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Continuous therapy response references for BCR::ABL1 monitoring in pediatric chronic myeloid leukemia.

ABSTRACT: Response to tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia (CML) is monitored by quantification of BCR::ABL1 transcript levels. Milestones for assessing optimal treatment response have been defined in adult CML patients and are applied to children and adolescents although it is questionable whether transferability to pediatric patients is appropriate regarding genetic and clinical differences. Therefore, we analyzed the molecular response kinetics to TKI therapy in 129 pediatric CML patients and investigated whether response assessment based on continuous references can support an early individual therapy adjustment. We applied a moving quantiles approach to establish a high-resolution response target curve and contrasted the median responses in all patients with the median of the ideal target curve obtained from a subgroup of optimal responders. The high-resolution response target curve of the optimal responder group presents a valuable tool for continuous therapy monitoring of individual pediatric CML patients in addition to the fixed milestones. By further comparing BCR::ABL1 transcript levels with BCR::ABL1 fusion gene copy numbers, it is also possible to model the differential dynamics of BCR::ABL1 expression and cell number under therapy. The developed methodology can be transferred to other biomarkers for continuous therapy monitoring.

SUBMITTER: Volz C

PROVIDER: S-EPMC10598002 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Continuous therapy response references for BCR::ABL1 monitoring in pediatric chronic myeloid leukemia.

Volz Christian C Zerjatke Thomas T Gottschalk Andrea A Semper Sabine S Suttorp Meinolf M Glauche Ingmar I Krumbholz Manuela M Metzler Markus M

Scientific reports 20231024 1

Response to tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia (CML) is monitored by quantification of BCR::ABL1 transcript levels. Milestones for assessing optimal treatment response have been defined in adult CML patients and are applied to children and adolescents although it is questionable whether transferability to pediatric patients is appropriate regarding genetic and clinical differences. Therefore, we analyzed the molecular response kinetics to TKI therap ...[more]

PMID: 37875583

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Project description:Beta Catenin signaling is critical for the self-renewal of leukemic stem cells in chronic myeloid leukemia. It is driven by multiple events, enhancing beta catenin stability and promoting its transcriptional co-activating function. We investigated the impact of BCR-ABL1 on Chibby1, a beta catenin antagonist involved in cell differentiation and transformation. Relative proximity of the Chibby1 encoding gene (C22orf2) on chromosome 22q12 to the BCR breakpoint (22q11) lets assume its involvement in beta catenin activation in chronic myeloid leukemia as a consequence of deletions of distal BCR sequences encompassing one C22orf2 allele. Forty patients with chronic myeloid leukemia in chronic phase were analyzed for C22orf2 relocation and Chibby1 expression. Fluorescent in situ hybridization analyses established that the entire C22orf2 follows BCR regardless of chromosomes involved in the translocation. In differentiated hematopoietic progenitors (bone marrow mononuclear cell fractions) of 30/40 patients, the expression of Chibby1 protein was reduced below 50% of the reference value (peripheral blood mononuclear cell fractions of healthy persons). In such cell context, Chibby1 protein reduction is not dependent on C22orf2 transcriptional downmodulation; however, it is strictly dependent upon BCR-ABL1 expression because it was not observed at the moment of major molecular response under tyrosine kinase inhibitor therapy. Moreover, it was not correlated with the disease prognosis or response to therapy. Most importantly, a remarkable Chibby1 reduction was apparent in a putative BCR-ABL1+ leukemic stem cell compartment identified by a CD34+ phenotype compared to more differentiated hematopoietic progenitors. In CD34+ cells, Chibby1 reduction arises from transcriptional events and is driven by C22orf2 promoter hypermethylation. These results advance low Chibby1 expression associated with BCR-ABL1 as a component of beta catenin signaling in leukemic stem cells.

Project description:Although the use of ATP-competitive tyrosine kinase inhibitors of oncoprotein BCR-ABL1 has enabled durable responses in patients with chronic myeloid leukemia (CML), issues of drug resistance and residual leukemic stem cells remain. To test whether the degradation of BCR-ABL1 kinase could offer improved response, we developed a series of proteolysis-targeting chimera (PROTAC) that allosterically target BCR-ABL1 protein and recruit the E3 ligase Von Hippel-Lindau, resulting in ubiquitination and subsequent degradation of the oncogenic fusion protein. In both human CML K562 cells and murine Ba/F3 cells expressing BCR-ABL1, lead compound GMB-475 induced rapid proteasomal degradation and inhibition of downstream biomarkers, such as STAT5, and showed increased sensitivity compared with diastereomeric controls lacking degradation activity. Notably, GMB-475 inhibited the proliferation of certain clinically relevant BCR-ABL1 kinase domain point mutants and further sensitized Ba/F3 BCR-ABL1 cells to inhibition by imatinib, while demonstrating no toxicity toward Ba/F3 parental cells. Reverse phase protein array analysis suggested additional differences in levels of phosphorylated SHP2, GAB2, and SHC associated with BCR-ABL1 degradation. Importantly, GMB-475 reduced viability and increased apoptosis in primary CML CD34+ cells, with no effect on healthy CD34+ cells at identical concentrations. GMB-475 degraded BCR-ABL1 and reduced cell viability in primary CML stem cells. Together, these findings suggest that combined BCR-ABL1 kinase inhibition and protein degradation may represent a strategy to address BCR-ABL1-dependent drug resistance, and warrant further investigation into the eradication of persistent leukemic stem cells, which rely on neither the presence nor the activity of the BCR-ABL1 protein for survival. SIGNIFICANCE: Small-molecule-induced degradation of BCR-ABL1 in CML provides an advantage over inhibition and provides insights into CML stem cell biology. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/18/4744/F1.large.jpg.

Dataset Information

Continuous therapy response references for BCR::ABL1 monitoring in pediatric chronic myeloid leukemia.

Publications

Continuous therapy response references for BCR::ABL1 monitoring in pediatric chronic myeloid leukemia.

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