Abstract
High-risk B-cell acute lymphoblastic leukemia (B-ALL) remains a therapeutic challenge despite advances in the use of tyrosine kinase inhibitors and chimeric-antigen-receptor engineered T cells. Lymphoblastic-leukemia precursors are highly sensitive to oxidative stress. KLF5 is a member of the Krüppel-like family of transcription factors. KLF5 expression is repressed in B-ALL, including BCR-ABL1+ B-ALL. Here, we demonstrate that forced expression of KLF5 in B-ALL cells bypasses the imatinib resistance which is not associated with mutations of BCR-ABL. Expression of Klf5 impaired leukemogenic activity of BCR-ABL1+ B-cell precursors in vitro and in vivo. The complete genetic loss of Klf5 reduced oxidative stress, increased regeneration of reduced glutathione and decreased apoptosis of leukemic precursors. Klf5 regulation of glutathione levels was mediated by its regulation of glutathione-S-transferase Mu 1 (Gstm1), an important regulator of glutathione-mediated detoxification and protein glutathionylation. Expression of Klf5 or the direct Klf5 target gene Gstm1 inhibited clonogenic activity of Klf5∆/∆ leukemic B-cell precursors and unveiled a Klf5-dependent regulatory loop in glutamine-dependent glutathione metabolism. In summary, we describe a novel mechanism of Klf5 B-ALL suppressor activity through its direct role on the metabolism of antioxidant glutathione levels, a crucial positive regulator of leukemic precursor survival.
Highlights
Philadelphia chromosome-positive (Ph+) hematological malignancies arise from the reciprocal translocation, t(9,22) (q34;q11.2), which encodes the protein BCR-ABL1
An analysis of a genome-scale shRNA screen of 501 cancer cell lines, revealed that five non-BCR-ABL B-cell acute lymphoblastic leukemia (B-ALL) cell lines are not enriched for a dependency on KLF5, indicating that KLF5 does not score as an oncogenic- or tumor suppressor-dependency for non-BCR-ABL B-ALL (Supplementary Figure 1B) [20]
We found KLF5 mRNA expression decreased in BCR-ABL1 expressing cell lines compared with cell lines expressing other oncogene drivers that are known to transform in B-ALL, including those with MLL rearrangement or TEL/AML1 translocations (Figure 1A–1B)
Summary
Philadelphia chromosome-positive (Ph+) hematological malignancies arise from the reciprocal translocation, t(9,22) (q34;q11.2), which encodes the protein BCR-ABL1. BCR-ABL1 is the transformation driver of ~5–30% of B-ALL in patients [1, 2] where the expression of the p190 form of BCR-ABL1 is the most frequent form in children and is associated with the transformation of an early B-cell precursor. While resistance-inducing mutations have been successfully targeted with novel inhibitors like dasatinib, nilotinib or ponatinib (reviewed in [5]), acquired resistance due to genomic events resulting in activation of alternative signaling pathways and non-oncogene addiction (reviewed in [6]) contribute to the poor prognosis of these patients, whose only hope frequently relies on chimeric antigen receptor transgenic T-cell (CAR-T) therapies [5]. Identification and targeting of downstream signaling cascades by BCR-ABL1 may lead to more effective primary therapeutic strategies with the aim of preventing the development and/or selection of leukemic clones that are resistant to TK inhibition. Multi-targeted approaches are appropriate in treating Ph+ leukemia
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