Is going for cure in chronic myeloid leukemia possible and justifiable? Francois-Xavier Mahon 1,2

Francois-Xavier Mahon 1,2

1 Laboratoire d’He´ matologie, Centre Hospitalier Universitaire de Bordeaux, and
2 Laboratoire He´ matopoïe` seLeuce´ mique et Cible The´ rapeutique, Biothe´ rapies des maladies ge´ ne´ tiques et cancers, Inserm U1035,
Universite´ Bordeaux Segalen, Bordeaux, France

After more than a decade of treatment of chronic myeloid leukemia (CML) patients with the BCR-ABL tyrosine kinase
inhibitor imatinib, and despite the impressive clinical results of this targeted therapeutic, many questions remain
unresolved. One major question is how to cure CML, and the next step for the future will be to address this key issue.
CML is a good model of cancer. The fact that the majority of CML patients who respond very well but discontinue
tyrosine kinase inhibitors later show evidence of molecular recurrence focuses attention on the need for further
research on leukemic stem cells. The challenge now is to understand why, after stopping treatment, the leukemia
recurs in some patients but not in others. If we win this battle, this progress will certainly benefit the treatment and
management of other leukemias and solid tumors and will validate this new topic.

"....Having said already that we still do not know if LSCs are really the true enemies because progression to AP may occur predominantly
at the level of a more committed progenitor cell, a large number of publications have focused on targeting the LSCs.46,47 These investigators have clearly been motivated by the important work showing that, at least in vitro, quiescent LSCs are insensitive to TKIs despite
kinase inhibition.48,49 Several strategies have been proposed to target the LSCs. For example, JAK/STAT, JAK2 kinase, the protein
phosphatase 2A (PP2A), arachidonate 5-lipoxygenase gene (ALOX5), histone deacetylases (HDACs), Sirtuin 1 (SIRT1), and
BCL6 are among the most relevant targets for such a strategy.50-54

However, 2 of the most important pathways for self-renewal of CML LSCs are the Wnt--catenin and the Hedgehog (Hh) pathways.55,56 Targeting of the Hh pathway in solid tumors has been attempted by smoothened homolog (SMO) inhibitors.57 These drugs
(LDE225 and BMS-833923) are currently being combined with TKIs in phase 1 and 2 trials to investigate if such combination can eliminate LSCs and improve the curability of CML."

http://asheducationbook.hematologylibrary.org/content/2012/1/122.full.pdf