Leukemia is not so much a capital sentence as it is a living sojourn in death row - with an uncertain mortal climax. The blood of leukemic victims having gone bad, its white cells multiply non-stop, like the cancerous cells they are, accompanied by dire side effects riddling the body. In the year 2003, 30,600 U.S. patients were diagnosed with leukemia, and 7,800 died of their disease. Of that number, more than a third succumbed to AML - acute myelogenous leukemia.
And that's just half of the acute variety. Besides AML, there's ALL - acute lymphoblastic leukemia. Then there's the chronic form. There are two apparent second chronic types, namely: CLL (chronic lymphocytic leukemia) and CML (chronic myelocytic leukemia). From infancy to adolescence to prime-of-life adulthood, the onset stages and sub-varieties poison the blood of all age groups. Little wonder that medical researchers worldwide are focused on seeking cures for leukemia.
The Jan. 30, 2004, issue of the Molecular Cell presents on its cover a pair of full-color squiggles illustrating key molecules on the front-burner drawing boards of Vertex Pharmaceuticals Inc., of Cambridge, Mass. The ribbon and surface diagrams of FLT3 are a culprit in patients with AML. (The "F" stands for "FMS," a separate acronym; "LT" for "-like tyrosine kinase.") The cover shows the spatial arrangement of the molecule's various structural elements. The Molecular Cell cover story is titled "The structural basis for autoinhibition of FLT3 by the Juxtamembrane domain." One co-author is Vertex research physicist Carlos Faerman. He and biologist Michael Su, program executive of Vertex kinase research, shared an interview with BioWorld Today, defining their scientific mission.
"FLT3 is expressed at high levels in a wide range of leukemias," Su explained, "including 70 to 100 percent of AML, ALL and CML. Furthermore, activated FLT3 mutations are present in up to 40 percent of AML patients. The mutated form of this tyrosine kinase is believed to promote uncontrolled growth of abnormal immature blood cells. These crowd out the normal blood cells from bone marrow and spleen cells, thereby leading to deadly forms of leukemia."
Leukemias, From Acute To Chronic Versions
Su observed that, "The mechanism our co-authors identified may have broad implications for the development of small oral compounds for the potential treatment of leukemia and other cancer types - where tyrosine kinases use the same mechanism. These kinases act like master switches, turning cells and their functions on or off. We have published the first crystal structure," Su continued, "to a resolution of 2.1 Angstroms. It is implicated in the development and progression of leukemia. We hypothesize that specific mutations cause FLT3's juxtamembrane domain to adopt a conformation that enables its receptor to phosphorylate itself. This results in uncontrolled proliferation, the mark of leukemia."
"The juxtamembrane [JM] on the inside of the blood cell carries a string of some 20 amino-acid residues. The 3-dimensional receptors are embedded from inside of the cell, which connects the JM domain. There's a wedge to keep these kinase domains inactive," Su noted. "One part is the JM domain, the other the business end of the kinase. The JM domain is positioned in such a way that it blocks the kinase activity. That is one of the novelties in this paper," he added. "By shutting down the regulated kinase activity, one would be able to stop the growth of the AML cells. The goal of our industry," he pointed out, "is to design an inhibitor that can shut down the activity in these misregulated leukemia cells."
"The FLT3 gene is primarily expressed in immature hematopoetic cells," Faerman added, "which are responsible for generating blood cells. It is essential for the normal functioning of stem cells and the immune system. Mutations in FLT3 are most common in AML, and are associated with a poor prognosis of disease. The findings of this study are very intriguing," he went on, "and we believe they may well open a window of opportunity for the design of new drugs that address the mechanism of mutated FLT3 in leukemia patients - as well as other cancer types where tyrosine kinases use the same mechanism."
Mice Enter Picture To Verify Blocker Efficacy
"We have transfected a mouse cell line containing FLT3 mutations," Su recounted. "Those leukemic cells become growth factor independent in the presence of mutated FLT3 cells. After we injected these leukemia cells into mice, the animals became sick from that overload. We have been able to confirm the efficacy of our TK inhibitors. One preclinical blocker that we are testing inhibits FLT3. We have made a lot of preclinical progress with potential therapeutic compounds in our pipeline," Su said, "and we expect to have the compound going into clinical development by clinician collaborators some time in 2004."
"It's very important, the information we draw out of this Molecular Cell article," Faerman pointed out. "It can be extended, first, to other members of the receptor tyrosine kinase, for example. If we can walk away and connect mechanical sense solving the crystal structure of our target, I think that might shed a lot of light, and in turn design novel tyrosine kinase inhibitors that might save a lot of lives. Second, the work is not for that one single target," he concluded, "but may be relevant to other members of the kinase family."
The journal article ends with these concluding remarks: "We report here the structure of FLT3 with the full-length JM domain, which provides insight into the mechanism by which the JM domain inhibits the catalytic activity of the kinase domain. We propose a mechanism of autoinhibition for the JM domain that delineates three structural components and describes the role they play in the physiological functioning of FLT3. Equally important, this structure provides a framework to explain the aberrant behavior of FLT3 in disease. We have identified the loci of the [internal tandem duplication] and the activation loop mutants frequently seen in patients with AML. . . The structure of FLT3 opens a window of opportunity for the design of inhibitors of FLT3, thus addressing the need for novel drugs for the treatment of AML."