Response: too much BCR-ABL to live on, but too little BCR-ABL to die on?

The mechanistic understanding of persistence of leukemic stem cells during tyrosine kinase inhibitor therapy is an important unmet prerequisite for targeting residual CML and eradicating the disease. Unfortunately, the rarity of BCR-ABL–positive cells during major and complete molecular remission (MMR; CMR) makes it notoriously difficult to investigate genetic or biologic features of CML clones that persist in vivo under imatinib. The analysis by Chomel and colleagues on hundreds of single residual CML stem and progenitor cell clones, derived from precious marrow samples of yearlong-followed CML patients deserves respect—also for the elaborate translational approach.¹ 

In keeping with our referenced finding,²  Chomel et al demonstrate that persisting CML stem cells (in vitro referred to as long-term culture initiating cells, LTC-IC), but also committed precursor cells express substantially less BCR-ABL mRNA than their imatinib-resistant counterparts. These results can be interpreted as follows: high-level BCR-ABL expression is incompatible with persistence under imatinib, whereas low BCR-ABL levels contribute to intrinsic BCR-ABL kinase inhibitor resistance.

This has 2 important implications. First, if low BCR-ABL expression is a hallmark of persisting stem and progenitor cells under kinase inhibitor therapy in vivo, then 20-300 times more potent second generation BCR-ABL inhibitors such as nilotinib and dasatinib will presumably not be more potent in eradicating persistent CML. CML eradication concepts should consequently target BCR-ABL independent pathways.

Secondly, the data by Chomel and colleagues lend support to the conclusion that the genetic pressure to mutate BCR-ABL is low in persistent CML.¹  For example, oncogene-initiated signal flux must exceed a critical threshold to trigger cell intrinsic tumor suppressive responses via activation of Arf/p53.^2,3  Hence, low-level oncogenic BCR-ABL may not suffice to induce oncogene addiction in the first place. As a consequence, even potent BCR-ABL inhibition by imatinib at the stem cell level⁴  would not generate a genetic pressure toward mutating BCR-ABL in persistent residual CML cells, because the resolution of this pressure (eg, by kinase mutations) would not result in a growth/survival advantage. Indeed, this presumption is evidenced by the clinical observation that relapsing CMR patients retain imatinib sensitivity after imatinib discontinuation.⁵  Altogether, this is good news for the patients, because the data imply that we can “afford to let sleeping dogs lie” (see Deininger and Holyoake⁷ ), as long as imatinib therapy continues.

As Chomel et al point out, it would now be important to study BCR-ABL expression regulation in CMR patients after imatinib discontinuation.¹  However, this may not only enable the prediction relapse candidates as Chomel et al suppose, but could also lead to the discovery of signaling molecules and pathways that stimulate BCR-ABL expression. Their inhibition would specifically attack BCR-ABL–positive persistent disease and represent a novel approach to eradicate residual CML.