM2) Mutations in Adult T-cell Acute Lymphoblastic Leukemia.

BACKGROUND: The objective of the present study was to improve the risk stratification of T-cell Acute Lymphoblastic Leukemia (T-ALL) patients. It aimed to identify the frequency and clinical impact of DNM2 gene mutations among adult T-ALL cases. METHODS: The current study included 25 T-ALL patients before starting their treatment. Mutational analysis of DNM2 gene (exons 18 and 22) was performed for all patients using Macrogen 3730 apparatus. RESULTS: We identified DNM2 gene mutations in 19 out of 25 (76%) patients. The detected mutations were either missense or deletion. Only active mutations (deletion) were associated with poor induction remission response and high frequency of relapse. Two novel mutations were addressed among the studied cohort of patients. They included c.1866G>C (p.V596L) and c.1872delA in exon 18. A high frequency of silent mutations was also found in T-ALL patients, but with no impact on clinical features. CONCLUSION: The DNM2 mutations were prevalent among adult T-ALL patients and might have a role in the pathogenesis of the disease. Active DNM2 mutations were associated with poor clinical outcome. Moreover, high frequency of DNM2 mutations indicated that these mutations could be utilized in detection of minimal residual disease in T-ALL patients.

Significance of CEBPE Gene Promoter Polymorphism (Rs2239630 G > A ) Assessment in Childhood B-cell Acute Lymphoblastic Leukemia.

BACKGROUND: A significant association has been reported between CEBPE gene promoter polymorphisms (rs2239630 G > A ) and the incidence of B-cell acute lymphoblastic leukemia (B-ALL). However, no previous study on this issue has been included among the Egyptian cohort of pediatric patients with B-ALL. Therefore, this study was designed to address the associations between CEBPE polymorphisms and susceptibility to B-ALL, as well as its impact on the outcome of B-ALL Egyptian patients with B-ALL. PATIENTS AND METHODS: In the current study, we evaluated the rs2239630 polymorphism in 225 pediatric patients and 228 controls to assess the association of different rs2239630 genotypes with childhood susceptibility to B-ALL and the impact on the outcome of the patients. RESULTS: The frequency of the A allele was significantly higher in the cases of B-ALL compared with the control group ( P = 0.004). By analyzing different genotypes for the predictive value of disease development, the GA and AA genotypes have been identified to be the highest among multivariate factors with an odds ratio of 3.330 (95% CI: 1.105-10.035). Likewise, the A allele was significantly associated with the shortest overall survival. CONCLUSIONS: CEBPE gene promoter polymorphism (rs2239630 G > A ) AA is frequently associated with B-ALL; and has the worst overall survival among the 3 genotypes, followed by the GA and GG genotypes ( P < 0.001).

Prognostic value of MTSS1 gene expression on acute leukemia patients outcome.

Background: This study aimed to evaluate the prognostic value of the MTSS1 gene expression in patients with acute leukemia. Patients & methods: MTSS1 gene expression was quantified in 120 newly diagnosed acute leukemia patients, by quantitative reverse transcription PCR at diagnosis and after induction chemotherapy therapy. Results: Baseline MTSS1 gene expression was significantly higher in acute leukemia patients compared to the control group (p < 0.001). Acute leukemia patients with low baseline MTSS1 gene expression at diagnosis have significantly shorter overall survival and disease-free survival compared with those with higher expression (p < 0.001 for both). Conclusion: Downregulation of MTSS1 gene expression at diagnosis was associated with poor outcome in either cytogenetic acute myeloid leukemia or B-cell acute lymphoblastic leukemia.

Clinical Implication of DNMT3A and TET2 Genes Mutations in Cytogenetically Normal Acute Myeloid Leukemia.

BACKGROUND: Refining risk stratification of cytogenetically  normal AML (CN-AML) cases is important for decision making and tailoring of therapy. In this context genetic and epigenetic mutations was considered. Among these epigenetic regulators are DNMT3A & TET2 genes. Therefore, the aim of  this study was to determine the prevalence of DNMT3A and TET2 genes mutations and their impact on the outcome of  adult AML patients. SUBJECTS AND METHODS: The present study is cross sectional study which was conducted on 39 adult CN-AML patients at diagnosis. For all included patients sanger sequencing was done for DNMT3A exon 23 and TET2 exon 3 genes. RESULTS: DNMT3A mutations were detected in 8 of 39 patients (20.5%), and in 5 of 39 patients(12.8%) in TET gene. Two CN-AML  patients had combined mutations in both genes. All of the mutations detected were missense and only one was frame shift. Mutated TET2 or DNMT3A genes were significantly associated with failure of complete remission (CR) (p <0.001), higher mortality rate, shorter OS (mean=16 versus 22.7 months) and shorter DFS (mean= 9.5 versus 21.4 months) when compared to non-mutated ones. CONCLUSION: Mutated TET2 and DNMT3A detection define a subgroup of CN-AML patients with poor outcome.

DNA Repair Genes Polymorphisms: Impact on Acute Myeloid Leukemia Patients Outcome.

BACKGROUND: ATM; XRCC6 and LIG4 genes play an important role in repairing the double-strand DNA breaks and maintaining the genome stability. Single nucleotide polymorphisms (SNPs) in these genes could affect these genes expression and function. The aim of this study was to address the effect of SNP of the DNA repairing genes on corresponding  gene expression as well as AML patient's outcome. SUBJECTS AND METHODS: This is cross sectional study included 95 newly diagnosed AML patients. For all subjects included in our study SNPs  and expression of ATM (rs189037G>A), XRCC6 (rs2267437C>G) and LIG4 (rs1805388C>T) genes were evaluated by RFLP and real time PCR. RESULTS: The following SNPs in ATM (AA); XRCC6 (GG); and LIG4 (TT) are associated with down regulation of the corresponding genes (P<0.001). The lower expression of ATM and LIG4 genes are associated with shorter OS and DFS. Cox regression multivariate analysis revealed that lower expression of ATM HR : 2.02 (CI: 1.12-3.64; p=0.020. CONCLUSION: The following SNPs of ATM (AA); XRCC6 (GG); and LIG4 (TT) are associated with down regulation of corresponding genes expression. ATM and XRCC6 lower expression are predictors of OS while ATM is predictor of DFS and could be used for optimizing the AML therapy.

Association of vitamin B12/ferritin deficiency in cancer patients with methylomic changes at promotors of TET methylcytosine dioxygenases.

Aim: To investigate potential DNA methylation in methylcytosine dioxygenases and correlation of TET genes with vitamin B12/ferritin levels in cancer patients. Materials & methods: 200 blood samples were obtained from both cancer patients and healthy individuals. Results: The expression of DNMT1, DNMT3a and DNMT3b was increased in patients with low vitamin B12 and ferritin levels, while the expression of MTR, TET1 and TET3 significantly decreased. DNA methylation analysis in patients with deficient vitamin B12/ferritin levels showed methylomic changes within the location 318/CG and 385/CG in the promoter region of TET1 and TET3, respectively. Conclusion: Vitamin B12/ferritin deficiency contributes to DNA methylation progress in cancer patients.

Clinical Implication of Toll-Like Receptors (TLR2 and TLR4) Polymorphisms in Adult Patients with Acute B-cell Lymphoblastic Leukemia.

BACKGROUNDS: Neutropenia after intensive chemotherapy of acute lymphoblastic leukemia (ALL) could lead to infectious complications that affect outcome of acute leukemia patients. Many single-nucleotide polymorphisms (SNPs) of Toll-like receptors (TLRs) can affect the genetic susceptibility to infections. We investigated the impact of different SNPs on the incidence of developing sepsis and pneumonia in patients with newly diagnosed B-ALL following induction chemotherapy. SUBJECTS AND METHODS: We analyzed three SNPs in the TLR2 (Arg753Gln) and TLR4 (Asp299Gly& Thr399Ile) genes using polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) in a case control study of 40 precursor B-ALL patients and 50 control subjects. The risk of developing sepsis and pneumonia were assessed by multiple logistic regression analyses. RESULTS: The presence of the TLR-2 AG polymorphism was significantly associated with pneumonia in B-ALL patients. Furthermore, TLR4 Thr399Ile AG was a risk factor for sepsis in B-ALL patients. Moreover; Significant association between TLR-2 AA, TLR-4 CC and TL-4 AA genotypes and longer OS were detected in studied B-ALL patients. CONCLUSION: We concluded that TLR-4 (AG and CT) genotypes are associated with high susceptibility to sepsis and pneumonia respectively; while, TLR-2, TLR-4 AA and TLR-4 CC genotypes  could predict good B-ALL patients outcome.

Diagnostic Value of 1H NMR-Based Metabolomics in Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, and Breast Cancer.

Cancer refers to a massive number of diseases distinguished by the development of abnormal cells that divide uncontrollably and have the capability of infiltration and destroying the normal body tissue. It is critical to detect biomarkers that are early detectable and noninvasive to save millions of lives. The aim of the present work is to use NMR as a noninvasive diagnostic tool for cancer diseases. This study included 30 plasma and 21 urine samples of patients diagnosed with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), 25 plasma and 17 urine samples of patients diagnosed with breast cancer (BC), and 9 plasma and urine samples obtained from healthy individuals as controls. They were prepared for NMR measurements; then, the metabolites were identified and the data were analyzed using multivariate statistical procedures. The OPLS-DA score plots clearly discriminated ALL, AML, and BC from healthy controls. Plots of the PLS-DA loadings and S-line plots showed that all metabolites in plasma were greater in BC than in the healthy controls, whereas lactate, O-acetylcarnitine, pyruvate, trimethylamine-N-oxide (TMAO), and glucose were higher in healthy controls than in ALL and AML. On the other hand, urine samples showed lower amounts of lactate, melatonin, pyruvate, and succinate in all of the studied types of cancer when compared to those of healthy controls. 1H NMR can be a successful and noninvasive tool for the diagnosis of different types of cancer.

Predictive Value of B reg and Serum IL-10 Concentration Levels for Acute ITP Progression to Chronic Phase.

INTRODUCTION: Pediatric immune thrombocytopenia (ITP) is a potentially life threating autoimmune disorder with different responses to therapy and different bleeding phenotypes in critical organs. The molecular basis for the variable response has not yet been fully elucidated. This study was designed to address the predictive value of regulatory B-cell (B reg ) count and interleukin-10 (IL-10) serum levels for acute ITP patients who progress to chronic phase. The present study included 80 children with acute ITP )38 males and 42 females (with median age of 8 years and 40 matched healthy controls. Assessment of B reg (CD19 + CD24 hi CD38 hi ) was carried out by a multicolor flowcytometry, however, IL-10 serum levels were evaluated by enzyme-linked immunosorbent assay. A significant reduction of B reg percentage and a significant increase in serum IL-10 levels were identified in children with acute ITP as compared with controls ( P <0.001 for both). Fourteen ITP patients passed to chronic phase, while 66 patients achieved remission within 6 months. The absolute B reg was significantly lower, while IL-10 was significantly higher in patients with acute ITP who progressed to chronic phase in comparison with acute ITP patients who achieved complete remission. Cox proportional hazards for ITP chronicity revealed that IL-10 OR was 2.46 (confidence interval: 1.42-4.27; P =0.001) and absolute B reg OR was 0.147 (confidence interval: 0.128-0.624; P =0.005) in the peripheral blood. Therefore, they could predict chronicity in ITP cases. CONCLUSION: Reduced B reg count and elevated IL-10 levels in patients with acute ITP at diagnosis can predict chronicity.

Circulating CXCL13 could be serving as a biomarker for chronic lymphocytic leukemia severity.

BACKGROUND: Recent reports indicated the importance of chemotractant CXCL-13 in solid tumors and lymphoid malignancies. However, the prognostic value of the mentioned cytokines as biomarkers in chronic lymphocytic leukemia patient's remains to be identified. Therefore; this study was designed in order to address the relation between CXCL-13 concentrations levels and markers of severity in CLL patients. METHODS: Our study included 150 CLL patients and 20 controls. Serum CXCL-13 was determined by ELISA for CLL patients at diagnosis as well as controls. RESULTS: The serum CXCL-13 levels were significantly higher in CLL patients as compared to controls. The high CXCL-13 concentration levels was significantly associated with high number of smudge cells; high LDH; high grade of Rai stage, short time to first treatment (TTT). Cox regression analysis was conducted for prediction of TTT, using age, gender, WBCs, smudge cells, CXCL-13, LDH, ZAP70, CD38, ß2-microglobulin, Rai staging as covariates. High LDH, CXCL-13 and CD38% were significantly independent predictor for shorter TTT. CONCLUSION: High CXCL-13 serum levels at CLL diagnosis is correlated with other markers of disease activity; and could be served as biomarkers that predict CLL patient's outcome.

Predictive Value of miR-146a rs2431697 Polymorphism to Myelofibrosis Progression in Patients with Myeloproliferative Neoplasm.

BACKGROUND: Bone marrow myelofibrosis (BMF) that develop on top of Polycythaemia vera (PV) and essential thrombocythemia leads to shortening of the patient's overall survival. This study aimed to address the impact of miR-146a rs2431697 polymorphism on inflammatory biomarkers and genes expression and the hazards of myelofibrosis progression. PATIENTS AND METHODS: The study included 88 myeloproliferative neoplasm (40 PV; 27 ET; 21 MF) and 90 healthy controls. For all investigated subjects miR-146a rs2431697 genotypes were identified by sequencing and the expression of miR-146a; IL-1ß; NF-κB; a NOD-like receptor family, pyrin domain containing 3 (NLRP3) (NLRP3) genes were estimated by real time PCR. RESULTS: miR146a genotypes revealed that there was significant association between TT and TC genotypes with MF. The degree of miR146a expression was significantly reduced in MF as compared to both PV and ET. In contrast; the levels of IL-1ß; NF-κB; NLRP3 genes expression were significantly elevated in MF patients group as compared to PV and ET patients' group. Multivariate analysis identified TT genotype as poor predictor of MF progression. CONCLUSION: miR-146a rs2431697 TT genotype is associated with high risk of MF progression in MPN patients. Targeting of IL-1ß; NF-κB; NLRP3 genes might help  in hindering of  MF progression in  MPN patients,
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CD34+/CD38- Stem Cell Burden Could Predict Chronic Myeloid Leukemia Patients' Outcome.

BACKGROUND: The current predictor of the Chronic myeloid leukemia (CML)  patients' outcome is the degree of response to targeted therapy; here we search for a biomarker predicting CML outcome before start of therapy. This study aimed to assess the impact of the  CD34+/CD38- stem cells (SCs) burden in chronic myeloid leukemia (CML) on  treatment response and patients' outcomes. METHODS: Our study included 65 CML patients in the chronic phase. The patients'  CD34+/CD38- stem cells were quantified  using flowcytometry before and after treatment by frontline imatinib (IM) therapy. The median follow-up for all patients was 18 months. RESULTS: CD34+/CD38- stem cells frequency at diagnosis and after therapies are correlated to known prognostic markers (blast cells count, spleen size, total White cell count, and clinical scores). After therapy, the leukemic stem cells count dropped rapidly. The pretreatment CD34+/CD38- stem cells burden predicts response to frontline therapy. In addition, high SCs frequency at diagnosis predicts poor molecular response, transformation to AML, and poor patients' outcomes. CONCLUSION: The percentage of CD34+/CD38- SCs burden at diagnosis reflects the CML disease behavior and is considered a biomarker for predicting CML patients' response to first-line Tyrosine kinase inhibitors (TKI) therapy.