Two-hit therapy for acute lymphoblastic leukaemia?

Edward Carr, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0SP

Writing in Nature, Duy and colleagues demonstrate that Bcl6 can allow acute lymphoblastic leukaemia (ALL) to escape from imatinib inhibition (1).

The Philadelphia chromosome (Ph) is the result translocation of a portion of chromosome 9 to chromosome 22. Ph is found in 95% of chronic myeloid leukaemias (CML). It is also found in approximately 20% of ALL. The translocation yields a fusion protein, BCR-ABL, which has constitutive receptor tyrosine kinase activity. Imatinib is a receptor tyrosine kinase inhibitor (RTKi) with high affinity for BCR-ABL, which has revolutionized CML treatment. In Ph+ ALL, imatinib is less efficacious – it fails to eradicate leukaemia-initiating cells allowing ALL to become resistant to RTKi. Duy et al. identify a mechanism by which ALL escapes imatinib treatment.

In response to imatinib ALL cell lines upregulate Bcl6 expression in vitro, suggesting that Bcl6 might mediate imatinib escape. Bcl6 is a transcription factor that is frequently involved in translocations to the immunoglobulin heavy chain locus in diffuse large B cell lymphoma – Bcl6 has pedigree in the world haematological malignancy. To demonstrate the importance of Bcl6 in vivo, two separate engraftment experiments where performed by Duy et al.. Administration of Bcl6+/+ ALL cells resulted in the development of ALL, whereas Bcl6-/- ALL cells did not develop into frank leukaemia, unless huge numbers (5 x 106 cells) were injected. The authors concluded that leukaemia initiating cells (LICs) required Bcl6 for survival such that transfer of small numbers of Bcl6-/- ALL cells contained to few LICs to confer disease.

In their final experiments, Duy et al. used an inhibitor of Bcl6, RI-BPI, alongside nilotinib (another RTKi) to demonstrate tumour control in an animal engraftment model of human Ph+ALL. RI-BPI, retro-inverso BCL6 peptide-inhibitor, is a peptide that blocks the binding site on Bcl6 for the recruitment of other proteins through which Bcl6 mediates its actions. Co-treatment with RI-BPI and nilotinib resulted in a significantly increased survival, from 100% mortality within 100 days to an 87.5% survival at 140 days.

The work published by Duy et al. paves the way for dual therapy in Ph+ALL, combining an RTKi with a Bcl6 inhibitor – a ‘two-hit’ approach to therapy for haematological malignancy.

References: 

1. Duy C, Hurtz C, Shojaee S, Cerchietti L, Geng H, Swaminathan S, Klemm L, Kweon S-mi, Nahar R, Braig M, Park E, Kim Y-mi, Hofmann W-K, Herzog S, Jumaa H, Koeffler HP, Yu JJ, Heisterkamp N, Graeber TG, Wu H, Ye BH, Melnick A, Muschen M. BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR-ABL1 kinase inhibition. Nature 2011 May;473(7347):384-388.
doi:10.1038/nature09883

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