Deregulated expression in Ph+ human leukemias of AHI-1, a gene activated by insertional mutagenesis in mouse models of leukemia

Abstract

AbstractAhi-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 (G0) 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.