Correspondence

Deletion of IKZF1 and Prognosis in Acute Lymphoblastic Leukemia

N Engl J Med 2009; 360:1787-1788April 23, 2009

Article

To the Editor:

Mullighan et al. (Jan. 29 issue)1 report on the prognostic significance of IKZF1 alterations in pediatric patients with acute lymphoblastic leukemia (ALL). The authors also find that the gene-expression signature in patients with BCR-ABL–negative ALL, which is associated with a poor outcome (as predicted by IKZF1 alterations), is similar to the gene-expression profile in patients with BCR-ABL–positive ALL. Given that approximately 85% of children with BCR-ABL–positive ALL also have a deletion of IKZF1, 2 two questions with potential clinical and prognostic implications come to mind.

First, could a supervised analysis detect significant differences in the gene-expression signatures between patients with BCR-ABL–positive ALL who also have an alteration in IKZF1 and those who have wild-type IKZF1?

Second, since IKZF1 alterations confer a poor prognosis in patients with standard-risk ALL and patients with high-risk B-cell ALL, is the poor outcome for children with BCR-ABL–positive ALL simply a reflection of the high incidence of IKZF1 alterations in this population? In other words, do patients with BCR-ABL–positive ALL and wild-type IKZF1 have a better outcome than patients with BCR-ABL–positive ALL who have a deletion of IKZF1?

Bruno C. Medeiros, M.D.
Stanford University School of Medicine, Stanford, CA 94305
brunom@stanford.edu

2 References

1. 1

   Mullighan CG, Su X, Zhang J, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med 2009;360:470-480
   Full Text | Web of Science | Medline

2. 2

   Mullighan CG, Miller CB, Radtke I, et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature 2008;453:110-114
   CrossRef | Web of Science | Medline

Author/Editor Response

Medeiros raises two interesting questions related to the clinical and prognostic implications of IKZF1 mutations in pediatric ALL. Both questions concern the very small subgroup of patients with BCR-ABL1–positive ALL who do not have an alteration of IKZF1. Specifically, Medeiros asks whether patients with BCR-ABL1–positive ALL who have wild-type IKZF1 have a distinct gene-expression profile or outcome as compared with patients with BCR-ABL1–positive ALL who have an IKZF1 mutation. Unfortunately, neither our original ALL cohort1 nor an expanded cohort2 had a sufficient number of patients with BCR-ABL1–positive ALL who did not have an IKZF1 alteration to enable us to perform statistically sound analyses of differences in the gene-expression profile and outcome. Only 5 of 21 patients with BCR-ABL1–positive ALL did not have an IKZF1 mutation. The analysis of a much larger number of pediatric and adult patients with BCR-ABL1–positive ALL will be required to definitively answer these important questions.

James R. Downing, M.D.
Charles G. Mullighan, M.D.
St. Jude Children's Research Hospital, Memphis, TN 38105
james.downing@stjude.org

2 References

1. 1

   Mullighan CG, Goorha S, Radtke I, et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukemia. Nature 2007;446:758-764
   CrossRef | Web of Science | Medline

2. 2

   Mullighan CG, Miller CB, Radtke I, et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature 2008;453:110-114
   CrossRef | Web of Science | Medline