Genomic instability may originate from imatinib-refractory chronic myeloid leukemia stem cells

Abstract

• Imatinib does not prevent accumulation of genomic instability in CML-CP.• Imatinib-refractory leukemia stem cells may be a source of genomic instability in CML-CP.Genomic instability is a hallmark of chronic myeloid leukemia in chronic phase (CML-CP) resulting in BCR-ABL1 mutations encoding resistance to tyrosine kinase inhibitors (TKIs) and/or additional chromosomal aberrations leading to disease relapse and/or malignant progression. TKI-naive and TKI-treated leukemia stem cells (LSCs) and leukemia progenitor cells (LPCs) accumulate high levels of reactive oxygen species (ROS) and oxidative DNA damage. To determine the role of TKI-refractory LSCs in genomic instability, we used a murine model of CML-CP where ROS-induced oxidative DNA damage was elevated in LSCs, including quiescent LSCs, but not in LPCs. ROSinduced oxidative DNA damage in LSCs caused clinically relevant genomic instability in CML-CP-like mice, such as TKI-resistant BCR-ABL1 mutations (E255K, T315I, H396P), deletions in Ikzf1 and Trp53, and additions in Zfp423 and Idh1. Despite inhibition of BCR-ABL1 kinase, imatinib did not downregulate ROS and oxidative DNA damage in TKIrefractory LSCs to the levels detected in normal cells, and CML-CP-like mice treated with imatinib continued to accumulate clinically relevant genetic aberrations. Inhibition of class I p21-activated protein kinases by IPA3 downregulated ROS in TKI-naive and TKI-treated LSCs. Altogether, we postulate that genomic instability may originate in the most primitive TKI-refractory LSCs in TKI-naive and TKI-treated patients. (Blood. 2013;121(20):4175-4183)

Gene expression and mutation-guided synthetic lethality eradicates proliferating and quiescent leukemia cells

“…Quiescent and proliferating tumor cells accumulate spontaneous and treatment-induced DSBs, which are eventually repaired and thereby tolerated (18,24,25). Inhibition of DSB repair has emerged as a promising antitumor treatment, especially in the context of synthetic lethality, which targets specific pathways to eradicate tumor cells while sparing normal cells (26).…”

“…CML-CP-like leukemia was characterized by splenomegaly and leukocytosis associated with expansion of mature myeloid cells as described previously (18,19 Microarray analysis. Gene expression data for 15 genes were used to select BRCA/DNA-PK-deficient and -proficient AMLs from a dataset of 172 samples arrayed on an Illumina HT-12 (supplemental data: AML gene expression levels).…”

“…. Human leukemia cells were detected by anti-human CD45 antibody and leukemia stem and progenitor cells were detected by anti-human CD34 and CD38 antibodies as described previously (18). Median survival time was determined.…”

MLL-AF9 leukemias are sensitive to PARP1 inhibitors combined with cytotoxic drugs

“…Quiescent (CFSE max ) and proliferating (CFSE low ) leukemia and normal hematopoietic stem and progenitor cells were detected by flow cytometry using fluorochrome-conjugated anti-Lin, anti-CD34, and anti-CD38 antibodies (BD Pharmingen), as described previously. 10,14 Cell viability was determined by Trypan blue exclusion. Cell death and g-H2AX were measured by flow cytometry using Fixable Viability Dye eFluor 660 (eBioscience) and Alexa Fluor 488 Mouse anti-H2AX (phosphoserine 139) (BD Pharmingen) as described before.…”

The Choice of First-Line Chronic Myelogenous Leukemia Treatment

“…In the IRIS study, patients with low-, intermediate-, or high-risk Sokal's score showed significantly different response rates as 5-year CCyR (89, 82, and 69 %, respectively: P<0.001) and progression to advanced disease (3,8, and 17 %, respectively: P=0.002) [1].…”