ALL, a cancer of the bone marrow affecting 4,000 US residents annually, is characterized by the over-production of immature white blood cells. An aggressive form of ALL results from a chromosomal translocation, known as the Philadelphia chromosome (Ph), in which segments from chromosomes 9 and 22 are aberrantly fused together. Ph+ ALL is far more prevalent in adults (~30% of adult ALL) than in children (~4% of pediatric ALL), but it carries a poor prognosis in both age groups. Ph+ cells express a protein (encoded by an oncogene created by the chromosome fusion) called BCR-ABL. BCR-ABL is a constitutively active enzyme, a tyrosine kinase, which promotes uncontrolled cell proliferation.
Continuous treatment with the BCR-ABL tyrosine kinase inhibitor, imatinib, has revolutionized the therapy of another form of Ph+ cancer, chronic myelogenous leukemia (CML), by inducing durable remissions. However, the response of Ph+ ALL patients is not nearly as good, leading to shorter remissions and more rapid emergence of imatinib resistance. In general, Ph+ CML and ALL patients that fail imatinib therapy develop mutations in the BCR-ABL kinase that make them drug-resistant, but the reasons underlying the increased rate of emergence of mutant clones in Ph+ ALL has not been satisfactorily explained.
Williams and colleagues tracked the development of imatinib resistance, using a mouse model of Ph+ ALL. They engineered BCR-ABL-expressing lymphocyte progenitors that also lack the tumor suppressor protein ARF (which is deleted in more than 30% of Ph+ ALL patients, but not in CML patients, at their time of diagnosis). Interestingly, ARF-deficient lymphocytes expressing BCR-ABL were so highly aggressive that inoculation of as few as 20 such cells into healthy mice induced fatal ALL in less than 3 weeks. “Although experiments with CML support the concept that these leukemias arise from a rare population of ‘cancer stem cells’, our work on Ph+ ALL emphasizes that this need not be the case,” says Williams.
Further genetic experiments revealed that signals from the bone marrow micro-environment of the host animals were able to sustain the viability of ARF-deficient leukemia cells in the face of imatinib therapy. “We suspect that similar signals may nurture ARF-deficient Ph+ ALL cells in patients,” says Sherr, “thereby allowing the rapid emergence of imatinib-resistant clones.”
Heather Cosel | EurekAlert!
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