Acceleration of chronic myeloproliferation by enforced expression of Meis1 or Meis3 in Icsbp-deficient bone marrow cells.
Identifying genetic pathways that cooperate in leukemogenesis facilitates our understanding of the molecular mechanisms at play. Interferon consensus sequence-binding protein (ICSBP) is a tumor suppressor, whose downregulation cooperates with BCR-ABL and NUP98-TOP1 gene products to accelerate leukemia induction in mouse models. Similarly, Meis1 synergizes with HoxA9 or NUP98-HOX (but not NUP98-TOP1) fusion genes to promote the early onset of leukemia. To investigate whether Icsbp deficiency interacts with Meis1 or its family member Meis3, we transplanted Icsbp(-/-) bone marrow (BM) cells after transduction with Meis1 or Meis3 retroviral vectors. Here, we show that enforced expression of Meis1 or Meis3 in Icsbp(-/-) BM cells induces a fatal, invasive myeloproliferative disease. Secondary mutations, such as activation of Mn1, led to the progression to acute myeloid leukemia in a few mice. Interestingly, expression of endogenous Meis1 and Meis3 mRNAs was repressed in the granulocytic progenitor population of Icsbp(-/-) mice. These results reveal a novel collaboration between Icsbp deficiency and Meis1/Meis3 in the acceleration of chronic myeloid leukemia-like disease.
Hara
T
T
Stem Cell Project Group, The Tokyo Metropolitan Institute of Medical Science, Tokyo Metropolitan Organization for Medical Research, Tokyo, Japan. thara@rinshoken.or.jp
Schwieger
M
M
Kazama
R
R
Okamoto
S
S
Minehata
K
K
Ziegler
M
M
Löhler
J
J
Stocking
C
C
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000502:physiology*; D002455:Cell Division; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics*; D050835:Interferon Regulatory Factors / Q000172:deficiency* / Q000235:genetics*; D007700:Kinetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D000099185:Interferon Regulatory Factor-8
D018398:Homeodomain Proteins; D050835:Interferon Regulatory Factors; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D014157:Transcription Factors; D000099185:Interferon Regulatory Factor-8; C000616392:Meis1 protein, mouse; C530615:Meis3 protein, mouse