An analysis of the work by Research Professor Wally Langdon and Assistant Professor Christine Thien at UWA’s School of Pathology and Laboratory Medicine and researchers at Yale University School of Medicine in the United States is published this week in the journal Cancer Cell.
Professors Langdon and Thien produced genetically modified mice with a mutation in the c-Cbl gene and found that these mice develop a lethal myeloid leukemia. c-Cbl is a cancer-causing gene discovered by Professor Langdon that is mutated in some human blood cancers.
“These mice provide a preclinical model for studying human leukemias with c-Cbl mutations,” Professor Langdon said. “We are currently using these mice to identify anti-cancer drugs that will be effective for treating c-Cbl associated leukemias.
“We found that mice with a c-Cbl mutation have enhanced activity of a growth factor receptor called FLT3 which is expressed on undifferentiated blood cells known as multipotent progenitors (MPPs). A consequence of this enhanced activity is a marked increase in the numbers of MPPs in the bone marrow of c-Cbl mutant mice.
“This finding prompted us to generate c-Cbl mutant mice with an additional mutation that deleted the gene for the growth factor that binds to and activates FLT3. Remarkably, by deleting this growth factor we completely blocked the expansion of MPPs and prevented the development of leukemia.”
Professor Langdon said the finding was significant as it indicates that leukemia patients with c-Cbl mutations would benefit from treatment with drugs that specifically target FLT3 and block its activity.
Caption for the graphic. Mice with a mutation in a region of the c-Cbl gene called the RING finger domain develop a lethal leukemia. This is shown in the upper blood film where there is a marked increase in the number of white blood cells (stained blue). When we mate c-Cbl mutant mice with mice that can’t produce a growth factor called FLT3 ligand the mice no longer develop leukemia. This is shown in the lower blood film where white blood cell numbers are now equivalent to that of a normal healthy mouse.
Research Professor Wallace Langdon (Pathology and Laboratory Medicine) (+61 8) 9346 2939
Research Assistant Professor Christine Thien (Pathology and Laboratory Medicine) (+61 8) 9346 2932
Janine MacDonald (UWA Public Affairs) (+61 8) 6488 5563 / (+61 4) 32 637 716