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INTRODUCTION

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LEARNING OBJECTIVES

After studying this chapter, you should understand:

  • The pathogenic role of specific tyrosine kinase mutations in various myeloproliferative neoplasms.

  • The role of BCR-ABL in the diagnosis and targeted therapy of chronic myelogenous leukemia.

  • The diagnostic and pathogenic role of JAK2 mutations in polycythemia vera.

  • The diagnostic and pathogenic roles of JAK2, calreticulin and thrombopoietin receptor mutations in essential thrombocytosis and primary myelofibrosis

  • The pathophysiology and clinical features of the myelodysplastic syndromes.

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CANCER AS A GENETIC DISEASE

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Like other cancers, hematologic malignancies are caused by acquired somatic mutations that alter cell behavior, resulting in groups of genetically related cells (clones) with a survival or proliferative advantage. Remarkably, we now know that at least some of these potentially oncogenic events occur from time to time in the hematologic cells of healthy people, the vast majority of whom will not suffer from a hematologic malignancy during their lifetimes. More than 10% of people aged 70 years or older have a clonal mutation associated with a hematologic malignancy detectable in their blood, but the rate at which people with these mutations develop a malignancy is less than 1% per year. It follows that no single mutation is sufficient to create these cancers. Instead, hematologic cancers appear to result from the interplay of multiple mutations that collaborate to create a transformed phenotype. Molecular analyses have proven that although tumor cells within an individual cancer demonstrate some degree of genetic heterogeneity, all share a core set of identical mutations, indicating that they originate from a single, transformed cell.

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The appearance and behavior of specific hematologic malignancies stem from two major factors: 1) the identity of the oncogenic mutations found in the tumor cells and 2) the cellular context, which is to say the identity of the founding cell from which the tumor originates. The latter dictates the effects of the former on cellular proliferation, survival, and differentiation. These two themes—acquired mutations and cellular context—will be woven through our discussion of all of the hematologic malignancies. In this chapter, we discuss the myeloproliferative neoplasms and myelodysplastic syndromes, tumors that alter marrow function and which originate in early hematopoietic progenitors that give rise to differentiated progeny. Subsequent chapters will cover the acute leukemias, aggressive tumors of early myeloid or lymphoid progenitor cells that lose the ability to differentiate, and, toward the end of the book, the diverse collection of tumors that are derived from mature lymphocytes and plasma cells.

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MYELOPROLIFERATIVE NEOPLASMS

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A molecular hallmark of the myeloproliferative neoplasms is the presence of gain-of-function mutations that activate tyrosine kinases, enzymes that phosphorylate tyrosine residues in proteins. In general, these aberrant tyrosine kinases turn on the same pathways that are normally activated by hematopoietic growth factors, but they do so in a growth factor–independent fashion. In Chapter 2, we noted that the pathways activated by hematopoietic growth factors enhance the growth and ...

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