Deregulated expression in Ph+ human leukemias of AHI-1, a gene activated by insertional mutagenesis in mouse models of leukemia.
Ahi-1/AHI-1 (Abelson helper integration site-1) encodes a family of protein isoforms containing one Src homology 3 (SH3) domain and multiple tryptophan-aspartic acid 40 (WD40)-repeat domains. The function of these proteins is unknown, but involvement in leukemogenesis has been suggested by the high frequency of Ahi-1 mutations seen in certain virus-induced murine leukemias. Here we show that in both mice and humans, Ahi-1/AHI-1 expression is highest in the most primitive hematopoietic cells with specific patterns of down-regulation in different lineages. Cells from patients with chronic myeloid leukemia (CML; n = 28) show elevated AHI-1 transcripts in all disease phases and, in chronic phase, in the leukemic cells at all stages of differentiation, including quiescent (G(0)) CD34(+) cells as well as terminally differentiating cells. In the most primitive lin(-)CD34(+)CD38(-) CML cells, transcripts for the 2 shorter isoforms of AHI-1 are also increased. Although 15 of 16 human lymphoid and myeloid leukemic cell lines showed aberrant control of AHI-1 expression, this was not seen in blasts obtained directly from patients with acute Philadelphia chromosome-negative (Ph(-)) leukemia (n = 15). Taken together, our results suggest that down-regulation of AHI-1 expression is an important conserved step in primitive normal hematopoietic cell differentiation and that perturbations in AHI-1 expression may contribute to the development of specific types of human leukemia.
Jiang
Xiaoyan
X
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada. xjiang@bccancer.bc.ca
Zhao
Yun
Y
Chan
Wing-Yiu
WY
Vercauteren
Suzanne
S
Pang
Emily
E
Kennedy
Sean
S
Nicolini
Frank
F
Eaves
Allen
A
Eaves
Connie
C
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000328:Adult; D000818:Animals; D001854:Bone Marrow Cells / Q000737:chemistry; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D006412:Hematopoietic Stem Cells / Q000737:chemistry; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D009363:Neoplasm Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics*; D012326:RNA Splicing
C487178:AHI1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; C465818:Ahi1 protein, mouse; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins