Physiopathogenesis of Hematological Cancer

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The fate of hematopoietic stem cells (HSCs) is largely regulated by interactions with the bone marrow environment. In the bone marrow, multiple stem cell niches have been proposed to control different stem cell behaviors, including mobilization, circulation and homing. Currently, the hematopoietic niche is conceptually divided into an osteoblastic niche (located near osteoblasts) and a vascular niche (near the sinusoids). It has been suggested that the osteoblastic niche is responsible for retain stem cells in a quiescent state maintaining a sufficient stem cells number while the vascular niche has an important role in supporting proliferation, differentiation, and transendothelial migration of HSCs. These niche’s functions are controlled by multiple signaling and adhesion molecules. Leukemic stem cells (LSC) are derived from HSCs or proliferating progenitor cells through the acquisition of stem cell properties including the ability to selfrenewal. Similar to normal HSCs, LSCs depend upon interactions within a specific niche to maintain and to support cell growth. This review addresses the interactions between HSC and LSC with their microenvironment, exploring mechanisms that regulate normal and malignant hematopoiesis.

Recent studies have demonstrated that tumor cells have hierarchical organization with cancer stem cells at the apex. Cancer stem cells, also termed cancer initiating cells, have self-renewal capacity and might not be sensitive to cytotoxic drugs. Thus, these cells may be responsible for the high frequency of relapse in many cancers, such as acute leukemias, brain and breast cancer. This chapter will approach the evidences of the presence of leukemia stem cells and the therapeutic perspectives to reach these cells.

Cancer initiation and progression has been linked to oxidative stress, a condition in which the balance between production and disposal of reactive oxygen or nitrogen species is altered. Accumulation of such damage provokes noxious effects on individuals, resulting in diseases such as leukemias, multiple myeloma and lymphomas. Although the hematopoietic cells have multiple mechanisms to protect themselves from oxidative stresses, redox regulation accompanied by the change in reactive oxygen species (ROS) amount, it has been shown to be an important component in tumor therapy, as well as in malignant cell survival and induced-ROS cell death. In order to better understand the physiopathogenesis of hematological cancer in molecular and cellular levels of formation and growth of hematological tumors, this chapter will synthetize important points in cell death ( apoptosis, autophagy, necrosis) and production of free radicals as reactive oxygen and nitrogen species (ROS and RNS) and oxidative stress process.

The 26S proteasome is a large multi-subunit complex responsible for the ATP-dependent degradation of ubiquitylated proteins, a critical process for signal transduction and regulation of transcription and receptor function. In cancer, deregulation of this process may contribute to progression, drug resistance and altered immune surveillance. Proteasome inhibition (PI) cause cellular apoptosis by affecting levels of short-lived proteins, by inhibition of NFκB activity and increased activity of p53, Bax and cyclin-dependent kinase inhibitors p27 and p21. Preclinical studies showed that malignant cells are more susceptible to PI than normal cells. Although a concrete explanation for this selectivity is not available yet, one possibility is that sensitivity is linked to proliferation and/or deregulated cell cycle progression. Numerous proteasome inhibitors have been developed and the first approved, bortezomib is a boronic acid dipeptide that binds directly to the 20S proteasome and blocks its enzymatic activity.

DNA methylation and post-transcriptional histone modifications interact in an epigenetic network crucial for the regulation of chromatin structure and transcriptional activity. Aberrant gene promoter hypermethylation patterns, leading to transcriptional silencing, have been recognized as a key epigenetic mechanism in the process of malignant transformation. The growing list of genes affected by epigenetic changes reveals not only new insights in the molecular pathogenesis of hematopoietic malignancies, but also provides novel biomarkers that may contribute to the improvement of diagnostic methods and prognostic assessment. Moreover, both regional DNA hypermethylation and histone hypoacetylation have been recognized as promising novel therapeutic targets in hematopoietic malignancies. Currently, two hypomethylating agents are in clinical use for myelodysplastic syndromes, 5-azacitidine and 5-aza-2- deoxycytidine (decitabine), with an impact on disease evolution. Our increasing knowledge regarding the epigenetic network that controls the aberrant silencing of cancer-related genes, and how these events interact with genetic alterations to drive tumor progression, may help us derive novel treatment concepts against human cancer.

microRNAs (miRNAs) are a distinct subset of non-coding RNAs that control gene expression post-transcriptionally. These molecules generally bind to the 3’-UTR (untranslated region) of specific messenger RNAs (mRNAs) and induce its translational suppression or direct cleavage, based on sequence complementarity. miRNAs play a pivotal role in many cellular processes and their aberrant expression is associated with several human diseases. Their role in normal hematopoiesis has been elucidated by a large number of studies, revealing specific variations of miRNAs expression during the commitment and development of hematological stem cells in different lineages. Aberrant expression of these molecules has also been well documented in the majority of hematological malignancies. Here we discuss the current information available about miRNA expression and its function in normal hematopoiesis and in hematological malignancies.

Transcription factors are key regulators of the pattern of gene expression in a cell and directly control central processes such as proliferation, survival, self-renewal, and invasion. Alterations in the mechanisms that normally control these functions can lead to hematological malignancies. This chapter will describe the highlights of the main transcription factors in hematological malignancies.

Isoprenylation is a posttranslational modification of proteins in which a farnesyl (15-carbon) or a geranylgeranyl (20-carbon) group is attached to a C-terminal cysteine. Isoprenylation provides a protein with abilities that allow it to interact with cell membrane and with other molecules. Such interactions are essential to the biological functions of a significant number of proteins involved in the signaling of cell growth, differentiation, cytoskeletal function and vesicle trafficking. Thus, isoprenylation is extremely relevant to the development of transformation-related cell phenotypes. There are extensive works in the literature documenting the involvement of prenylated protein or their downstream signaling partners in various aspects of pathogenesis of hematological malignancies. This chapter reviews the importance of isoprenylation and these proteins to the biology of hematological malignancies and analyzes the results of clinical studies evaluating the use of inhibitors of protein prenylation in the treatment of these disorders.

Angiogenesis, a term applied to the formation of capillaries from preexisting vessels is a crucial phenomenon for the continuous growth of neoplastic cells and cancer progression. This relationship has been described in several hematologic malignancies such as leukemia, lymphoma, multiple myeloma, myelodysplastic syndromes. Vascular endothelial growth factor and basic fibroblast growth factor are predictors of poor prognosis in leukemia and Non-Hodgkin's lymphoma. Furthermore, microvessel density is correlated with decreased survival in leukemia, myeloma and lymphoma patients. This review addresses evidence of the role of angiogenesis in hematopoietic malignancies.

The term lymphoma encompasses both Hodgkin and non-Hodgkin lymphoma and comprises several lymphoproliferative malignant diseases with remarkable biological and clinical heterogeneity. Hodgkin lymphoma is recognized by the presence of Reed-Sternberg cells in involved tissues and almost all cases are originated from B-cells. Non-Hodgkin lymphomas are also predominantly derived from B-cells, and only 12% of the cases have a T-cell or NK-cell origin. Non-Hodgkin lymphomas do not present any characteristic cell type and the great majority of the cells in the tumor are clonally derived from a transformed precursor. In this chapter, the biology, cellular origin and molecular pathogenesis of lymphomas are discussed, focusing on the most common subtypes of B-cell non- Hodgkin lymphomas. Selected topics of the epidemiology, clinical presentation and diagnosis of lymphomas are also introduced, and an overview of the main issues related to pretreatment evaluation, staging and treatment of lymphomas is provided.

Acute lymphoblastic leukemia (ALL) is the most frequent cancer in children and originates from genetic lesions in progenitor cells responsible for the malignant transformation. The knowledge of the molecular basis of the ALL is important not only for a better understanding of this disease but also for the identification of prognostically relevant ALL sub-groups and potential pathways to target therapy. In this chapter we discuss the molecular basis of acute lymphoblastic leukemia, including the identification of different genetic alterations in B and T-lineages ALL and the use of the Immunoglobulin (IG) and T-cell receptor (TR) genes rearrangements, as marker of clonality and minimal residual disease (MRD) detection.

Multiple myeloma (MM) is a neoplastic plasma cells (PC) disease that has a heterogeneous clinical course and outcome. MM is usually associated, particularly in the advanced forms, with lytic bone lesions, anemia, renal impairment and increased bone marrow angiogenesis. Several factors like activating factors of osteoclast, pro-angiogenic factors, cytokines, growth factors, adhesion molecules and proteinases are involved in these manifestations. Although several aspects of the MM pathogenesis remain uncertain, significant progress occurred in the last decade. This chapter focuses on the current knowledge of the molecular pathogenesis of the disease as well as the pathogenesis of angiogenesis, bone involvement, anemia and renal impairment, which are frequent in MM patients.

The Myeloproliferative Neoplasms (MPN) are clonal hematopoietic stem cell disorders characterized by proliferation of one or more of the myeloid lineages, hipercellularity of the bone marrow with hematopoietic maturation and increased numbers of granulocytes, red blood cells and/or platelets in the peripheral blood. Several genes are involved in the pathogenesis of these diseases, like bcr-abl in chronic myeloid leukemia, JAK-2 in polycithemia vera, myelofibrosis and essential thrombocithemia, c-kit in systemic mastocytosis and PDGRF in chronic eosinophilic leukemia. The advances in the understanding of the pathogenesis of the MPN has improved the diagnosis and will contribute in the development of target therapies for these diseases.

Acute myeloproliferative disease is a heterogeneous group of malignant disorders. In spite of the great variability regarding genetic and clinical aspects, all forms present common mechanisms underlying their pathogenesis: the disruption of genes tightly involved in the control of cell differentiation, proliferation and/or apoptosis. Major progress has been made to better understand such events and recurrent genetic abnormalities have been acknowledged based on both physiopathologic and prognostic relevance: t(15;17), t(8;21), inv(16)/t(16;16), in addition to mutations in the genes NPM1, FLT3 and CEBPA. These genetic alterations have identified particular subgroups of patients and their resultant aberrant proteins have become targets for drug development, intending to improve therapy efficacy and to diminish its toxicity.

Protein kinase inhibition has become a promising strategy for cancer therapy since the successful results obtained with Imatinib in the treatment of Chronic Myeloid Leukemia. Several other compounds that target specific kinases are now in clinical development for myeloid and lymphoid neoplasms. In this chapter we discuss the role of kinase dysregulation in hematologic malignancies and the development of inhibitors for these targets.