The Flt3 receptor tyrosine kinase collaborates with NUP98-HOX fusions in acute myeloid leukemia.
In leukemogenesis, several genetic changes conferring a proliferative and/or survival advantage to hematopoietic progenitor cells in addition to a block in differentiation are required. Here, we demonstrate that overexpression of the wild-type (wt) Flt3 receptor tyrosine kinase collaborates with NUP98-HOX fusions (NUP98-HOXA10 and NUP98-HOXD13) to induce aggressive acute myeloid leukemia (AML). We used a mouse transplantation model to show their synergism in cotransduced bone marrow cells as well as in a cellular model of leukemic progression. Furthermore, our data support the finding that Meis1 overexpression leads to marked elevation in Flt3 transcription and extend it to the context of NUP98-HOX-induced leukemia. Together, these results support a multistep model where the synergism between NUP98-HOX and wt-Flt3 is the result of the ability of Flt3 to increase proliferation of myeloid progenitors blocked in differentiation by NUP98-HOX fusions and reveal a direct role for wt-Flt3 in the pathobiology of AML. Given the similarities in the leukemogenic role of native HOX and NUP98-fused HOX genes, our results underscore the clinical significance of the recurrent co-overexpression of wt-FLT3 and HOX in human leukemia and suggest that specific FLT3 inhibitors could be useful in treatment of HOX-induced AML or acute lymphoblastic leukemia (ALL).
Palmqvist
Lars
L
Terry Fox Laboratory, British Columbia Cancer Agency, 11th Floor, 675 West 10th Ave, Vancouver, BC, Canada V5Z 1L3.
Argiropoulos
Bob
B
Pineault
Nicolas
N
Abramovich
Carolina
C
Sly
Laura M
LM
Krystal
Gerald
G
Wan
Adrian
A
Humphries
R Keith
RK
D000208:Acute Disease; D000818:Animals; D001854:Bone Marrow Cells; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000235:genetics*; D007951:Leukemia, Myeloid / Q000209:etiology* / Q000235:genetics; D051379:Mice; D028861:Nuclear Pore Complex Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; C084118:Hoxd13 protein, mouse; D028861:Nuclear Pore Complex Proteins; C465451:Nup98 protein, human; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; C069634:HOXA10 protein, human; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3