Gamma-catenin contributes to leukemogenesis induced by AML-associated translocation products by increasing the self-renewal of very primitive progenitor cells.
Acute myeloid leukemia (AML) is characterized by the block of differentiation, deregulated apoptosis, and an increased self-renewal of hematopoietic precursors. It is unclear whether the self-renewal of leukemic blasts results from the cumulative effects of blocked differentiation and impaired apoptosis or whether there are mechanisms directly increasing self-renewal. The AML-associated translocation products (AATPs) promyelocytic leukemia/retinoic acid receptor alpha (PML/RAR alpha), promyelocytic leukemia zinc finger (PLZF)/RAR alpha (X-RAR alpha), and AML-1/ETO block hematopoietic differentiation. The AATPs activate the Wnt signaling by up-regulating gamma-catenin. Activation of the Wnt signaling augments self-renewal of hematopoietic stem cells (HSCs). Therefore, we investigated how AATPs influence self-renewal of HSCs and evaluated the role of gamma-catenin in the determination of the phenotype of HSCs expressing AATPs. Here we show that the AATPs directly activate the gamma-catenin promoter. The crucial role of gamma-catenin in increasing the self-renewal of HSCs upon expression of AATPs is demonstrated by (i) the abrogation of replating efficiency upon hindrance of gamma-catenin expression through RNA interference, and (ii) the augmentation of replating efficiency of HSCs upon overexpression of gamma-catenin itself. In addition, the inoculation of gamma-catenin-transduced HSCs into irradiated recipient mice establishes the clinical picture of AML. These data provide the first evidence that the aberrant activation of Wnt signaling by the AATP decisively contributes to the pathogenesis of AML.
Zheng
Xiaomin
X
Medizinische Klinik III/Abteilung Hämatologie, Laboratorium für Experimentelle Hämatolgie, Johan Wolfgang Goethe-Universität Frankfurt, Germany.
Beissert
Tim
T
Kukoc-Zivojnov
Natasa
N
Puccetti
Elena
E
Altschmied
Joachim
J
Strolz
Corinna
C
Boehrer
Simone
S
Gul
Hilal
H
Schneider
Orinta
O
Ottmann
Oliver Gerhard
OG
Hoelzer
Dieter
D
Henschler
Reinhard
R
Ruthardt
Martin
M
D000208:Acute Disease; D000818:Animals; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051180:Desmoplakins; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007951:Leukemia, Myeloid / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D014161:Transduction, Genetic; D014178:Translocation, Genetic; D015854:Up-Regulation; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051185:gamma Catenin
D003598:Cytoskeletal Proteins; D051180:Desmoplakins; C495292:JUP protein, human; C495293:Jup protein, mouse; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051185:gamma Catenin