Correlation between the type of bcr-abl transcripts and blood cell counts in chronic myeloid leukemia – a possible influence of mdr1 gene expression

The impact of BCR-ABL mRNA type (b3a2 vs. b2a2) on chronic myeloid leukemia (CML) phenotype is still a subject of controversies. We searched for a correlation between the BCR-ABL transcripts type and CML patients' characteristics, including MDR1 gene expression. Ninety-eight untreated chronic phase CML patients were studied. The type of BCR-ABL fusion transcripts and MDR1 gene expression were determined by reverse transcriptase polymerase chain reaction. B3a2 and b2a2 transcripts were found in 53 [54%] and 44 [45%] patients, respectively. One patient co-expressed b3a2/b2a2 and was excluded from analysis. The only difference in the clinical characteristics between the two groups was the platelets count, that was higher in b3a2(+) patients [791.3±441.3×109/L vs. 440.4±283.4×109/L in b2a2(+); P=0.007]. MDR1 over-expression [MDR1(+)] was observed in 48 patients (49.5%), more frequently in older patients >60 years [71% (24/34) vs. 38% (24/63) in younger; P=0.008], and was associated with a lower white blood cells (WBC) count [105.5±79.8× 109/L vs. 143.6±96.5×109/L in MDR1(−) cases; P=0.047]. On performing the analysis only within the MDR1(+) group, the b3a2(+) cases were characterized with a significantly higher platelets count [908.7±470.1×109/L vs. 472.9±356.1×109/L; P=0.006] and a lower WBC count [85.4±61.2×109/L vs. 130±93.9×109/L; P=0.004) compared to b2a2(+) patients. No similar differences were found between b3a2(+) and b2a2(+) groups with normal MDR1 levels. These results indicate that the type of BCR-ABL transcripts correlates with the hematological parameters of CML, however only in the subgroup of patients characterized by MDR1 over-expression

Clofarabine and Adult Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a clonal, malignant disease of hematopoietic tissues that is characterized by accumulation of abnormal blast cells, principally in the marrow and impaired production of normal blood cells. The unsatisfactory clinical outcomes of AML patients urged the development of new therapy strategies, one of which includes the implementation of new nucleoside analogs. Clofarabine has offered new promising perspectives within induction and consolidation therapies. This chapter will evaluate the efficacy and tolerability of clofarabine as a single agent and in combination therapy, including hematopoietic stem cell transplantation, for AML patients

Chronic eosinophilic leukemia with FIP1L1-PDGFRA transcripts after occupational and therapeutic exposure to radiation

We present for the first time a 40-year-old male patient with a 20 year history of occupational exposure to radiation as a nuclear power plant worker, who developed FIP1L1-PDGFRA-positive chronic eosinophilic leukemia 27 months after radiotherapy for testicular seminoma. After an one-year history of dry cough, itching and night sweats, the patient presented with an elevated leukocyte count with absolute eosinophilia of 14.2×109/L, bone marrow and lymph node involvement. Treatment with Imatinib was initiated, resulting in complete hematological remission at the sixth month and complete molecular response by nested primers reverse transcription polymerase chain reaction - at the end of the first year. This case contributes to the clinical heterogeneity of a rare entity such as FIP1L1-PDGFA-positive myeloproliferative neoplasms, and for the possible role of occupational and therapeutic radiation, raising the question if one or both of them might be the causative factor

Chronic Lymphocytic Leukemia — Microenvironment and B Cells

Chronic lymphocytic leukemia (CLL) has been considered as an accumulative disease deriving from defects in apoptosis, but recent studies showed that CLL is a dynamic process in which monoclonal B cells proliferate within pseudofollicular proliferation centers. Microenvironmental interactions are essential for the survival and proliferation of CLL cells. The cell traffic between blood and secondary lymphoid tissues is controlled by tissue-specific chemokines and their specific receptors on B lymphocytes. Interstitial cell migration and adhesion events, predisposed by activational stimuli, determine CLL cell localization. Stimulation through the B cell receptor plays an important role in the expansion of the malignant clone in CLL. B cell receptors become activated either in an antigen-dependent or in an antigen-independent fashion in the secondary lymphatic tissues. However, low expression of the BCR correlates with reduced induction of protein tyrosine kinase activity and defective intracellular calcium mobilization and tyrosine phosphorylation. In contrast to normal B cells, leukemic cells are poor antigen presenting cells. This is due to the fact that leukemic cells have a reduced expression of costimulatory molecules and defects in the formation of immunological synapse with T cells. Increased surface expression of the costimulatory molecules on CLL cells correlates with their proliferation. At present, conventional treatments are not directed to interactions between CLL cells and their microenvironment, which is probably one of the reasons why, despite the significant progress in treatment, the disease still remains incurable. In this regard, identifying key biomarkers of intercellular interactions of neoplastic CLL population in comparison with clinical laboratory abnormalities in CLL enable clarification of essential processes in the development of the disease, and can be the basis for stratifying patient groups in order to optimize therapeutic approaches, which will make them relevant and promising

The Role of <em>BAALC</em> Gene in the Transformation of Myeloid Progenitor Cells to Acute Myeloid Leukemia

One of the unanswered questions in hematology is the question concerning disorders in the regulation of gene expression in different subtypes of acute myeloid leukemia (AML), leading to changes in the functional activity of certain genes and acting as a component of a series of events in the leukemogenesis. One example of such a gene is BAALC gene (brain and acute leukemia and cytoplasmic), localized in chromosome 8, which plays a role in the regulation of myeloid progenitors’ differentiation. This role is associated with several other oncogenes, such as HoxA9, ERK, and RUNX1. Gene interactions determine normal proliferation and differentiation of cells, and any disturbances could lead to leukemic development. What is the role of BAALC in normal/impaired balance? What are the connections of BAALC with the mutations established in AML: FLT3, NPM1, etc.? What are the correlations of its overexpression with clinical and laboratory findings in AML patients? What are the changes in the expression of BAALC, after successful therapy of AML and after therapy failure? Can we use it as a predictive marker in AML patients? This chapter summarizes available data about functions of BAALC gene, the frequency of overexpression, and its importance as a predictive marker in the development of AML

Roads of Drug Resistance in Acute Myeloid Leukemia—Is It Dead End?

Acute myeloid leukemia (AML) is a biologically and clinically heterogeneous neoplasm, which is characterized by abnormal proliferation, impaired apoptosis, and differentiation of leukemic immature cells. Nowadays, the first line treatment of AML is the chemotherapy regimen, which combines both cytosine arabinoside and anthracycline. Despite that complete remission (CR) can be achieved in 40–80% of patients depending on age, a considerable number will eventually relapse (acquired resistance) or have refractory disease (primary resistance). Finally, the estimated 5-year overall survival (OS) is less than 30%. Recent investigations reveal various mechanisms, responsible for drug resistance leading to AML persistence and recurrence. In order to improve clinical outcomes and develop successful therapeutic strategies, it is necessary to better explore the major adverse factors for escape from treatment, as well as to explore ways to predict and prevent or target drug resistance

Zinc Oxide Nanoparticles and Photodynamic Therapy for the Treatment of B-chronic Lymphocytic Leukemia

The generation of singlet oxygen (SO) in the presence of specific photosensitizers (PS) or semiconductor nanoparticles (NPs) and its application in photodynamic therapy (PDT) has great interest for the development of new cancer therapies. Our work focused on the identification of factors leading to the enhancement of B-Chronic Lymphocytic Leukemia (B-CLL) intracellular SO production and cell killing using Manganese (Mn) doped and undoped Zinc Oxide (ZnO) NPs as potential photosensitizers with and without PDT. Mn can enhance ZnO NPs generation of SO by targeted cells. Multi drug resistant B-Chronic Lymphocytic Leukemia (B-CLL) cells spontaneously produce high amounts of Reactive Oxygen Species (ROS) having an altered redox state in relation to that of normal B lymphocytes. These little variations of its SO intracellular concentrations could allow ZnO NPs to execute specific deadly programs against these leukemic cells with no significant damage to normal lymphocytes. A 0.5% Mn Doped ZnO NP was finally selected for further probes as it had the best killing activity in fludarabine resistant B-CLL cells, especially when combined with PDT. This could be an innovative specific therapy against resistant B-CLL probably contributing in the near future for the definitive benefit of these bad prognostic patients.Facultad de Ciencias Médicas (FCM

Zinc Oxide Nanoparticles and Photodynamic Therapy for the Treatment of B-chronic Lymphocytic Leukemia

The generation of singlet oxygen (SO) in the presence of specific photosensitizers (PS) or semiconductor nanoparticles (NPs) and its application in photodynamic therapy (PDT) has great interest for the development of new cancer therapies. Our work focused on the identification of factors leading to the enhancement of B-Chronic Lymphocytic Leukemia (B-CLL) intracellular SO production and cell killing using Manganese (Mn) doped and undoped Zinc Oxide (ZnO) NPs as potential photosensitizers with and without PDT. Mn can enhance ZnO NPs generation of SO by targeted cells. Multi drug resistant B-Chronic Lymphocytic Leukemia (B-CLL) cells spontaneously produce high amounts of Reactive Oxygen Species (ROS) having an altered redox state in relation to that of normal B lymphocytes. These little variations of its SO intracellular concentrations could allow ZnO NPs to execute specific deadly programs against these leukemic cells with no significant damage to normal lymphocytes. A 0.5% Mn Doped ZnO NP was finally selected for further probes as it had the best killing activity in fludarabine resistant B-CLL cells, especially when combined with PDT. This could be an innovative specific therapy against resistant B-CLL probably contributing in the near future for the definitive benefit of these bad prognostic patients.Facultad de Ciencias Médicas (FCM