FIP1L1 presence in FIP1L1-RARA or FIP1L1-PDGFRA differentially contributes to the pathogenesis of distinct types of leukemia.
FIP1-like 1 (FIP1L1) is associated with two leukemogenic fusion genes: FIP1L1-retinoic acid receptor alpha (RARA) and FIP1L1-platelet-derived growth factor receptor alpha (PDGFRA). Analyses of a series of deletion mutants revealed that the FIP1 motif in FIP1L1-RARA plays a pivotal role in its homodimerization and transcriptional repressor activity. However, in FIP1L1-PDGFRA, the C-terminal PDGFRA portion possesses the ability of forming a homodimer by itself, making FIP1L1 dispensable for constitutive activation of this kinase. Both the full-length and the C-terminal PDGFRA portion of FIP1L1-PDGFRA could transform the IL-3-dependent hematopoietic cell line, BAF-B03. Moreover, when either the full-length or the C-terminal PDGFRA portion of FIP1L1-PDGFRA was introduced in these cells, they grew in the absence of IL-3. The cells having the C-terminal PDGFRA portion of FIP1L1-PDGFRA, however, were partially IL-3 dependent, whereas the cells having the full-length FIP1L1-PDGFRA became completely IL-3 independent for their growth. Taken together, these results show that FIP1L1 differentially contributes to the pathogenesis of distinct types of leukemia.
Department of Hematology, Hokkaido University Graduate School of Medicine, Kita 15 Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.
Junko
J
Iwasaki
Takeshi
T
Kondo
Stephanie
S
Darmanin
Makoto
M
Ibata
Masahiro
M
Onozawa
Daigo
D
Hashimoto
Naoya
N
Sakamoto
Takanori
T
Teshima
D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D007938:Leukemia / Q000145:classification* / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000502:physiology*; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D055503:Protein Multimerization / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000737:chemistry / Q000502:physiology*; D039221:mRNA Cleavage and Polyadenylation Factors / Q000737:chemistry / Q000502:physiology*
C479818:FIP1L1 protein, human; C534071:FIP1L1-RARA fusion protein, human; C508596:IL3 protein, human; D007377:Interleukin-3; D015514:Oncogene Proteins, Fusion; D039221:mRNA Cleavage and Polyadenylation Factors; C479819:FIP1L1-PDGFRA fusion protein, human; D020796:Receptor, Platelet-Derived Growth Factor alpha