After studying this chapter you should understand:
The pathogenic role of specific tyrosine kinase mutations in various myeloproliferative disorders.
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 pathophysiology and clinical features of the myelodysplastic syndromes.
CANCER AS A GENETIC DISEASE
Like other cancers, hematologic malignancies are caused by acquired somatic mutations that activate proto-oncogenes or inactivate tumor suppressors. Remarkably, we now know that at least some of these potentially oncogenic events occur from time to time in the hematologic cells of most if not all healthy people, the vast majority of whom will not suffer from a hematologic malignancy during their lifetimes. It follows that no single mutation is sufficient to create these cancers. Instead, they 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.
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 disorders and myelodysplastic syndromes, tumors that originate in early hematopoietic progenitors that primarily affect marrow function and give rise to differentiated progeny. Subsequent chapters will cover the acute leukemias, aggressive tumors of early myeloid or lymphoid progenitors, and the diverse collection of tumors that are derived from mature lymphocytes and plasma cells.
The molecular hallmark of the myeloproliferative disorders is the presence of gain-of-function mutations that activate tyrosine kinases, enzymes that phosphorylate proteins on tyrosine residues. 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 survival of myeloid progenitors in the bone marrow. As a result of constitutive activation of pro-growth and pro-survival signaling pathways, the bone marrow in the myeloproliferative disorders is hypercellular, and early in the course of the disease there is an increase in one or more of the formed myeloid elements (granulocytes, platelets, and/or red cells) in the peripheral blood. Differentiation is initially unaffected or altered in relatively subtle ways, such that patients tend to suffer from symptoms ...