ABL1 (ABL proto-oncogene 1)

Notably, genetic or pharmacological inhibition of PELI1 effectively suppresses the proliferation of both tyrosine kinase inhibitors (TKIs)-sensitive and TKI-resistant CML cells, as well as Leukemia stem cells (LSCs), which consequently ameliorates the disease burden and progression of CML. Collectively, our findings demonstrated that targeting PELI1 is a promising therapeutic strategy for CML that can overcome TKI resistance and eliminates LSCs.

P2, N=17, Active, not recruiting, Baylor College of Medicine | N=100 --> 17 | Recruiting --> Active, not recruiting

BCR::ABL1 e6a3 demonstrated enhanced sensitivity to active-state selective inhibitors dasatinib and bosutinib, whereas BCR::ABL1 e6a3/T315I remained resistant. These data show that treatment with asciminib and ponatinib can select for mutations with notably elevated enzymatic activity, effectively targeted by an axitinib-based triple combination. These data highlight the remarkable mutability of the BCR::ABL1 kinase, including through novel isoforms and provides a strong rationale for the clinical assessment of a triple inhibitor combination as a strategy to overcome resistance to dual ponatinib and asciminib therapy.

By comparison, mechanistic learning achieves comparable or improved combination scores for BCR::ABL1-positive and MRD-positive disease, with scores of 0.81 and 0.71, respectively, using only de-differentiation for BCR::ABL1 and primitive-state persistence together with differentiation-directed exit for MRD. Thus, the mechanistic-learning approach not only preserves predictive performance, but also provides a biological hypothesis for why stemness is predictive of these clinically relevant outcomes.

This led to development of tyrosine kinase inhibitors (TKIs) such as Imatinib, Nilotinib, and Ponatinib. Asciminib does not appear to induce a prothrombotic or proinflammatory state under the conditions studied, which may be advantageous for CML patients. However, the observed increase in thrombin generation over time suggests a potential effect on secondary haemostasis that warrants further investigation in controlled studies.

In this setting, Peg-IFN combined with nilotinib induced higher initial rates of MR4·5 compared to TKI monotherapy, despite additional side effects. The onset of psychiatric events might promote immediate cease of Peg-IFN and psychiatrist advice Whether this early molecular response translates into sustained treatment-free survival should be studied in a randomised trial sufficiently powered for this outcome.

P2, N=406, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2026 --> Mar 2027

It also focuses on bypass pathways, the B-cell/CLL lymphoma 2 family, tumor suppressor genes, microRNAs, and molecular chaperones as independent resistance mechanisms. Furthermore, the potential for combination therapies targeting these resistance mechanisms is discussed, anticipating further advances in research aimed at overcoming TKI resistance in CML.

While JAK2 V617F mutation was associated with distinct hematologic profiles, it was not independently linked to thrombotic risk. These findings highlight the significance of clinical comorbidities and hematologic parameters in thrombotic event occurrences in MPN patients.

Circulating CD34+CD38-h-MICL+ cells represent a promising biomarker; their quantification may aid in subclassification, particularly in distinguishing prefibrotic MF from ET, and may serve as a potential target for future therapeutic strategies. Further validation in larger cohorts is warranted.

Collectively, these findings suggest that MUC3A P258S acts as a potential candidate biomarker of CML progression and influences therapeutic response, highlighting Capmatinib and related inhibitors as candidates for drug repurposing in hematological malignancies. To our knowledge, this is the first report implicating MUC3A in leukemia biology, extending its role beyond epithelial cancers.