The activation of Chk1 has been demonstrated to influence response to chemotherapy in patients with BCR-ABL-positive chronic myeloid leukemia patients (Nieborowska-Skorska et al, Cell Cycle 2006). Chk1 and Chk2 are serine threonine kinase activated by different insults leading to DNA damage and involved in DNA repair and cell cycle control. Since, their role has not been established in BCR-ABL+ ALL, we investigated the expression of Chk1/Chk2 in blast cells from adult BCR-ABLpositive ALL patients (n=48) compared with normal bone marrow precursor cells (n=9) using the BioMark instrument (Fluidigm) and Fluidigm Dynamic Array 48 x 48. The expression of Chk1 but not Chk2 was higher (p=0,0005) in BCR-ABL+ leukemia patients (median value 0,69) compared with normal samples (median value 0,27). In order to better understand the biological role of Chk1 in ALL, we included in the analysis different B (BCR-ABL-positive: BV-173 and SUP-B15; BCR-ABL-negative: REH, NALM-6 and NALM-19) and T (MOLT-4, RPMI-8402 and CCRFCEM) leukemia cell lines. The expression of Chk1 was very homogeneous among the cell lines, with no difference between BCR-ABL-positive or negative cells. Since Chk1/2 inhibitors are currently available, we investigated the efficacy of Chk1/2 inhibition by PF-0477736 (Sigma) both as single agent and in combination with tyrosine kinase inhibitors (TKIs), imatinib and nilotinib, in BCR-ABL+ leukemia cell lines. Results showed that the combination (TKIs + Chk1/2 inhibitor) is more effective than the single inhibitors in inducing cell death. In conclusion, adult ALL patients show an higher expression of Chk1 compared with normal bone marrow precursor cells. This abnormal expression could be found also in different B-/T-ALL cell lines, suggesting that the inhibition of Chk1 could be a target for new therapeutic strategies in ALL.

DEREGULATED EXPRESSION OF CHECKPOINT KINASE 1 (CHK1) IN BCR-ABL-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA (BCR-ABL+ ALL) SUGGESTS A NEW THERAPEUTIC TARGET

GHELLI LUSERNA DI RORÀ, ANDREA;IACOBUCCI, ILARIA;FERRARI, ANNA;Papayannidis, C;Robustelli, V;LONETTI, ANNALISA;Parisi, S;
2013

Abstract

The activation of Chk1 has been demonstrated to influence response to chemotherapy in patients with BCR-ABL-positive chronic myeloid leukemia patients (Nieborowska-Skorska et al, Cell Cycle 2006). Chk1 and Chk2 are serine threonine kinase activated by different insults leading to DNA damage and involved in DNA repair and cell cycle control. Since, their role has not been established in BCR-ABL+ ALL, we investigated the expression of Chk1/Chk2 in blast cells from adult BCR-ABLpositive ALL patients (n=48) compared with normal bone marrow precursor cells (n=9) using the BioMark instrument (Fluidigm) and Fluidigm Dynamic Array 48 x 48. The expression of Chk1 but not Chk2 was higher (p=0,0005) in BCR-ABL+ leukemia patients (median value 0,69) compared with normal samples (median value 0,27). In order to better understand the biological role of Chk1 in ALL, we included in the analysis different B (BCR-ABL-positive: BV-173 and SUP-B15; BCR-ABL-negative: REH, NALM-6 and NALM-19) and T (MOLT-4, RPMI-8402 and CCRFCEM) leukemia cell lines. The expression of Chk1 was very homogeneous among the cell lines, with no difference between BCR-ABL-positive or negative cells. Since Chk1/2 inhibitors are currently available, we investigated the efficacy of Chk1/2 inhibition by PF-0477736 (Sigma) both as single agent and in combination with tyrosine kinase inhibitors (TKIs), imatinib and nilotinib, in BCR-ABL+ leukemia cell lines. Results showed that the combination (TKIs + Chk1/2 inhibitor) is more effective than the single inhibitors in inducing cell death. In conclusion, adult ALL patients show an higher expression of Chk1 compared with normal bone marrow precursor cells. This abnormal expression could be found also in different B-/T-ALL cell lines, suggesting that the inhibition of Chk1 could be a target for new therapeutic strategies in ALL.
2013
Vol 98, Issue supplement 3
21
21
Ghelli Luserna Di Rorà, A; Iacobucci, I; Ferrari, A; Papayannidis, C; Derenzini, E; Venturi, C; Imbrogno, E; Abbenante, Mc; Perricone, M; Robustelli, V; Guadagnuolo, V; Vitale, A; Elia, L; Musuraca, G; Ronconi, S; Carloni, S; Ottaviani, E; Lonetti, A; Paolini, S; Parisi, S; Sartor, C; Cattina, F; Russo, D; Martinelli, G
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/604858
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