RIZ1 is potential CML tumor suppressor that is down-regulated during disease progression.
BACKGROUND
RIZ1 expression and activity are reduced in many cancers. In AML cell lines and patient material, RIZ1 expression is reduced relative to normal bone marrow. In chronic myelogenous leukemia (CML), blastic transformation is associated with loss of heterozygosity in the region where RIZ1 is located. RIZ1 is a PR domain methyltransferase that methylates histone H3 lysine 9, a modification important for transcriptional repression. In CML blast crisis cell lines RIZ1 represses insulin-like growth factor-1 expression and autocrine signaling. Together these observations suggest that RIZ1 may have a role in the chronic phase to blast crisis transition in CML.


RESULTS
In CML patient material, we observed that RIZ1 expression was decreased during progression from chronic phase to blast crisis. RIZ1 was expressed in mature myeloid and CD34+ cells demonstrating that decreased RIZ1 expression in blast crisis is not due to an increased immature cell population. Expression of RIZ1 CML blast crisis cell lines decreased proliferation, increased apoptosis, and enhanced differentiation.


CONCLUSIONS
RIZ1 is a candidate tumor suppressor gene whose expression is decreased in blast crisis. Loss of RIZ1 activity results in decreased apoptosis and differentiation and enhanced proliferation. Together these results suggest that loss of RIZ1 expression will lead to an increase in myeloid blast cell population resulting in CML progression.
Lakshmikuttyamma
Ashakumary
A
Cancer Stem Cell Research Group, University of Saskatchewan, Saskatoon, SK, Canada. ashakum@htmail.com
Takahashi
Naoto
N
Pastural
Elodie
E
Torlakovic
Emina
E
Amin
Hesham M
HM
Garcia-Manero
Guillermo
G
Voralia
Michael
M
Czader
Magdalena
M
DeCoteau
John F
JF
Geyer
C Ronald
CR
D001752:Blast Crisis / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D018450:Disease Progression; D015536:Down-Regulation; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology; D016147:Genes, Tumor Suppressor / Q000502:physiology; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014162:Transfection
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D011495:Histone-Lysine N-Methyltransferase; C093563:PRDM2 protein, human