Transformation of hematopoietic cell lines to growth-factor independence and induction of a fatal myelo- and lymphoproliferative disease in mice by retrovirally transduced TEL/JAK2 fusion genes.
Recent reports have demonstrated fusion of the TEL gene on 12p13 to the JAK2 gene on 9p24 in human leukemias. Three variants have been identified that fuse the TEL pointed (PNT) domain to (i) the JAK2 JH1-kinase domain, (ii) part of and (iii) all of the JH2 pseudokinase domain. We report that all of the human TEL/JAK2 variants, and a human/mouse chimeric hTEL/mJAK2(JH1) fusion gene, transform the interleukin-3 (IL-3)-dependent murine hematopoietic cell line Ba/F3 to IL-3-independent growth. Transformation requires both the TEL PNT domain and JAK2 kinase activity. Furthermore, all TEL/JAK2 variants strongly activated STAT 5 by phosphotyrosine Western blots and by electrophoretic mobility shift assays (EMSA). Mice (n = 40) transplanted with bone marrow infected with the MSCV retrovirus containing either the hTEL/mJAK2(JH1) fusion or its human counterpart developed a fatal mixed myeloproliferative and T-cell lymphoproliferative disorder with a latency of 2-10 weeks. In contrast, mice transplanted with a TEL/JAK2 mutant lacking the TEL PNT domain (n = 10) or a kinase-inactive TEL/JAK2(JH1) mutant (n = 10) did not develop the disease. We conclude that all human TEL/JAK2 fusion variants are oncoproteins in vitro that strongly activate STAT 5, and cause lethal myelo- and lymphoproliferative syndromes in murine bone marrow transplant models of leukemia.
Schwaller
J
J
Division of Hematology and Oncology, Harvard Medical School, Boston, MA 02115, USA.
Frantsve
J
J
Aster
J
J
Williams
I R
IR
Tomasson
M H
MH
Ross
T S
TS
Peeters
P
P
Van Rompaey
L
L
Van Etten
R A
RA
Ilaria
R
R
Marynen
P
P
Gilliland
D G
DG
D000818:Animals; D016026:Bone Marrow Transplantation; D002455:Cell Division; D002461:Cell Line, Transformed; D004247:DNA / Q000378:metabolism; D004274:DNA, Recombinant; D004279:DNA, Viral / Q000032:analysis; D004268:DNA-Binding Proteins / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D007377:Interleukin-3 / Q000502:physiology; D008232:Lymphoproliferative Disorders / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008894:Milk Proteins; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000502:physiology; D012190:Retroviridae / Q000235:genetics; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014170:Transformation, Genetic; D016662:Virus Integration; D053614:Janus Kinase 2; D000097764:ETS Translocation Variant 6 Protein
D004247:DNA; D004274:DNA, Recombinant; D004279:DNA, Viral; D004268:DNA-Binding Proteins; D007377:Interleukin-3; D008894:Milk Proteins; D015514:Oncogene Proteins, Fusion; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; C108603:TEL-JAK2 fusion protein, human; D053614:Janus Kinase 2; D000097764:ETS Translocation Variant 6 Protein; C491568:TEL-JAK2 fusion protein, mouse