JAK 1 mutation analysis in T-cell acute lymphoblastic leukemia cell lines

early relapses within 20 months after diagnosis. Taken together, these results suggest that mutations in the JAK2, KIT and FLT3 genes are associated with unfavorable clinical outcome in patients with t(8;21) AML. Our study also implies that patients with RTK and JAK2 mutations may benefit from allogeneic HSCT. Three patients with mutations received allogeneic HSCT after relapse and have achieved continuous second CR. Three patients in each group also received allogeneic HSCT at the first CR. As a consequence, 6 out of 9 patients with AML harboring KIT, FLT3 and JAK2 mutations who continued CR received allogeneic HSCT. When patients who underwent HSCT were censored at the date of the HSCT, the 6-year overall survival in patients with mutations was 25% compared to 62% in those without mutations (p=0.1368) (Figure 1B). These findings are of significant clinical import as activating mutations in KIT, FLT3 and JAK2 could be potential therapeutic targets for specific tyrosine kinase inhibitors and JAK2 pathway inhibitors in patients with t(8;21) AML harboring the mutations.

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

[2]  R. Wilson,et al.  Identification of somatic JAK1 mutations in patients with acute myeloid leukemia. , 2008, Blood.

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

[4]  M. Odero,et al.  JAK2-V617F activating mutation in acute myeloid leukemia: prognostic impact and association with other molecular markers , 2007, Leukemia.

[5]  T. Golub,et al.  Identification of driver and passenger mutations of FLT3 by high-throughput DNA sequence analysis and functional assessment of candidate alleles. , 2007, Cancer cell.

[6]  Govind Bhagat,et al.  Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia , 2007, Nature Medicine.

[7]  D. Gilliland,et al.  TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations , 2007, Leukemia.

[8]  J. Ihle,et al.  Jak2: normal function and role in hematopoietic disorders. , 2007, Current opinion in genetics & development.

[9]  P. Marynen,et al.  In vitro validation of gamma-secretase inhibitors for the treatment of T-cell acute lymphoblastic leukemia , 2007 .

[10]  P. Marynen,et al.  The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. , 2007, Haematologica.

[11]  G. Ehninger,et al.  Tyrosine kinase mutations of JAK2 are rare events in AML but influence prognosis of patients with CBF-leukemias. , 2007, Haematologica.

[12]  W. Hiddemann,et al.  Identification of additional cytogenetic and molecular genetic abnormalities in acute myeloid leukaemia with t(8;21)/AML1‐ETO , 2006, British journal of haematology.

[13]  S. H. Lee,et al.  The JAK2 V617F mutation in de novo acute myelogenous leukemias , 2006, Oncogene.

[14]  T. Brümmendorf,et al.  Prognostic impact of c-KIT mutations in core binding factor leukemias: an Italian retrospective study. , 2004, Blood.

[15]  H. Mitsuya,et al.  Mutations in the receptor tyrosine kinase pathway are associated with clinical outcome in patients with acute myeloblastic leukemia harboring t(8;21)(q22;q22) , 2005, Leukemia.

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

[17]  N. Asou.  The role of a Runt domain transcription factor AML1/RUNX1 in leukemogenesis and its clinical implications. , 2003, Critical reviews in oncology/hematology.