AMKL chimeric transcription factors are potent inducers of leukemia.
Acute megakaryoblastic leukemia in patients without Down syndrome is a rare malignancy with a poor prognosis. RNA sequencing of fourteen pediatric cases previously identified novel fusion transcripts that are predicted to be pathological including CBFA2T3-GLIS2, GATA2-HOXA9, MN1-FLI and NIPBL-HOXB9. In contrast to CBFA2T3-GLIS2, which is insufficient to induce leukemia, we demonstrate that the introduction of GATA2-HOXA9, MN1-FLI1 or NIPBL-HOXB9 into murine bone marrow induces overt disease in syngeneic transplant models. With the exception of MN1, full penetrance was not achieved through the introduction of fusion partner genes alone, suggesting that the chimeric transcripts possess a unique gain-of-function phenotype. Leukemias were found to exhibit elements of the megakaryocyte erythroid progenitor gene expression program, as well as unique leukemia-specific signatures that contribute to transformation. Comprehensive genomic analyses of resultant murine tumors revealed few cooperating mutations confirming the strength of the fusion genes and their role as pathological drivers. These models are critical for both the understanding of the biology of disease as well as providing a tool for the identification of effective therapeutic agents in preclinical studies.
Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
J
J
Dang
Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
S
S
Nance
Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
J
J
Ma
Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
J
J
Cheng
Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
M P
MP
Walsh
Department of Veterinary Pathology Core, St Jude Children's Research Hospital, Memphis, TN, USA.
P
P
Vogel
Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
J
J
Easton
Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
G
G
Song
Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
M
M
Rusch
Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
A L
AL
Gedman
Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
C
C
Koss
Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
J R
JR
Downing
Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.|Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
T A
TA
Gruber
D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D000066673:Cell Self Renewal; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008957:Models, Genetic; D022423:Myeloid Cells / Q000473:pathology; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D034741:RNA, Small Interfering / Q000235:genetics; D011828:Radiation Chimera; D034061:Thrombopoiesis / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D015514:Oncogene Proteins, Fusion; D034741:RNA, Small Interfering; D014157:Transcription Factors