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

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.

Nilotinib‐induced bone marrow CD34+/lin‐Ph+ cells early clearance in newly diagnosed CP‐Chronic Myeloid Leukemia: Final report of the PhilosoPhi34 study

“…Afterward, we performed GEP analysis of BM CD34+/lin− cells of 79 pts at diagnosis vs the same pts after 12 months of treatment vs 10 CTRLs. We demonstrated the over‐expression of genes involved in the cell cycle and mitosis (n = 34), genes belonging to the JAK‐STAT signaling pathway ( SOS1, PIK3CA, IL7, JAK2, STAM, and PTPN11 ), and the ABC transporter gene ABCD3 at diagnosis vs 12 months of Nilotinib vs CRTLs 28 …”

Abnormal expression of ABCD3 is an independent prognostic factor for colorectal cancer

“…At present, there are only a few studies on the role and underlying mechanism of ABCD3 in tumors, such as prostate tumor (16), ovarian cancer (15,17), colon cancer (14), chronic myeloid leukemia (25), melanoma (26) and retinoblastoma (27). However, the aforementioned studies only investigated the difference of ABCD3 mRNA or protein expression in tumors.…”

TCF7 knockdown inhibits the imatinib resistance of chronic myeloid leukemia K562/G01 cells by neutralizing the Wnt/β‑catenin/TCF7/ABC transporter signaling axis

“…Interestingly, a recent study by Trojani et al ( 51 ) demonstrated that long-term use of second-generation TKI (nilotinib) in CML patients can induce the upregulation of ABC transporters (ABCC4, ABCC5, ABCD3) in bone marrow CD34 + /lin − cells. Another independent study by Mehrvar et al ( 52 ) demonstrated the changes in expression pattern of ABCC transporters in peripheral blood leukocytes of patients with acute lymphoblastic leukemia (ALL) recurrence.…”