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BREAKTHROUGHS SUMMARY ARTICLE The Full-length version of this article is also available, published online as http://www.fasebj.org/cgi/content/full/16/3/273e.< /FONT> |
In the 1960s, children’s leukemia wards were filled with the chatter of little ones who could not expect to live more than a few months. Four decades later, almost 80% of all children with leukemia survive the disease. Impressive survival gains have also been made for adults with this leukemia.
Surprisingly, many important strides made in the treatment of leukemia did not hinge on the efforts of cancer researchers who specifically aimed to conquer the disease, but rather were made by a diverse group of curious scientists from pathologists and hematologists to chemists and geneticists. By pursuing answers to basic questions, these researchers collectively homed in on the molecular defects that underlie leukemia and ways to counter those flaws.
The success story of leukemia began in 1845 when Berlin pathologist, Rudolph Virchow, noticed leukemia patients had an excess of white or colorless cells.
With the advent of cell stains at the end of the 19th century, scientists discovered that leukemia occurs when a white blood cell, whose development is frozen, continues to duplicate itself. The resulting progeny of cells are all in the same stage of development and bear the distinctive hallmarks of the type of ancestral white blood cell in the bone marrow that gave rise to them.
Based on this understanding, by 1900 leukemia was no longer seen as a single disease but rather as four different entities that reflect from which type of cell the leukemia originates. But what caused these diseases remained a mystery and hampered the development of effective drugs for the disease.
By 1960, a number of serendipitous discoveries led to the development of three anti-leukemia drugs. Researchers concocted a fourth drug in an effort to jam DNA production in leukemia cells so they could no longer divide. None of these drugs by themselves, however, could save children with acute leukemia.
It took a diverse team of clinicians, pharmacologists, and geneticists to discover that although the new cancer drugs might kill almost all leukemia cells, so that no residual disease could be detected, a few leukemia cells remained. These cancer cells eventually multiplied to the point of causing a resurgence of the disease. This suggested that if doctors wanted to cure their patients of leukemia, they had to continue to treat them even after their symptoms disappeared. An animal model revealed that although leukemia tumors developed resistance to one drug, they became more sensitive to another.
Based on these findings, in 1962 hematologists at the National Cancer Institute and clinical researchers, Emil Freireich and Emil Frei III, began treating patients with all four anti-leukemia drugs available at the time. The regimen was highly effective, as evidenced by many of those patients who are still alive today.
But this regimen does not work for all types of leukemia and has many toxic side effects. To overcome these limitations, scientists needed to explore exactly what causes these leukemias. In the 1960s and 1970s, researchers discovered that one type of leukemia is caused by the translocation of a portion of chromosome 22 to chromosome 9.
A quest to uncover how that translocation causes the leukemia recently ended when oncologist Brian Druker discovered that the new protein, BCR-ABL, created by the translocation activates a molecule that prompts cells to continually divide. Druker and other researchers at a drug company discovered a compound that inhibits BCR-ABL and that apparently has cured many leukemia patients.
Researchers have pinpointed more than 100 different translocations in the cells of leukemia patients. Scientists are deciphering which of these translocations cause leukemia, and are developing drugs that target the damage these translocations effect.
Doctors already use the presence of specific translocations to classify patients’ leukemias. This classification scheme has led to more tailored treatments, as some drugs work better on leukemia cells with certain kinds of translocations.
More precise diagnoses and tailored treatments for leukemia also stem from the advent of the flow cytometer and the polymerase chain reaction technique, which have also dramatically improved the sensitivity of the detection of any leukemia cells remaining after treatment. This improved sensitivity enables doctors to better assess when therapy can be stopped. This has not only improved the cure rate for leukemia, but has also helped many patients avert deadly complications from chemotherapy.
Thanks to a succession of curious scientists from diverse fields, including laboratory researchers and clinicians, leukemia has gone from being a mysterious disease to being a group of well-defined disorders. Beginning with the gross abnormalities of these leukemias and zooming in on leukemia cells’ molecular fatal flaws, these researchers—from the bench to the bedside—are gathering information that is blossoming into cures for many afflicted with these cancers.
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FOOTNOTES |
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—Summary prepared by Margie Patlak.
This article has been cited by other articles:
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  K. Robien and C. M. Ulrich 5,10-Methylenetetrahydrofolate Reductase Polymorphisms and Leukemia Risk: A HuGE Minireview Am. J. Epidemiol., April 1, 2003; 157(7): 571 - 582. [Abstract] [Full Text] [PDF]
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