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Overcoming chronic myeloid leukemia stem cell resistance to imatinib by also targeting JAK2.

Chronic myeloid leukemia (CML) originates in the hematopoietic stem cell because of a reciprocal translocation of chromosomes 9 and 22. This translocation juxtaposes the ABL1 proto-oncogene with BCR, which translates into a constitutively active BCR-ABL kinase that drives expansion of leukemic progeny. Treatment of CML with ABL kinase inhibitors such as imatinib is very effective and brings about complete cytogenetic response in more than 80% of newly diagnosed patients. CML is a celebrated model disease because of its stem cell origin , straightforward oncogene, targeted therapy, easy monitoring, and high odds of remission. I remember treating patients with CML in the pre-imatinib era. Interferon-α was the standard of care, and the patients were miserable because of feverish side effects and frequent injections. When we opened our first clinical trial of imatinib in the late 1990s, one particular Veterans Health Administration (VA) patient whose CML responded wonderfully on study was distraught because he faced the possibility of being cured of his disease and that meant a possible loss of his VA health benefits. To mixed fortune, we continued imatinib in this patient out of fear of relapse. Since that time, we've learned that despite low to undetectable levels of BCR-ABL transcripts, discontinuing imatinib results in CML relapse in a majority of patients, indicating that disease-causing leukemic cells persist below limits of detection. Because of this risk of recurrence, the clinical standard is to continue imatinib lifelong, even at high cost and potential for severe side effects. One of the most pressing issues in leukemia, and possibly all of oncology, is how a model disease with such fantastic response to a targeted therapy can exhibit such recalcitrance. Our reductionist tendencies have brought us as far as they can with CML, and it is now time to admit that our model disease is much more tangled than a single oncogene. Several hypotheses have been proposed to explain how CML evades ABL kinase inhibition. Possibilities include minor populations of BCR-ABL kinase domain mutants (eg, T315I), increased expression of BCR-ABL, and sanctuary sites in the microenviron-ment. Alterations of imatinib influx and efflux appear less likely as explanations for resistant disease. The fact that minimal residual CML cells can persist despite years of imatinib therapy argued for a cancer stem cell hypothesis and led to the discovery that the imatinib-resistant CML population resides in a small subset of slow-cycling, self-renewing leukemia stem cells (1). Another basic …