Influence of Caspase-9 polymorphisms on the development of Chronic Myeloid Leukemia- A case-control study.

Introduction: Chronic Myeloid Leukemia (CML) is a myeloproliferative disorder, characterized by the overproduction of myeloid cells in all stages of maturation. It is usually defined by three sequential stages (Chronic, Accelerated and Blast-crisis) where the transition from chronic to accelerated to blast phases is presumed to occur due to secondary genetic changes, viz. accumulation of mutations, activation of downstream pathways and failure of apoptosis.

Significance of ATM Gene Polymorphisms in Chronic Myeloid Leukemia - a Case Control Study from India.

Background: Development of chronic myeloid leukemia (CML) involves formation of double strand breaks (DSBs) which are initially sensed by the ataxia telangiectasia mutated (ATM) signal kinase to induce a DNA damage response (DDR). Mutations or single nucleotide polymorphisms in ATM gene are known to influence the signaling capacity resulting in susceptibility to certain genetic diseases such as cancers.

Materials And Methods: In the present study, we have analyzed -5144A>T (rs228589) and C4138T (rs3092856) polymorphisms of theATM gene through polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) in 925 subjects (476 CML cases and 449 controls).

Association of promoter polymorphisms of Fas -FasL genes with development of Chronic Myeloid Leukemia.

Chronic myeloid leukemia (CML) is a monoclonal myeloproliferative disorder of hematopoietic stem cells (HSCs), characterized by reciprocal translocation, leading to the formation of BCR-ABL oncogene with constitutive tyrosine kinase (TK) activity. This oncogene is known to deregulate different downstream pathways which ultimately lead to cell proliferation, defective DNA repair, and inhibition of apoptosis. Fas (Fas cell surface death receptor) is a member of tumor necrosis factor (TNF) superfamily which interacts with its ligand, FasL, to initiate apoptosis.

Correlation of C/EBPα expression with response and resistance to imatinib in chronic myeloid leukaemia.

Objective: Altered differentiation is a common feature of haematopoietic malignancies with poor prognosis. CAAT/enhancer binding protein alpha (C/EBPα) is a key transcription factor that regulates myeloid differentiation. This study is aimed to know the prognostic value of CAAT/enhancer binding protein alpha expression and correlate its expression with response to imatinib therapy.

Role of the MDM2 promoter polymorphism (-309T>G) in acute myeloid leukemia development.

Background: The human homologue of the mouse double minute 2 (MDM2) gene is a negative regulator of Tp53. MDM2-309T>G a functional promoter polymorphism was found to be associated with overexpression thereby attenuation of Tp53 stress response and increased cancer susceptibility. We have planned to evaluate the possible role of MDM2-309T>G polymorphism with risk and response to chemotherapy in AML.

NRAS mutations in de novo acute leukemia: prevalence and clinical significance.

The activating mutations of the Ras gene or other abnormalities in Ras signaling pathway lead to uncontrolled growth factor-independent proliferation of hematopoietic progenitors. Oncogenic mutations in NRAS gene have been observed with variable prevalence in hematopoietic malignancies. In the present study, NRAS mutations were detected using bidirectional sequencing in 264 acute leukemia cases--129 acute lymphocytic leukemia (ALL) and 135 acute myeloid leukemia (AML) and 245 age- and gender-matched controls.

Incidence of Bcr-Abl kinase domain mutations in imatinib refractory chronic myeloid leukemia patients from South India.

Mutations in the Bcr-Abl kinase domain (KD) are a major cause for acquired resistance to imatinib (IM) treatment and have been associated with progression and poor prognosis in chronic myeloid leukemia patients. The present study includes 63 patients resistant to standard imatinib dose of 400 mg according to ELN guidelines. Direct sequencing method is used for mutational analysis.

Association of thymidylate synthase 5'-UTR 28bp tandem repeat and serine hydroxymethyltransfarase C1420T polymorphisms with susceptibility to acute leukemia.

The current study was aimed to elucidate the association of thymidylate synthase (TYMS) 5'- UTR 28bp tandem repeat and cytosolic serine hydroxymethyltransferase (cSHMT) C1420T polymorphisms with acute leukemia in South Indian subjects. A total of 812 subjects [523 healthy controls, 148 acute lymphoblastic leukemia (ALL) cases and 141 acute myeloid leukemia (AML) cases] were screened for TYMS 5'-UTR 28bp tandem repeat and cSHMT C1420T using PCR-AFLP and PCR-with confronting two-pair primers (CTPP) approaches. TYMS 5'-UTR 2R allele frequencies of controls, ALL and AML cases were 35.

Early molecular response in chronic myeloid leukemia patients predicts future response status.

Imatinib is the frontline therapy for chronic myeloid leukemia (CML) management. Most of the CML patients achieve major responses, but a proportion (nearly 25-35%) of them develop drug resistance. Molecular monitoring using quantitative real-time PCR at regular intervals according to European LeukemiaNet (ELN) helps in the assessment of long-term outcomes in imatinib-treated CML patients.

Association of XRCC5 VNTR polymorphism with the development of chronic myeloid leukemia.

Double-strand breaks (DSBs) inducing agents influence the fidelity of DNA repair in both normal cells and leukemic cells, causing major genomic instability. In eukaryotic cells, non-homologous end joining pathway (NHEJ) is the major mechanism for DSB repair. Human X-ray repair cross-complementing 5 (XRCC5) gene encodes for the protein KU86, an important component of NHEJ pathway.

Incidence of internal tandem duplications and D835 mutations of FLT3 gene in chronic myeloid leukemia patients from Southern India.

Objective: To screen two important FLT3 mutations (internal tandem duplication (ITD) and D835 point mutations) in chronic myeloid leukemia (CML) patients from Southern India and report their incidence.

Methods: Screened 350 CML patients and 350 controls for the two FLT3/mutations through polymerase chain reaction and restriction fragment length polymorphism methods.

Results: ITDs were detected in 12 of the 350 CML patients (3.

Methylation status of CEBPA gene promoter in chronic myeloid leukemia.

CCAAT/enhancer binding protein alpha is one of the crucial transcription factors for myeloid cell development that has been found to be involved in hematopoietic differentiation and leukemiogenesis. Recently, epigenetic regulation of CEBPA expression through DNA methylation has been demonstrated in leukemia. The aim of this study was to investigate the methylation status of CEBPA gene in chronic myeloid leukemia (CML) patients.

Association of XRCC1 gene polymorphisms with chronic myeloid leukemia in the population of Andhra Pradesh, India.

Chronic myeloid leukemia (CML), a clonal myeloproliferative disorder, is characterized primarily by the presence of chimeric BCR-ABL oncogene, and its progression from chronic to blast phase is associated with the accumulation of additional molecular and chromosomal abnormalities. The molecular mechanisms underlying this genetic instability are poorly understood. The activity of BCR-ABL is known to be associated with the increased production of intracellular reactive oxygen species and spontaneous DNA damage, which when effected by impaired/inaccurate DNA repair systems result in increased susceptibility to CML progression.

Fms like tyrosine kinase (FLT3) and nucleophosmin 1 (NPM1) mutations in de novo normal karyotype acute myeloid leukemia (AML).

Mutations in FLT3 and NPM1 are important prognostic factors in AML, influencing outcome in normal karyotype cases. We here analysed incidences of FLT3/ITD, D 835 and NPM1 mutations in patients with de novo normal karyotype AML using PCR and gene sequencing, along with laboratory parameters and treatment outcomes. There were 128 patients with a median age of 45 years (range, 19-65).

Association of the GSTP1 gene (Ile105Val) polymorphism with chronic myeloid leukemia.

The GSTP1 enzyme plays a key role in biotransformation and bioactivation of certain environmental pollutants such as benzo[a]pyrene-7, 8-diol-9,10-epoxide (BPDE) and other diol epoxides of polycyclic aromatic hydrocarbons. It catalyses the detoxification of base propanols that arise from DNA oxidation thus offering cellular protection against oxidative stress. A single nucleotide polymorphism at codon 105 results in the substitution of isoleucine (Ile) to valine (Val) causing a metabolically less active variant of the enzyme.