Sleeping Beauty transposon screen identifies signaling modules that cooperate with STAT5 activation to induce B-cell acute lymphoblastic leukemia.
Signal transducer and activator of transcription 5 (STAT5) activation occurs frequently in human progenitor B-cell acute lymphoblastic leukemia (B-ALL). To identify gene alterations that cooperate with STAT5 activation to initiate leukemia, we crossed mice expressing a constitutively active form of STAT5 (Stat5b-CA) with mice in which a mutagenic Sleeping Beauty transposon (T2/Onc) was mobilized only in B cells. Stat5b-CA mice typically do not develop B-ALL (<2% penetrance); in contrast, 89% of Stat5b-CA mice in which the T2/Onc transposon had been mobilized died of B-ALL by 3 months of age. High-throughput sequencing approaches were used to identify genes frequently targeted by the T2/Onc transposon; these included Sos1 (74%), Kdm2a (35%), Jak1 (26%), Bmi1 (19%), Prdm14 or Ncoa2 (13%), Cdkn2a (10%), Ikzf1 (8%), Caap1 (6%) and Klf3 (6%). Collectively, these mutations target three major cellular processes: (i) the Janus kinase/STAT5 pathway (ii) progenitor B-cell differentiation and (iii) the CDKN2A tumor-suppressor pathway. Transposon insertions typically resulted in altered expression of these genes, as well as downstream pathways including STAT5, extracellular signal-regulated kinase (Erk) and p38. Importantly, expression of Sos1 and Kdm2a, and activation of p38, correlated with survival, further underscoring the role these genes and associated pathways have in B-ALL.
Center for Immunology, University of Minnesota, Minneapolis, MN, USA.|Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.|Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
L M
LM
Heltemes-Harris
Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.|Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN, USA.
J D
JD
Larson
Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.|Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN, USA.|Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, MN, USA.|Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA.
T K
TK
Starr
Center for Immunology, University of Minnesota, Minneapolis, MN, USA.|Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.|Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
G K
GK
Hubbard
Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
A L
AL
Sarver
Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.|Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA.|Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
D A
DA
Largaespada
Center for Immunology, University of Minnesota, Minneapolis, MN, USA.|Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.|Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
M A
MA
Farrar
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004251:DNA Transposable Elements / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional; D009154:Mutation; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020837:SOS1 Protein / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C489421:Bmi1 protein, mouse; D004251:DNA Transposable Elements; D011518:Proto-Oncogene Proteins; D020837:SOS1 Protein; D050799:STAT5 Transcription Factor; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor; C547579:FBXL11 protein, mouse; D056484:Jumonji Domain-Containing Histone Demethylases; D063150:Polycomb Repressive Complex 1; D053613:Janus Kinase 1; D048051:p38 Mitogen-Activated Protein Kinases