Terra Sigillata

The 101st Annual Meeting of my primary professional society, the American Association for Cancer Research (AACR), convened in Washington, DC, on Saturday and will run through Wednesday, April 21. The theme for this year’s meeting is “Conquering Cancer Through Discovery Research,” and focuses strongly on the translation of discoveries into cancer treatments.

Although the Eyjafjallajökull volcanic dust cloud has delayed many European participants, over 17,000 attendees are expected at the Washington Convention Center where over 6,300 presentations are to be given.

AACR was founded in 1907 by 11 eminent physicians and scientists of their time and while “American” is in the name, AACR is truly an international organization.

Seven years ago, AACR instituted their Lifetime Achievement Award in Cancer Research. This year the award went to one of my heroes of cancer research, Dr. Janet D. Rowley of the University of Chicago. Dr. Rowley is best known for her work in the 1970s on chromosomal abnormalities in human cancer, specifically the translocation that involves the “Philadelphia chromosome” and led to the drug to target protein kinases, imatinib (Gleevec or Glivec).

AACR posted a five-minute interview with Dr. Rowley here and I’ll describe some history afterwards.



In 1960, David Hungerford at the Fox Chase Cancer Center and Peter Nowell at the University of Pennsylvania reported in the Journal of the National Cancer Institute that cells from patients with chronic myelogenous leukemia (CML) consistently had a smaller version of chromosome 22.

This short chromosome was called the Philadelphia chromosome after the city in which Penn and Fox Chase are located (as well as the headquarters of AACR).

Rowley Nature 1973 Ph chrom.jpgRowley advanced this work by examining chromosomes microscopically using a combination of staining techniques (Giemsa and the fluorescent antimalarial drug, quinacrine) to discern that the missing portion of chromosome 22 had been added to the long arm of chromosome 9 in CML patients. Remember that at this time there were no probes for doing fluorescent in situ hybridization (FISH). Rowley relied instead on the unique quinacrine staining patterns that appeared on partly elongated chromosomes generated by brief treatment of patient cells with the microtubule polymerization inhibitor, vinblastine. A figure of this work, published in Nature 1973;243:290-293, is shown here.

Finer techniques later showed that a small portion of chromosome 9 was translocated to chromosome 22 in a reciprocal manner.

Just prior to this work, Rowley had described the (8:21) translocation in acute myelogenous leukemia (AML) then later reported the (14:18) translocation in follicular lymphoma and the (15:17) translocation in acute promyelocytic leukemia (APL). The prevailing wisdom was that chromosomal abnormalities were merely after-effects of transformation but Rowley held that these specific changes could be causative in cancer. When she received the Presidential Medal of Freedom last year, she noted that her ideas were met with “amused tolerance.”

Nora Heisterkamp and her colleagues first cloned the t(9;22) breakpoint on chromosome 9 in 1983. She later demonstrated this region encoded an aberrantly regulated c-abl oncogene, a tyrosine kinase, fused with a normal gene that her group proposed naming bcr for “breakpoint cluster region.” (The name abl was derived from the viral version in the Abelson murine leukemia virus; hence the long name of the ABL protein is “v-abl Abelson murine leukemia virus oncogene homolog”).

Condensing many years of work, the resulting BCR-ABL protein was later shown to cause leukemia in mouse models with the protein activating several pathways regulating cell proliferation while also inhibiting apoptosis. In the late 1980s, imatinib emerged from a chemical library screen for PDGFR and ABL kinase inhibitory activity at Ciba-Geigy, now Novartis. In 1996, Dr. Brian Drucker at the Oregon Health and Science University showed in a series of critical experiments that imatinib (also known then as STI571) selectively killed cells expressing BCL-ABL but not the parental line. The drug entered clinical trials in 1998 and imatinib mesylate (Gleevec/Glivec) was approved by the US FDA in 2001 for the treatment of CML.

This is just one example of the impact of Rowley’s original work. Rowley’s identification of the (15;17) translocation in APL led to the use of all-trans-retinoic acid against this leukemia. She also demonstrated ten years ago that high levels of maternal ingestion of bioflavonoids could lead to chromosomal breakage and the MLL translocation responsible for infant leukemias. Her work has continued today to understand how breakpoints influence the expression of microRNAs involved in oncogenesis.

In the interview above, Rowley makes several noteworthy points. First, she notes that the Philadelphia chromosome translocation discovery was actually made on her dining room table when she was working part-time, bringing home the micrographs from lab and spreading them out at home. Rowley was noted elsewhere by Nobel laureate and incoming AACR president Elizabeth Blackburn as saying that working part-time actually gave her time to think, as opposed to all of the other activities that come along with a full-time position.

Rowley also mentioned that she made her major discovery at the age of 50. Noting that “we’re not like mathematicians,” Rowley encouraged young(er) investigators to be patient if things don’t go right early on. She also stressed the importance to junior scientists of having a more senior advisor who is truly committed to helping one develop as an independent investigators.

I would have been curious to know if Rowley thought her approach to her career would brought her the same success if she were coming up in the academic ranks today, especially when pursuing a part-time position might be considered not being serious about your science (although I suspect some may have felt that way in the 70s as well).

Dr. Rowley elaborates on her personal story and the impact of her work this 2009 article in Annual Review of Genomics and Human Genetics. I strongly encourage this article to those interested in further reading about Dr. Rowley and chromosomal translocations in leukemias.

Comments

  1. #1 msphd
    April 28, 2010

    Interesting. I’ve heard all kinds of rationalizations from women who were forced to take part-time positions for various reasons.

    I think the comment that it’s better than working full-time because it gives you time to think just goes to show how broken things are. Scientists should have built-in time to think. And full-time salaries to do it with.

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