MEMPHIS, Tenn. -- When imatinib (Gleevec) therapy fails in Philadelphia chromosome-positive acute lymphocytic leukemia (ALL), it may be because the B-cells involved lack a critical tumor suppressor gene, researchers here said.
MEMPHIS, Tenn., Aug. 30 -- When imatinib (Gleevec) therapy fails in Philadelphia chromosome-positive acute lymphocytic leukemia (ALL), it may be because the B-cells involved lack a critical tumor-suppressor gene, researchers here said.
In animal experiments, the missing gene, combined with cytokine signals in the bone marrow, gave rise to cell populations that were resistant to imatinib and quickly developed into fatal leukemias, according to Charles Sherr, M.D., Ph.D., of St. Jude Children's Research Hospital, and colleagues.
The findings may help explain why imatinib is highly effective in Philadelphia chromosome-positive chronic myelogenous leukemia (CML) but often fails quickly when ALL is caused by the Philadelphia chromosome, Dr. Sherr and colleagues reported in the Sept. 15 issue of Genes & Development.
The difference in response is puzzling, because most cases of CML and about 15% of ALL cases are caused by the Philadelphia chromosome, which generates a chimeric tyrosine kinase called BCR-ABL, the target of imatinib, the researchers noted.
The effect of BCR-ABL expression is uncontrolled cell growth.
To investigate, the researchers added the Philadelphia chromosome to mouse bone marrow cells from animals lacking the Arf tumor suppressor gene, which is also deleted in about 50% of human patients with ALL caused by the Philadelphia chromosome.
Even as few as 20 of the resulting cells, injected into mice, resulted in a fatal case of leukemia within four weeks, Dr. Sherr and colleagues found, and analysis showed that about one in every two cells was capable of generating disease.
That finding rules out the possibility that this form of ALL is caused by rare "cancer stem cells," the researchers said.
When the mice were treated with imatinib -- at 100 mg/kg twice daily -- the drug had little or no effect, even though that dose induces durable remissions of CML in mouse models, the researchers said.
But surprisingly, B-cells recovered from the moribund mice were fully sensitive to imatinib in vitro, Dr. Sherr and colleagues found, implying that host factors are also involved in resistance.
To test that idea, the researchers created transgenic mice lacking Arf -- and also lacking part of the receptor for interleukin-7.
When the animals were challenged with BCR-ABL cells, they were more sensitive to imatinib and several had prolonged remission, surviving for up to 180 days, the researchers found.
The researchers suggested that in CML -- which arises in bone marrow stem cells -- deletions of the Arf gene play no role, because the locus is usually turned off in any case.
But the cells involved in ALL appear to be committed lymphoid progenitors in which the gene can be activated. If the Philadelphia chromosome is present, deleting the gene may lead to imatinib resistance, they suggested.
The findings confirm the importance of the Arf gene, noted Kenneth Dorshkind, Ph.D., and Owen Witte, M.D., both of the University of California at Los Angeles.
But the most important result is the "demonstration that signals from the hematopoietic microenvironment also play a critical role in promoting the growth of leukemic cells," they said in an accompanying commentary.
"The challenge is to now exploit this observation to develop additional therapies," they said.