Blood Journal
Leading the way in experimental and clinical research in hematology

Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia (ALL)

  1. Shannon L. Maude1,
  2. Sarah K. Tasian2,
  3. Tiffaney Vincent1,
  4. Junior W. Hall1,
  5. Cecilia Sheen1,
  6. Kathryn G. Roberts3,
  7. Alix E. Seif1,
  8. David M. Barrett1,
  9. I-Ming Chen4,
  10. J. Racquel Collins3,
  11. Charles G. Mullighan3,
  12. Stephen P. Hunger5,
  13. Richard C. Harvey4,
  14. Cheryl L. Willman4,
  15. Jordan S. Fridman6,
  16. Mignon L. Loh7,
  17. Stephan A. Grupp1, and
  18. David T. Teachey1,*
  1. 1 Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA, United States;
  2. 2 Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States;
  3. 3 Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, United States;
  4. 4 UNM Cancer Research Facility, University of New Mexico Cancer Center, Albuquerque, NM, United States;
  5. 5 Pediatric Hematology/Oncology/BMT, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO, United States;
  6. 6 Incyte Corporation, Wilmington, DE, United States;
  7. 7 Division of Pediatric Hematology-Oncology, University of California, San Francisco, San Francisco, CA, United States
  1. * Corresponding author; email: teacheyd{at}


CRLF2 rearrangements, JAK1/2 point mutations, and JAK2 fusion genes have been identified in Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL), a recently described subtype of pediatric high-risk B-precursor ALL (B-ALL) which exhibits a gene expression profile similar to Ph-positive ALL and has a poor prognosis. Hyperactive JAK/STAT and PI3K/mTOR signaling are common in this high-risk subset. We, therefore, investigated the efficacy of the JAK inhibitor ruxolitinib and the mTOR inhibitor rapamycin in xenograft models of 8 pediatric B-ALL cases with and without CRLF2 and JAK genomic lesions. Ruxolitinib treatment yielded significantly lower peripheral blast counts compared to vehicle (P<.05) in 6 of 8 human leukemia xenografts and lower splenic blast counts (P<.05) in 8 of 8 samples. Enhanced responses to ruxolitinib were observed in samples harboring JAK activating lesions and higher levels of STAT5 phosphorylation. Rapamycin controlled leukemia burden in all 8 B-ALL samples. Survival analysis of 2 representative B-ALL xenografts demonstrated prolonged survival with rapamycin treatment compared to vehicle (P<.01). These data demonstrate preclinical in vivo efficacy of ruxolitinib and rapamycin in this high-risk B-ALL subtype, for which novel treatments are urgently needed, and highlight the therapeutic potential of targeted kinase inhibition in Ph-like ALL.

  • Submitted March 13, 2012.
  • Accepted August 21, 2012.