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

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/mammalian target of rapamycin (mTOR) signaling is 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 with 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 with 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.

[1]  Ryan D. Morin,et al.  Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. , 2012, Cancer cell.

[2]  Julie M Gastier-Foster,et al.  Aberrant STAT5 and PI3K/mTOR pathway signaling occurs in human CRLF2-rearranged B-precursor acute lymphoblastic leukemia. , 2012, Blood.

[3]  Xiaomin Lu,et al.  Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children's oncology group. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  D. R. Webster,et al.  Synergistic activity of rapamycin and dexamethasone in vitro and in vivo in acute lymphoblastic leukemia via cell-cycle arrest and apoptosis. , 2012, Leukemia research.

[5]  Jason Gotlib,et al.  A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. , 2012, The New England journal of medicine.

[6]  Francisco Cervantes,et al.  JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. , 2012, The New England journal of medicine.

[7]  Kiran C. Bobba,et al.  The genetic basis of early T-cell precursor acute lymphoblastic leukaemia , 2012, Nature.

[8]  Eric Vangrevelinghe,et al.  Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition , 2011, The Journal of experimental medicine.

[9]  R. Arceci.  Outcome modeling with CRLF2, IKZF1, JAK, and minimal residual disease in pediatric acute lymphoblastic leukemia: a Children's Oncology Group Study , 2012 .

[10]  M. Loh,et al.  Outcome modeling with CRLF 2 , IKZF 1 , JAK , and minimal residual disease in pediatric acute lymphoblastic leukemia : a Children ’ s Oncology Group Study , 2012 .

[11]  J. Shuster,et al.  Augmented therapy improves outcome for pediatric high risk acute lymphocytic leukemia: Results of Children's Oncology Group trial P9906 , 2011, Pediatric blood & cancer.

[12]  A. Ferrando,et al.  Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia , 2011, Nature Genetics.

[13]  Michael N. Edmonson,et al.  Key pathways are frequently mutated in high-risk childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group. , 2011, Blood.

[14]  M. Muckenthaler,et al.  Gain-of-function mutations in interleukin-7 receptor-α (IL7R) in childhood acute lymphoblastic leukemias , 2011, The Journal of experimental medicine.

[15]  S. Sallan,et al.  Targeting of active mTOR inhibits primary leukemia T cells and synergizes with cytotoxic drugs and signaling inhibitors. , 2011, Experimental hematology.

[16]  S. Richards,et al.  Demographic, clinical, and outcome features of children with acute lymphoblastic leukemia and CRLF2 deregulation: results from the MRC ALL97 clinical trial. , 2011, Blood.

[17]  Kevin K Dobbin,et al.  Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome. , 2010, Blood.

[18]  Ayalew Tefferi,et al.  Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. , 2010, The New England journal of medicine.

[19]  Erin F. Simonds,et al.  Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms. , 2010, Blood.

[20]  Nikesh Kotecha,et al.  Web‐Based Analysis and Publication of Flow Cytometry Experiments , 2010, Current protocols in cytometry.

[21]  J. Downing,et al.  Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia. , 2010, Blood.

[22]  Mondira Kundu,et al.  Lnk constrains myeloproliferative diseases in mice. , 2010, The Journal of clinical investigation.

[23]  E. Domany,et al.  Down syndrome acute lymphoblastic leukemia, a highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: a report from the International BFM Study Group. , 2010, Blood.

[24]  Jing Chen,et al.  Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor , 2010, Nature Medicine.

[25]  S. Keir,et al.  Stage 2 Combination Testing of Rapamycin with Cytotoxic Agents by the Pediatric Preclinical Testing Program , 2010, Molecular Cancer Therapeutics.

[26]  E. Domany,et al.  Down syndrome acute lymphoblastic leukemia, a highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: a report from the International BFM Study Group. , 2010, Blood.

[27]  R. Arceci.  Deletion of IKZF1 and Prognosis in Acute Lymphoblastic Leukemia , 2010 .

[28]  J. Fridman,et al.  INCB16562, a JAK1/2 selective inhibitor, is efficacious against multiple myeloma cells and reverses the protective effects of cytokine and stromal cell support. , 2010, Neoplasia.

[29]  P. D. Dal Cin,et al.  Functional screening identifies CRLF2 in precursor B-cell acute lymphoblastic leukemia , 2009, Proceedings of the National Academy of Sciences.

[30]  N. Heerema,et al.  Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group study. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  J. Downing,et al.  Rearrangement of CRLF2 in B-progenitor– and Down syndrome–associated acute lymphoblastic leukemia , 2009, Nature Genetics.

[32]  M. Carroll,et al.  A Phase I Study of the Mammalian Target of Rapamycin Inhibitor Sirolimus and MEC Chemotherapy in Relapsed and Refractory Acute Myelogenous Leukemia , 2009, Clinical Cancer Research.

[33]  Takashi Akasaka,et al.  Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia. , 2009, Blood.

[34]  M. Loh,et al.  JAK mutations in high-risk childhood acute lymphoblastic leukemia , 2009, Proceedings of the National Academy of Sciences.

[35]  D. Teachey,et al.  Mammalian target of rapamycin inhibitors and their potential role in therapy in leukaemia and other haematological malignancies , 2009, British journal of haematology.

[36]  S. Gery,et al.  Lnk inhibits myeloproliferative disorder‐associated JAK2 mutant, JAK2V617F , 2009, Journal of leukocyte biology.

[37]  W. Evans,et al.  A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. , 2009, The Lancet. Oncology.

[38]  G. Pruneri,et al.  Human acute leukemia cells injected in NOD/LtSz‐scid/IL‐2Rγ null mice generate a faster and more efficient disease compared to other NOD/scid‐related strains , 2008, International journal of cancer.

[39]  Jonathan M Irish,et al.  Single-cell profiling identifies aberrant STAT5 activation in myeloid malignancies with specific clinical and biologic correlates. , 2008, Cancer cell.

[40]  D. Teachey,et al.  mTOR inhibitors are synergistic with methotrexate: an effective combination to treat acute lymphoblastic leukemia. , 2008, Blood.

[41]  J. Dipersio,et al.  A Phase 2 Clinical Trial of Deforolimus (AP23573, MK-8669), a Novel Mammalian Target of Rapamycin Inhibitor, in Patients with Relapsed or Refractory Hematologic Malignancies , 2008, Clinical Cancer Research.

[42]  S. Keir,et al.  Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program , 2008, Pediatric blood & cancer.

[43]  J. Bourhis,et al.  Activation of cytotoxic T-cell receptor γδ T lymphocytes in response to specific stimulation in myelodysplastic syndromes , 2008, Haematologica.

[44]  Carl W. Miller,et al.  Molecular allelokaryotyping of pediatric acute lymphoblastic leukemias by high-resolution single nucleotide polymorphism oligonucleotide genomic microarray. , 2007, Blood.

[45]  D. Teachey,et al.  Thymic stromal-derived lymphopoietin induces proliferation of pre-B leukemia and antagonizes mTOR inhibitors, suggesting a role for interleukin-7Ralpha signaling. , 2007, Cancer research.

[46]  J. Hehir-Kwa,et al.  High-resolution genomic profiling of childhood ALL reveals novel recurrent genetic lesions affecting pathways involved in lymphocyte differentiation and cell cycle progression , 2007, Leukemia.

[47]  Christopher B. Miller,et al.  Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia , 2007, Nature.

[48]  T. Golub,et al.  Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance. , 2006, Cancer cell.

[49]  K. Sullivan,et al.  Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS). , 2006, Blood.

[50]  D. Teachey,et al.  The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL. , 2006, Blood.

[51]  M. Farrar,et al.  STAT5 Activation Underlies IL7 Receptor-Dependent B Cell Development1 , 2004, The Journal of Immunology.

[52]  S. Ziegler,et al.  Absence of an Essential Role for Thymic Stromal Lymphopoietin Receptor in Murine B-Cell Development , 2004, Molecular and Cellular Biology.

[53]  V. Brown,et al.  Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[54]  J. Melo,et al.  Bcr-Abl kinase modulates the translation regulators ribosomal protein S6 and 4E-BP1 in chronic myelogenous leukemia cells via the mammalian target of rapamycin. , 2003, Cancer research.

[55]  N. Danial,et al.  JAK-STAT signaling activated by Abl oncogenes , 2000, Oncogene.

[56]  M. Owen,et al.  The interleukin‐7 receptor alpha chain transmits distinct signals for proliferation and differentiation during B lymphopoiesis. , 1996, The EMBO journal.

[57]  A. Venkitaraman,et al.  Interleukin‐7 induces the association of phosphatidylinositol 3‐kinase with the α chain of the interleukin‐7 receptor , 1994, European journal of immunology.