Abstract
Chronic myeloid leukemia (CML) is characterized by the constitutive tyrosine kinase activity of the oncoprotein BCR-ABL1 in myeloid progenitor cells that activates multiple signal transduction pathways leading to the leukemic phenotype. The tyrosine-kinase inhibitor (TKI) nilotinib inhibits the tyrosine kinase activity of BCR-ABL1 in CML patients. Despite the success of nilotinib treatment in patients with chronic-phase (CP) CML, a population of Philadelphia-positive (Ph+) quiescent stem cells escapes the drug activity and can lead to drug resistance. The molecular mechanism by which these quiescent cells remain insensitive is poorly understood. The aim of this study was to compare the gene expression profiling (GEP) of bone marrow (BM) CD34+/lin- cells from CP-CML patients at diagnosis and after 12 months of nilotinib treatment by microarray, in order to identify gene expression changes and the dysregulation of pathways due to nilotinib action. We selected BM CD34+/lin- cells from 78 CP-CML patients at diagnosis and after 12 months of first-line nilotinib therapy and microarray analysis was performed. GEP bioinformatic analyses identified 2,959 differently expressed probes and functional clustering determined some significantly enriched pathways between diagnosis and 12 months of nilotinib treatment. Among these pathways, we observed the under expression of 26 genes encoding proteins belonging to the cell cycle after 12 months of nilotinib treatment which led to the up-regulation of chromosome replication, cell proliferation, DNA replication, and DNA damage checkpoint at diagnosis. We demonstrated the under expression of the ATP-binding cassette (ABC) transporters ABCC4, ABCC5, and ABCD3 encoding proteins which pumped drugs out of the cells after 12 months of nilotinib. Moreover, GEP data demonstrated the deregulation of genes involved in the JAK-STAT signaling pathway. The down-regulation of JAK2, IL7, STAM, PIK3CA, PTPN11, RAF1, and SOS1 key genes after 12 months of nilotinib could demonstrate the up-regulation of cell cycle, proliferation and differentiation via MAPK and PI3K-AKT signaling pathways at diagnosis.
Highlights
Chronic myeloid leukemia (CML) results from unfaithful repaired DNA damage in a hematopoietic stem cell, but specific features of leukemic stem cells (LSCs) have not yet been fully understood
The differential expression analysis detected 2,959 probes differently expressed (DE) between 78 patients at diagnosis compared to 12 months of nilotinib treatment (S1 Table)
We previously demonstrated the over expression of ABCC5 at diagnosis vs. 12 months of nilotinib treatment in 30 CP-CML patients [18]
Summary
CML results from unfaithful repaired DNA damage in a hematopoietic stem cell, but specific features of leukemic stem cells (LSCs) have not yet been fully understood. Several studies demonstrated that LSCs show a strong resistance to therapies in TKI-treated CML patients due to their ability to activate specific signaling biological pathways [1]. Previous studies demonstrated that the aberrant regulation of pathways involved in the self-renewal of stem cells is implicated in cancer [3]. Identifying such pathways and trying to exploit them therapeutically is important to achieve CML-LSC eradication and disease cure [4]. Altered cell cycle checkpoints and a low intracellular concentration of TKIs are among those mechanisms that can lead to drug resistance in CML stem cells [5]
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