Differential genomics and transcriptomics between tyrosine kinase inhibitor-sensitive and -resistant BCR-ABL-dependent chronic myeloid leukemia

Abstract

Previously, it has been stated that the BCR-ABL fusion-protein is sufficient to induce Chronic Myeloid Leukemia (CML), but additional genomic-changes are required for disease progression. Hence, we profiled control and tyrosine kinase inhibitors (TKI) alone or in combination with other drug-treated CML-samples in different phases, categorized as drug-sensitive and drug-resistant on the basis of BCR-ABL transcripts, the marker of major molecular-response. Molecular-profiling was done using the molecular-inversion probe-based-array, Human Transcriptomics-Array2.0, and Axiom-Biobank genotyping-arrays. At the transcript-level, clusters of control, TKI-resistant and TKI-sensitive cases were correlated with BCR-ABL transcript-levels. Both at the gene- and exon-levels, up-regulation of MPO, TPX2, and TYMS and down-regulation of STAT6, FOS, TGFBR2, and ITK lead up-regulation of the cell-cycle, DNA-replication, DNA-repair pathways and down-regulation of the immune-system, chemokine- and interleukin-signaling, TCR, TGF beta and MAPK signaling pathways. A comparison between TKI-sensitive and TKI-resistant cases revealed up-regulation of LAPTM4B, HLTF, PIEZO2, CFH, CD109, ANGPT1 in CML-resistant cases, leading to up-regulation of autophagy-, protein-ubiquitination-, stem-cell-, complement-, TGFβ- and homeostasis-pathways with specific involvement of the Tie2 and Basigin signaling-pathway. Dysregulated pathways were accompanied with low CNVs in CP-new and CP-UT-TKI-sensitive-cases with undetectable BCR-ABL-copies. High CNVs (previously reported gain of 9q34) were observed in BCR-ABL-independent and -dependent TKI, non-sensitive-CP-UT/AP-UT/B-UT and B-new samples. Further, genotyping CML-CP-UT cases with BCR-ABL 0-to-77.02%-copies, the identified, rsID239798 and rsID9475077, were associated with FAM83B, a candidate for therapeutic resistance. The presence of BCR-ABL, additional genetic-events, dysregulated-signaling-pathways and rsIDs associated with FAM83B in TKI-resistant-cases can be used to develop a signature-profile that may help in monitoring therapy.

Nilotinib interferes with cell cycle, ABC transporters and JAK-STAT signaling pathway in CD34+/lin- cells of patients with chronic phase chronic myeloid leukemia after 12 months of treatment

“…Gene expression profiling studies have been performed to identify biomarkers predictive of TKI failure [14–16]. In particular, analyses on CML CD34+ cells have revealed that some pathways were consistently deregulated in TKI non-responding patients [1].…”

Knockdown of ribonucleotide reductase regulatory subunit M2 increases the drug sensitivity of chronic myeloid leukemia to imatinib‑based therapy

“…It was also demonstrated that RRM2 may affect the cell survival via the Bcl-2/caspase cell apoptotic pathway and the Akt cell signaling pathway in imatinib therapy. It is noteworthy that different CML phases (chronic phase or accelerated phase) probably affect the level of a certain carcinoma biomarker (39), however, this was not taken into consideration in the present study. Therefore, to gain deeper insight into the predictive value of RRM2 for IR, a larger sample size and a more detailed sample classification are still needed in subsequent investigations.…”

<p>Comprehensive Characterization of Stage IIIA Non-Small Cell Lung Carcinoma</p>

“…RNA isolation was done as reported earlier. 12 The Ct value of investigated gene transcripts (SPP1, CDH2, and RIMS2) was measured on 7500 fast Dx Real-Time PCR instruments (Applied Bioscience inc.). Every gene was tested in triplicate for all RNA samples in a single run.…”