Pathophysiology

Most cases of MPD are now understood to be neoplasms, insofar as mature blood cells from patients with these disorders have been shown to arise from a single bone marrow stem cell. Although clonal derivation is a unifying pathophysiolog-ical theme, there are marked variations in the clinicopatholog-ical features of each of the MPDs. The evidence for clonal origin of the MPD is derived from several lines of evidence. The clinical observation that stable phase CML can transform into an acute leukemia with either myeloid, lymphoid, basophilic, megakaryoblastic, or eosinophilic features suggested that this entity is a neoplasm derived from a multipotent hematopoi-etic stem cell.12 Specific documentation that mature cells from different lineages in patients with CML were all descended from early stem cells was first proved by Fialkow et al.13 who studied women with CML who happened to be heterozygotes for the A/B forms of the glucose-6-phosphate dehydrogenase (G6PD) isoenzyme. Neutrophils obtained from normal females who are G6PD heterozygotes will be as likely to express the A as the B form due to random X-chromosome linked inactivation of one of the G6PD alleles in the heterogeneous population of bone marrow stem cells. However, if a single bone marrow stem cell undergoes malignant degeneration, the number of neutrophils having either A or B isoenzyme expression (depending on the particular inactivation event in the original stem cell) will be greatly expanded. Therefore, examination of the neutrophils from a patient with CML who is a G6PD heterozygote will show expression of virtually all A (or B) type of G6PD isoenzyme.

The clonal nature of CML can also be documented by means of detecting evidence for the bcr-abl translocation in mature cells. Routine karyotypic analysis, which can be used to define the characteristic translocation between the long arm of chromosome 9 and the long arm of chromosome 22 (i.e., the Philadelphia chromosome) requires metaphases and therefore cannot be used in mature nondividing cells such as neutrophils. However, it is now routinely possible to isolate granulocytes, obtain DNA, and document the rearrangement of the bcr or abl gene by Southern blotting techniques.14 Alternatively, the translocation can be sensitively detected by the use of the so-called reverse polymerase chain reaction. In this technique, RNA is isolated from neutrophils and cDNA is created by means of the enzyme reverse transcriptase.15 A standard polymerase chain reaction is then done, using a bcr and an abl primer, with amplification occurring only if a bcr-abl fusion transcript is present.

Because MPDs other than CML are not currently characterized by a specific chromosomal abnormality, and since it is rare to encounter a female heterozygous for G6PD isoenzyme, other techniques are required to prove clonality in PCV, AMM, and ET. The use of X-linked-restriction fragment length polymorphisms (RFLP) has enabled cells from virtually every female with an MPD to be informative. For example, the human androgen receptor gene, encoded on the X chromosome, is polymorphic in 90 percent of females.16 By using the appropriate restriction enzymes, and taking advantage of the fact that certain restriction enzymes will only cut in the absence of X-chromosome inactivation, it has been possible to prove a clonal origin of mature cells in the vast majority of patients with all of the MPDs,17,18 supplementing data derived previously from the rare female G6PD heterozygote.19 Clonality in PCV has also been assessed by detecting karyotypic abnormalities in mature cells via fluorescent in situ chromosomal hybridization.20

Although neutrophils, red cells, and platelets have been shown to be clonally derived, other cell types involved in the pathogenesis of the MPD may proliferate in reactive fashion in response to growth factors elaborated by the neoplastic cells. The marrow-derived fibroblasts in the MPD appear to be only indirectly involved in the neoplastic process. Various studies used to assign clonality, as indicated above, have been used to show that marrow fibroblasts in patients with MPD have a primarily mes-enchymal origin, rather than being descended from hematopoi-etic stem cells.21,22 Platelet-derived growth factor (PDGF),23 tumor growth factor beta (TGF-P),24 and other cytokines have been implicated as substances that may be fibroblast mitogens. Megakaryocytes, which are also increased in the marrows from many patients with MPD, may also, in some cases, proliferate in a reactive fashion. If fibrosis overwhelms the marrow, patients may display hematopoiesis in nonmarrow sites such as the spleen, liver,25 lung,26 brain,27 paraspinal areas,28 breast,29 and kidney.30 However, the signals responsible for the development of extramedullary hematopoietic cells are poorly understood.31 The precise molecular pathophysiology of the myeloprolif-erative disorders PCV, AMM, and ET remains elusive. However, cloning the genes at the CML t(9;22) breakpoint had led to the generally accepted theory that the dysregulated tyrosine kinase activity of bcr-abl fusion protein leads to overabundant prolif eration and hence to clinical disease.32,33 While a description of the relevance of bcr-abl can be found in Chapter 4, this is of critical importance given the ability of an oral administered drug inhibiting c-abl activity to cause remission in patients with CML, even in those with advanced disease.34 Chronic myelomonocytic leukemia, the disease subtype within the FAB classification scheme but with features of an MPD, is occasionally associated with chromosomal translocation involving fusion into another tyrosine kinase, also in the c-abl family, platelet-derived growth factor receptor P on chromosome 5. Patients with the t(5;12)35 (producing the TEL-PDGFR), or t(5;7)36 (HIP-PDGFR fusion) are rare, but are thought to have dysregulated tyrosine kinase function with consequences similar to those noted in CML. Without guiding chromosomal translocations, understanding the pathophysiology of AMM, ET, and PCV has been more elusive. However, abnormalities of the erythropoietin receptor37 in PCV and the thrombopoietin receptor, c-mpl,38 in ET are being intensely studied.

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