Recent advances in the bcr-abl negative chronic myeloproliferative diseases

Abstract

The chronic myeloproliferative disorders are clonal hematopoietic stem cell disorders of unknown etiology. In one of these (chronic myeloid leukemia), there is an associated pathognomonic chromosomal abnormality known as the Philadelphia chromosome. This leads to constitutive tyrosine kinase activity which is responsible for the disease and is used as a target for effective therapy. This review concentrates on the search in the other conditions (polycythemia vera, essential thrombocythemia and idiopathic mylofibrosis) for a similar biological marker with therapeutic potential. There is no obvious chromosomal marker in these conditions and yet evidence of clonality can be obtained in females by the use of X-inactivation patterns. PRV-1mRNA over expression, raised vitamin B12 levels and raised neutrophil alkaline phosphatase scores are evidence that cells in these conditions have received excessive signals for proliferation, maturation and reduced apoptosis. The ability of erythroid colonies to grow spontaneously without added external erythropoietin in some cases, provided a useful marker and a clue to this abnormal signaling. In the past year several important discoveries have been made which go a long way in elucidating the involved pathways. The recently discovered JAK2 V617F mutation which occurs in the majority of cases of polycythemia vera and in about half of the cases with the two other conditions, enables constitutive tyrosine kinase activity without the need for ligand binding to hematopoietic receptors. This mutation has become the biological marker for these conditions and has spurred the development of a specific therapy to neutralize its effects. The realization that inherited mutations in the thrombopoietin receptor (c-Mpl) can cause a phenotype of thrombocytosis such as in Mpl Baltimore (K39N) and in a Japanese family with S505A, has prompted the search for acquired mutations in this receptor in chronic myeloproliferative disease. Recently, two mutations have been found; W515L and W515K. These mutations have been evident in patients with essential thrombocythemia and idiopathic myelofibrosis but not in polycythemia vera. They presumably act by causing constitutional, activating conformational changes in the receptor. The discovery of JAK2 and Mpl mutations is leading to rapid advancements in understanding the pathophysiology and in the treatment of these diseases.

Figure 1

The domains of JAK2 illustrating binding to the receptor and changes consequent to receptor binding and mutation in the JH2 domain. The V617F mutation of the JH2 domain of JAK2 results in constitutive kinase activation. Panel A: When no ligand in bound to the EPO, TPO, G-CSF or GM-CSF receptors, the kinase activity of the JH1 domain is inhibited by the JH2 domain and JAK2 is inactive. Panel B: When EPO binding to it receptor, the two strands of the receptor come closer together, JAK2 changes conformation, the JH1 kinase activity in no longer inhibited by JH2. Panel C: The JAK2 V617F mutation prevents JH2 from inhibiting JH1 and the kinase is active even when no ligand is bound by the receptor.

Figure 2

Polymorphism and mutations of the thrombopoietin receptor, c-Mpl. Two polypmorphisms, c-Mpl K39N and S505A, lead to constitutive activity of c-Mpl and thrombocytosis. Somatic mutations in the juxtamembranal domain of c-Mpl also lead to constitutive activity and have been found in patients with ET and IMF.