HIC1 tumour suppressor gene is suppressed in acute myeloid leukaemia and induced during granulocytic differentiation.
A hallmark of acute myeloid leukaemia (AML) is a block in differentiation caused by deregulated gene expression. The tumour suppressor Hypermethylated In Cancer 1 (HIC1) is a transcriptional repressor, which is epigenetically silenced in solid cancers. HIC1 mRNA expression was found to be low in 128 patient samples of AML and CD34+ progenitor cells when compared with terminally differentiated granulocytes. HIC1 mRNA was induced in a patient with t(15;17)-positive acute promyelocytic leukaemia receiving all-trans retinoic acid (ATRA) therapy. We therefore investigated whether HIC1 plays a role in granulocytic differentiation and whether loss of function of this gene might contribute to the differentiation block in AML. We evaluated HIC1 mRNA levels in HL-60 and U-937 cells upon ATRA-induced differentiation and in CD34+ progenitor cells after granulocyte colony-stimulating factor-induced differentiation. In both models of granulocytic differentiation, we observed significant HIC1 induction. When HIC1 mRNA was suppressed in HL-60 cells using stably expressed short hairpin RNA targeting HIC1, granulocytic differentiation was altered as assessed by CD11b expression. Bisulphite sequencing of GC-rich regions (CpG islands) in the HIC1 promoter provided evidence that the observed suppression in HL-60 cells was not because of promoter hypermethylation. Our findings indicate a role for the tumour suppressor gene HIC1 in granulocytic differentiation. Low expression of HIC1 may very well contribute to pathogenic events in leukaemogenesis.
Britschgi
Christian
C
Experimental Oncology/Haematology, Department of Clinical Research, University of Bern, Bern, Switzerland.
Jenal
Mathias
M
Rizzi
Mattia
M
Mueller
Beatrice U
BU
Torbett
Bruce E
BE
Andres
Anne-Catherine
AC
Tobler
Andreas
A
Fey
Martin F
MF
Tschan
Mario P
MP
D000970:Antineoplastic Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D019175:DNA Methylation; D005786:Gene Expression Regulation / Q000187:drug effects; D006098:Granulocytes / Q000166:cytology*; D018922:HL-60 Cells; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000097:blood / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000235:genetics; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology; D020298:U937 Cells; D015854:Up-Regulation
D000970:Antineoplastic Agents; C499808:HIC1 protein, human; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D014212:Tretinoin