Effects of lenalidomide and/or imatinib treatment on gene expression of Ph-positive KOPN-57bi cells.

ABSTRACT: Even after the development of tyrosine kinase inhibitors (TKIs), the long-term prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) is still unsatisfactory, which is thought to be associated with the high incidence of genetic alterations of Ikaros family zinc finger 1 (IKZF1). Lenalidomide (LEN), a representative of immunomodulatory drugs (IMiDs), has been effectively used for the treatment of relapsed/refractory multiple myeloma (MM), and its cytotoxic effect was recently shown to be mediated, at least in part, by marked down-regulation of IKZFs 1 and 3 expression through the interaction with the receptor cereblon (CRBN) forming a part of the Cullin-RING E3 ubiquitin ligase. In the present study, we examined the effects of LEN on ALL cells with a variety of genetic alterations and found that Ph+ALL cells expressing a dominant-negative IKZF1 isoform Ik6 which lacks the CRBN binding site were specifically sensitive to LEN where accumulation of Ik6 with disappearance of functional IKZF1 isoforms and the abrupt fall from very high levels of IKZF3 expression were documented. To examine the effect of lenalidomide and/or imatinib treatment on Ph-positive ALL cells from the viewpoint of gene expression, we performed micro array analysis. Of importance, the induction of apoptosis of Ph+ALL cells, even with the T315I mutation of BCR-ABL, was enhanced when they were treated with TKI in the presence of LEN. This synergism between LEN and TKIs was demonstrated in the xenograft mice model. IMiDs, now called as CRBN modulators, should be an attractive approach for potentiating responsiveness of Ph+ALL cells to TKIs, and this drug repositioning certainly facilitates their long-term survival if the effective combination regimen is warranted.

ORGANISM(S): Homo sapiens

PROVIDER: GSE155597 | GEO | 2021/06/16

REPOSITORIES: GEO