Several species of kinetoplastid protozoa cause major human infectious diseases. Trypanosoma cruzi is responsible for the fatal Chagas disease in large parts of South America, the various species of Leishmania cause a number of different human diseases with millions of patients world-wide, and the African trypanosome Trypanosoma brucei is the agent of human sleeping sickness, a disastrously re-emerging epidemic of fatal infections in Sub-Saharan Africa. Chemotherapy of all of these infections is in a very unsatisfactory state. cAMP signalling pathways in humans have provided interesting drug targets for a number of clinical conditions, from asthma to impotency. Similarly, cAMP signalling in kinetoplastids might offer useful targets for the development of novel antiparasitic drugs, which makes their exploration an urgent need. Current knowledge suggests that cAMP signalling proceeds along very similar pathways in all kinetoplastid pathogens (T. cruzi, the Leishmanias and T. brucei). Their adenylyl cyclases are structurally very different from the human enzymes and appear to function as enzyme-linked cell surface receptors. They might represent the major sensory apparatus of the kinetoplastids, guiding much of their environmental sensing and host/parasite interaction. The cAMP-specific phosphodiesterases of the kinetoplastids are rather similar to those of human cells and might function in similar ways. Essentially nothing is known on downstream effectors of cAMP in the kinetoplastids. Homologues of protein kinase A and its regulatory subunits have been identified, but their biochemical properties seem to be disctinct from that of mammalian protein kinase A.

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Several studies involving identical twins with concordant leukemia and retrospective scrutiny of archived neonatal blood spots have shown that the TEL-AML1 fusion gene in childhood acute lymphoblastic leukemia (ALL) frequently arises before birth. A prenatal origin of childhood leukemia was further supported by the detection of clonotypic immunoglobulin gene rearrangements on neonatal blood spots of children with various other subtypes of ALL. However, no comprehensive study is available linking these clonotypic events. We describe a pair of 5-year-old monozygotic twins with concordant TEL-AML1-positive ALL. Separate leukemic clones were identified in the diagnostic samples since distinct IGH and IGK-Kde gene rearrangements could be detected. Additional differences characterizing the leukemic clones included an aberration of the second, nonrearranged TEL allele observed in one twin only. Interestingly, both the identical TEL-AML1 fusion sequence and distinct immunoglobulin gene rearrangements were identified on the neonatal blood spots indicating that separate preleukemic clones evolved already before birth. Finally, we compared the reported twins with an additional 31 children with ALL by using the microarray technology. Gene expression profiling provided evidence that leukemia in twins harbours the same subtype-typical feature as TEL-AML1-positive leukemia in singletons suggesting that the leukemogenesis model might also be applicable generally.

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