What can PTEN expression tell us about CML progression? Free

The introduction of tyrosine kinase inhibitors (TKIs) has revolutionized the natural course of Chronic Myeloid Leukemia (CML), significantly reducing the risk of disease progression. However, even with the use of these agents, a subset of patients fails to achieve the key milestones considered essential for an optimal response, as defined by the European LeukemiaNet (ELN), which remains an ongoing challenge for hematologists.

Although the BCR-ABL1 protein is the main pathogenic driver of CML, other molecular pathways may also contribute to TKI resistance and disease progression. Among these, the PI3K/AKT/mTOR signaling pathway stands out as a highly conserved network in eukaryotic cells, involved in promoting cell survival, growth, and cell cycle progression. Alterations in components of this pathway have been widely associated with therapeutic resistance and tumor progression in various types of cancer, with the PTEN gene acting as a key negative regulator of this signaling axis. PTEN activity relies, specially, on its capacity to maintain a finely tuned balance of PIP3 levels, thereby restraining aberrant cell growth and proliferation.

In this study, PTEN gene expression was evaluated in CML patients at different disease stages: chronic phase at diagnosis without progression (CP), chronic phase at diagnosis with progression (CPp), and blast crisis (BC). A total of 84 samples were analyzed: 51 from CP patients, 12 paired samples collected at CP (CPp) and at progression to BC from the same patients, and 9 additional samples from BC cases, totaling 21 BC samples. The median age was 46 years (range: 26–75 years). Laboratory parameters were as follows: hemoglobin (g/dL): 11.2 (4.53–16.2); white blood cells (×10³/mm³): 113.65 (11.2–499.3); platelets (×10³/mm³): 334 (90–1,500); and basophils (×10³/mm³): 2.85 (0–30.9). Regarding BCR-ABL1 transcripts, 29 patients expressed e13a2, 49 expressed e14a2, and 6 expressed both transcripts. All patients were treated with imatinib mesylate as first-line therapy, all CP patients remained in molecular response throughout the entire follow-up period (from 2005 to 2020) and the average time to progression of CB patients was 517 days.

Gene expression quantification was performed by RT-qPCR using pre-designed TaqMan assays (Thermo Fisher, USA): hs00910358_s1 for PTEN and Hs01104728_m1 for ABL1, used as the reference gene. The analysis was conducted using the 2^–ΔCt method, and comparisons between groups were performed using the Wilcoxon Rank Sum test. Results were expressed as fold change.

A significant reduction in PTEN gene expression was observed in patients in blast crisis compared to those in chronic phase without progression (fold change: 0.34; p < 0.0001). However, when comparing BC and CPp groups, no statistically significant difference in PTEN expression was found (fold change: 1,06; p = 0.44).

Thus, reduced PTEN expression at diagnosis may contribute to evolution to blast crisis once uncontrolled cell proliferation and survival, may increase the genetic instability of leukemic cells, leading to the emergence of additional chromosomal abnormalities or mutations, both hallmarks of blast crisis, contributing to TKI resistance.

In conclusion, although the advent of TKIs has reduced the incidence of progression to blast crisis, evaluating PTEN gene expression at the diagnosis may serve as an additional tool to help guide patient management.