Stem cells in childhood acute lymphoblastic leukemia: identifying the most relevant targets for therapy

Response

We thank Heidenreich and Vormoor for their interest in our paper and we welcome the opportunity to respond. We agree with the authors that this is a very exciting time for research in acute lymphoblastic leukemia (ALL) stem cells and that standardization of methodologies will be paramount for generation of the most clinically relevant data. Indeed, in the discussion of our paper,¹  we postulate that the apparent discrepancies in the published phenotypes of ALL stem cells could be attributed to several variables in the methodologies used. There are differences in the strains of immune-deficient mice used, the inoculation techniques, and in the age of the recipient animals. Kong et al used recipient mice at only 48 hours after birth.²  Interestingly, the abstract by Morisot et al, to which the authors refer, noted a similar frequency of leukemia stem cells using both nonobese diabetic severe combined immune-deficient (NOD/SCID) gamma (NSG) and the classic NOD/SCID strains, although the onset of leukemia was delayed in the NOD/SCIDs in some cases.³  It is also important to recognize that different subtypes of leukemia may also contribute to differences in the phenotype of the leukemia initiating cells. Two publications that reported multiple ALL cell phenotypes with leukemia engrafting capacity mainly used samples from high-risk cases.^2,4 

It is interesting to note in the paper by le Viseur⁴  and the table included in the letter that fewer CD19^low cells were required to achieve engraftment levels similar to that observed with CD19^high cells in the samples where these phenotypes were compared. Not only will it be crucial to develop xenotransplant models that are profoundly immune deficient to permit identification of any leukemia cells that have stem cell properties, it will also be important to use more sophisticated assays that incorporate cell tracking or transplantation of finite cell numbers to discriminate between leukemia cells with extensive self-renewal ability and those that can proliferate to engraft animal models but have limited self-renewal capacity. Leukemia cells with greater self-renewal ability are likely to be the most relevant to target with novel therapeutic approaches.