Acute lymphoblastic leukaemia (ALL) that is positive for the translocation fusion product BCR–ABL (Ph+ ALL) does not respond well to imatinib therapy. At least 30% of Ph+ ALL patients have deletions in cyclin-dependent kinase inhibitor 2A ( CDKN2A ), which encodes the two tumour-suppressor proteins INK4A and ARF. Richard Williams and colleagues now show that loss of ARF is necessary to trigger lympholeukaemias in pre-B cells that express Bcr–Abl, and that ALLs that arise in mice receiving Arf−/− Bcr–Abl+/+ pre-B cells do not respond to imatinib.

The authors first introduced Bcr–Abl, which was tagged with green fluorescent protein or a control vector, into pre-B cells derived from Arf+/+, Arf+/− or Arf−/− mice and cultured them on bone-marrow-derived stromal cells, which produced the lymphopoiesis inducer interleukin 7 (IL-7). Although Bcr–Abl eliminates the dependency of pre-B cells on IL-7, induction of Arf by Bcr–Abl triggers p53-dependent apoptosis. However, Arf−/− cells did not die and continued to proliferate.

So what effect does the loss of Arf have on the development of leukaemia? When Arf+/+ bone-marrow progenitors that were transduced with Bcr–Abl were introduced into lethally irradiated mice, lympholeukaemias developed slowly, but Arf loss significantly decreased disease latency and increased the clinical severity of the leukaemia. In a second more stringent ALL model, transiently cultured pre-B cells that expressed Bcr–Abl were injected into immunocompetent mice — Arf+/+ pre-B cells rarely induced tumours, Arf+/− cells induced tumours in which the wild-type Arf allele was inactivated, and Arf−/− cells rapidly induced highly aggressive, disseminated disease.

As patients with Ph+ ALL are insensitive to imatinib treatment, the authors investigated whether immunocompetent mice that received Bcr–Abl+/+ Arf−/− pre-B cells would also prove to be resistant to this drug. Although imatinib inhibited the tyrosine phosphorylation of BCR–ABL, the Arf−/− or Arf+/− mice developed lympholeukaemia and rapidly died, even if they were maintained on clinically effective doses of imatinib. Importantly, tumour cells recovered from moribund mice showed the same sensitivity to imatinib as the donor cells, which implies that resistance was non-cell-autonomous. The addition of IL-7 to Bcr–Abl+/+ Arf−/− pre-B cells heightened resistance to imatinib, and the addition of a small-molecule inhibitor of JAK kinases — which inhibits IL-7 signalling — resensitized the cells to imatinib.

The mechanisms by which ARF inactivation overrides sensitivity to imatinib in vivo still need to be elucidated, but the authors reason that a combination of imatinib and a JAK-kinase inhibitor to treat Ph+ ALL is worth further investigation.