American Association for Cancer Research
15357163mct141065-sup-142465_3_supp_3164517_nvf687.doc (3.17 MB)

Supplementary Figure from Specific Antileukemic Activity of PD0332991, a CDK4/6 Inhibitor, against Philadelphia Chromosome–Positive Lymphoid Leukemia

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journal contribution
posted on 2023-04-03, 14:08 authored by Atsushi Nemoto, Satoshi Saida, Itaru Kato, Jiro Kikuchi, Yusuke Furukawa, Yasuhiro Maeda, Koshi Akahane, Hiroko Honna-Oshiro, Kumiko Goi, Keiko Kagami, Shinya Kimura, Yuko Sato, Seiichi Okabe, Akira Niwa, Kenichiro Watanabe, Tatsutoshi Nakahata, Toshio Heike, Kanji Sugita, Takeshi Inukai

Supplementary Fig. S1-S5. Fig. S1. Anti-leukemic activity of PD0332991 against Ph+ lymphoid leukemia cell lines. Fig. S2. Effect of cytokines and PD0332991 on cell growth of Ph+ lymphoid leukemia cell lines. Fig. S3. Anti-leukemic activity of PD0332991 against a Ph+ALL cell lines with a T315I mutation of BCR-ABL in vitro. Fig. S4. Anti-leukemic activity of PD0332991 against a Ph+ ALL cell line with a T315I mutation of BCR-ABL in a xenograft model using NOG mice. Fig. S5. Expression of cell cycle regulators in Ph+ lymphoid leukemia cells.



S-phase progression of the cell cycle is accelerated in tumors through various genetic abnormalities, and, thus, pharmacologic inhibition of altered cell-cycle progression would be an effective strategy to control tumors. In the current study, we analyzed the antileukemic activity of three available small molecules targeting CDK4/CDK6 against lymphoid crisis of chronic myeloid leukemia (CML-LC) and Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL), and found that all three molecules showed specific activities against leukemic cell lines derived from CML-LC and Ph+ ALL. In particular, PD0332991 exhibited extremely high antileukemic activity against CML-LC and Ph+ ALL cell lines in the nanomolar range by the induction of G0–G1 arrest and partially cell death through dephosphorylation of pRb and downregulation of the genes that are involved in S-phase transition. As an underlying mechanism for favorable sensitivity to the small molecules targeting CDK4/CDK6, cell-cycle progression of Ph+ lymphoid leukemia cells was regulated by transcriptional and posttranscriptional modulation of CDK4 as well as Cyclin D2 gene expression under the control of BCR-ABL probably through the PI3K pathway. Consistently, the gene expression level of Cyclin D2 in Ph+ lymphoid leukemia cells was significantly higher than that in Ph− lymphoid leukemia cells. Of note, three Ph+ ALL cell lines having the T315I mutation also showed sensitivity to PD0332991. In a xenograft model, PD0332991, but not imatinib, suppressed dissemination of Ph+ ALL having the T315I mutation and prolonged survival, demonstrating that this reagent would be a new therapeutic modality for relapsed CML-LC and Ph+ ALL patients after treatment with tyrosine kinase inhibitors. Mol Cancer Ther; 15(1); 94–105. ©2015 AACR.

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