PTPN2 negatively regulates oncogenic JAK1 in T-cell acute lymphoblastic leukemia.

We have recently reported inactivation of the tyrosine phosphatase PTPN2 (also known as TC-PTP) through deletion of the entire gene locus in ∼ 6% of T-cell acute lymphoblastic leukemia (T-ALL) cases. T-ALL is an aggressive disease of the thymocytes characterized by the stepwise accumulation of chromosomal abnormalities and gene mutations. In the present study, we confirmed the strong association of the PTPN2 deletion with TLX1 and NUP214-ABL1 expression. In addition, we found cooperation between PTPN2 deletion and activating JAK1 gene mutations. Activating mutations in JAK1 kinase occur in ∼ 10% of human T-ALL cases, and aberrant kinase activity has been shown to confer proliferation and survival advantages. Our results reveal that some JAK1 mutation-positive T-ALLs harbor deletions of the tyrosine phosphatase PTPN2, a known negative regulator of the JAK/STAT pathway. We provide evidence that down-regulation of Ptpn2 sensitizes lymphoid cells to JAK1-mediated transformation and reduces their sensitivity to JAK inhibition.

[1]  J. Cools,et al.  MOHITO, a novel mouse cytokine-dependent T-cell line, enables studies of oncogenic signaling in the T-cell context , 2011, Haematologica.

[2]  R. Mesa.  Ruxolitinib, a selective JAK1 and JAK2 inhibitor for the treatment of myeloproliferative neoplasms and psoriasis. , 2010, IDrugs : the investigational drugs journal.

[3]  Donna Neuberg,et al.  Inactivation of LEF1 in T-cell acute lymphoblastic leukemia. , 2010, Blood.

[4]  A. Hagemeijer,et al.  ABL1 rearrangements in T‐Cell acute lymphoblastic leukemia , 2010, Genes, chromosomes & cancer.

[5]  H. Dombret,et al.  JAK1 mutations are not frequent events in adult T‐ALL: a GRAALL study , 2010, British journal of haematology.

[6]  J. Renauld,et al.  ALL-associated JAK1 mutations confer hypersensitivity to the antiproliferative effect of type I interferon. , 2009, Blood.

[7]  A. Ferrando,et al.  Deletion of the protein tyrosine phosphatase gene PTPN2 in T-cell acute lymphoblastic leukemia , 2009, Nature Genetics.

[8]  L. Chin,et al.  High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia. , 2009, Blood.

[9]  H. Dombret,et al.  NOTCH1/FBXW7 mutation identifies a large subgroup with favorable outcome in adult T-cell acute lymphoblastic leukemia (T-ALL): a Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) study. , 2009, Blood.

[10]  Y. Chung,et al.  Somatic Mutations of JAK1 and JAK3 in Acute Leukemias and Solid Cancers , 2008, Clinical Cancer Research.

[11]  E. Clappier,et al.  Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia , 2008, The Journal of experimental medicine.

[12]  M. Tremblay,et al.  PTP1B and TC-PTP: regulators of transformation and tumorigenesis , 2008, Cancer and Metastasis Reviews.

[13]  I. Lossos,et al.  T-Cell Protein Tyrosine Phosphatase, Distinctively Expressed in Activated-B-Cell-Like Diffuse Large B-Cell Lymphomas, Is the Nuclear Phosphatase of STAT6 , 2007, Molecular and Cellular Biology.

[14]  Sungjoon Kim,et al.  Ba/F3 cells and their use in kinase drug discovery , 2007, Current opinion in oncology.

[15]  C. Pui,et al.  Treatment of acute lymphoblastic leukemia. , 2006, The New England journal of medicine.

[16]  F. Sigaux,et al.  HOXA genes are included in genetic and biologic networks defining human acute T-cell leukemia (T-ALL). , 2005, Blood.

[17]  Peter Marynen,et al.  Fusion of EML1 to ABL1 in T-cell acute lymphoblastic leukemia with cryptic t(9;14)(q34;q32). , 2005, Blood.

[18]  Andrew P. Weng,et al.  Activating Mutations of NOTCH1 in Human T Cell Acute Lymphoblastic Leukemia , 2004, Science.

[19]  A. Ferrando,et al.  Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia , 2004, Nature Genetics.

[20]  M. Tremblay,et al.  The T Cell Protein Tyrosine Phosphatase Is a Negative Regulator of Janus Family Kinases 1 and 3 , 2002, Current Biology.

[21]  E. Lander,et al.  Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. , 2002, Cancer cell.

[22]  F. Sigaux,et al.  Candidate tumor-suppressor genes MTS1 (p16INK4A) and MTS2 (p15INK4B) display frequent homozygous deletions in primary cells from T- but not from B-cell lineage acute lymphoblastic leukemias. , 1994, Blood.

[23]  B. Sefton,et al.  Oncogenic activation of the Lck protein accompanies translocation of the LCK gene in the human HSB2 T-cell leukemia , 1994, Molecular and cellular biology.

[24]  A. Pardanani.  JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trials , 2008, Leukemia.

[25]  P. Marynen,et al.  Genetic insights in the pathogenesis of T-cell acute lymphoblastic leukemia. , 2005, Haematologica.

[26]  Yu-Rong Fu,et al.  Identification of a Nuclear Stat 1 Protein Tyrosine Phosphatase , 2002 .