Sample 2 Acute Leukemia OMIM 151390
Key Words
| Alu Sequences | Intron |
| Evolutionary Conservation | Oncogene |
| Germline Mutation | Somatic Mutation |
| Homeotic Mutant | Transcription Factor |
| Homology | Tumor Suppressor |
People who develop acute (rapid onset and progression) leukemia often have a translocation that cuts chromosome 11 at a certain band in the long arm and places it on either chromosome 4 or 9. The aberration appears only in the leukemic cells. The translocation breakpoint on chromosome 11 occurs within an intron of a gene that encodes an 11.5 kilobase transcript. The breakpoint is within a cluster of sequences called "Alu." An Alu sequence is a 300 base pair segment repeated about 500,000 times throughout the human genome.
Leukemia arrests the normal process by which stem cells in the bone marrow give rise, through a series of developmental decisions, to several more specialized cell types. The acute leukemias associated with translocations affect mature white blood cells called monocytes and lymphocytes, which descend from the same stem cells.
The gene disturbed by the translocation in the human leukemias encodes a protein that is remarkably similar in sequence to a gene in the fruit fly Drosophila melanogaster called trithorax. Trithorax is a homeotic mutation, controlling segmentation and early embryogenesis. Functional homeotic genes determine which developmental pathways a cell follows. When homeotic genes are mutant, cells develop into the "wrong" structure – such as a fly with legs where its antennae should be.
The human leukemia gene is very similar in sequence to genes in cows, pigs, rodents and rabbits. In all of these species, the related genes encode a similar transcription factor.
Worksheet
1. How can two different translocations – t(4:11) and t(9:11) – cause the same
phenotype?
2. What do leukemia in humans and homeotic mutations in fruit flies have in common
conceptually that might explain the extensive homology between the human
chromosome 11 leukemia gene and the fly’s trithorax gene?
3. Explain how the chromosome 11 translocation might cause cancer if an oncogene is
involved, compared to if a tumor suppressor gene is implicated.
4. How can a mutation in an intron, which is not represented in the gene’s protein
product, nevertheless affect the phenotype?
5. Why is acute leukemia not inherited?
6. How might the presence of highly repeated Alu sequences within an intron cause a
translocation?
7. What is the evidence that the human leukemia gene may be quite ancient?