Chromosome copy number and leukemia–Lessons from Down's syndrome

Abstract

Cancer is a genetic disease of the somatic cell. Virtually all cancers, including leukemias, harbor multiple acquired genetic abnormalities. These abnormalities are commonly manifested by growth chromosomal abnormalities. These abnormalities can be either structural or numerical. Aneuploidy, change in the normal chromosomal copy number, is one of the frequent abnormalities in cancer. For example high hyperdiploid acute lymphoblastic leukemia (ALL) is the most common leukemia observed in young children. The leukemic cells contain extra copies of multiple chromosomes. The chromosomes involved are non-random. Chromosomes 21, X, and 6 are almost always involved, as are chromosomes 4,10,17 and occasionally 18. This specific leukemia syndrome suggest a causative role for the chromosomal numerical aberrations. Yet it the mechanisms by which acquired trisomies contribute to leukemia is unknown. Children with Down Syndrome (DS) have a 20-fold risk and about 600 risk for acute metakaryocytic leukemia. This strong association between germline trisomy 21 and leukemia strongly suggest that trisomy 21 is leukemogenic. Elucidation of the pathogenesis of the leukemias of DS is likely to reveal the mechanisms by which aneuploidy contribute to leukemia and cancer. Approximately 10% of children with DS are born with a megakaryocytosis syndrome commonly called ‘‘transient myeloproliferative disorder’’ (TMD) or ‘‘transient abnormal myelopoiesis’’ (TAM) or ‘‘transient leukemia’’. As suggested by the different names the disorder is usually transient and resolves spontaneously within up to several months. The term ‘‘transient leukemia’’ is occasionally used because the blasts in this transient disorder are mostly of clonal megakaryoblastic origin. The biological mechanism of the spontaneous resolution is unclear. About 1 /2% of DS patient will develop, however, full blown malignant acute megakaryoblastic leukemia (AMKL) during their first four years of life that will not regress without chemotherapy. In fact, the risk of AMKL is about 600 times higher in children with DS. The factor(s) underlying the transformation from ‘‘benign’’ TMD into ‘‘malignant’’ AMKL are largely unknown. Thus the megakaryocytic malignancies of DS provide a ‘‘natural genetic model’’ of multistep lineage specific leukemogenesis. Both the congenital disorder and the full blown AMKL are characterized by differentiation arrest of the megakaryocytic lineage. The marrow and the liver of infants with TMD contain a large number of dysplastic micromegakaryocytes. Identical cells are observed in the early stages of the AMKL of DS. Both disorders are also characterized by thrombocytopenia, indicative of poor platelets formation by the dysplastic megakaryocytes. The peculiar association between DS and childhood megakaryoblastic disorders has led to intensive search for gene or genes on chromosome 21 than may cause the differentiation arrest and initiate the leukemia. A surprising twitch in this story came with the discovery that a gene on chromosome X , GATA1, was mutated in the megakaryoblasts from all the patients with DS and either TMD or AMKL. The mutations were also found in fetal liver of aborted DS fetuses. The mutations are acquired as they are not found in remission samples, and are specific to the megakaryoblastic disorders associated with trisomy 21. No GATA1 mutations were found in other AMKLs, in sporadic acute myeloid leukemia (AML) or in the acute lymphoblastic leukemia (ALL) associated with DS. Thus a clear model for multistep