Short interfering RNA (siRNA) targeting the Lyn kinase induces apoptosis in primary, and drug-resistant, BCR-ABL1(+) leukemia cells

Authors:
Ptasznik A, Nakata Y, Kalota A, Emerson SG and Gewirtz AM
In:
Source: Nat Med
Publication Date: (2004)
Issue: 10(11): 1187-1189
Research Area:
Cancer Research/Cell Biology
Immunotherapy / Hematology
Cells used in publication:
HL-60
Species: human
Tissue Origin: blood
K-562
Species: human
Tissue Origin: blood
T cell, human stim.
Species: human
Tissue Origin: blood
CD34+ cell, human
Species: human
Tissue Origin: blood
M-07e
Species: human
Tissue Origin: blood
Platform:
Nucleofectorâ„¢ I/II/2b
Experiment
Lyn siRNA was transfected into different human primary cells (CD34+ cells, leukemic blasts) and cell lines (K562, HL-60, EM2, EM3, LAMA84, Mo7e). In all cells that express BCR-ABL1 (leukemic blasts from patients; K562, EM2, EM3, LAMA84) Lyn knock-down led to apoptosis, all cells not expressing BCR-ABL1 (normal CD34+ cells; Mo7e) did not go into apoptosis upon Lyn knock-down. In a rescue experiment for the apoptosis phenotype K562 cells were cotransfected with siRNA to the 3'UTR of Lyn mRNA together with a Lyn expression construct lacking the 3'UTR.
Abstract
We studied the effects of Lyn ablation on the survival of drug-resistant chronic myelogenous leukemia (CML) blast crisis cells using siRNA. Lyn siRNA reduced Lyn protein in both normal hematopoietic cells and BCR-ABL1-expressing (BCR-ABL1(+)) blasts by 80-95%. Within 48 h, siRNA-treated BCR-ABL1(+) blasts underwent apoptosis, whereas normal cells remained viable. This increased dependence on Lyn signaling for BCR-ABL1(+) blast survival provides the basis for rational treatment of drug-resistant CML blast crisis, particularly when lymphoid in nature.