Hes1 immortalizes committed progenitors and plays a role in blast crisis transition in chronic myelogenous leukemia.
Hairy enhancer of split 1 (Hes1) is a basic helix-loop-helix transcriptional repressor that affects differentiation and often helps maintain cells in an immature state in various tissues. Here we show that retroviral expression of Hes1 immortalizes common myeloid progenitors (CMPs) and granulocyte-macrophage progenitors (GMPs) in the presence of interleukin-3, conferring permanent replating capability on these cells. Whereas these cells did not develop myeloproliferative neoplasms when intravenously administered to irradiated mice, the combination of Hes1 and BCR-ABL in CMPs and GMPs caused acute leukemia resembling blast crisis of chronic myelogenous leukemia (CML), resulting in rapid death of the recipient mice. On the other hand, BCR-ABL alone caused CML-like disease when expressed in c-Kit-positive, Sca-1-positive, and lineage-negative hematopoietic stem cells (KSLs), but not committed progenitors CMPs or GMPs, as previously reported. Leukemic cells derived from Hes1 and BCR-ABL-expressing CMPs and GMPs were more immature than those derived from BCR-ABL-expressing KSLs. Intriguingly, Hes1 was highly expressed in 8 of 20 patients with CML in blast crisis, but not in the chronic phase, and dominant negative Hes1 retarded the growth of some CML cell lines expressing Hes1. These results suggest that Hes1 is a key molecule in blast crisis transition in CML.
Nakahara
Fumio
F
Department of Cell Therapy and Transplantation Medicine, University of Tokyo, Tokyo, Japan.
Sakata-Yanagimoto
Mamiko
M
Komeno
Yukiko
Y
Kato
Naoko
N
Uchida
Tomoyuki
T
Haraguchi
Kyoko
K
Kumano
Keiki
K
Harada
Yuka
Y
Harada
Hironori
H
Kitaura
Jiro
J
Ogawa
Seishi
S
Kurokawa
Mineo
M
Kitamura
Toshio
T
Chiba
Shigeru
S
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis* / Q000235:genetics; D001752:Blast Crisis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002461:Cell Line, Transformed; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis / Q000235:genetics; D055014:Granulocyte-Macrophage Progenitor Cells / Q000378:metabolism* / Q000473:pathology; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D007377:Interleukin-3 / Q000235:genetics / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D000072056:Transcription Factor HES-1
D051792:Basic Helix-Loop-Helix Proteins; D016044:Fusion Proteins, bcr-abl; D018398:Homeodomain Proteins; D007377:Interleukin-3; D012097:Repressor Proteins; D000072056:Transcription Factor HES-1; C489735:Hes1 protein, rat; C508596:IL3 protein, human; C078493:HES1 protein, human