[Molecular mechanisms in the resistance of CML stem cells to tyrosine kinase inhibitors and novel targets for achieving a cure].

Abstract

Tyrosine kinase inhibitors (TKIs) have dramatically improved the clinical outcomes of patients with chronic myeloid leukemia (CML) in the chronic phase. However, even if these patients achieve and maintain marked molecular responses such as a complete molecular response (BCR-ABL/ABL≤0.032% by international scale), discontinuation of TKI treatment results in early molecular relapse in most cases. Although several factors such as the Sokal score and the duration of TKI treatment have been identified as being related to treatment-free remission (TFR), identification of more definite factors or clinical conditions that would enable us to select patients who can maintain TFR is required. Relapse after TKI discontinuation is considered to be attributable to CML stem cells surviving even in patients who maintain marked molecular responses. A number of in vitro experiments have shown that TKI by itself cannot kill CML stem cells. Also, CML stem cells are resistant to TKI in a manner dependent on self-renewal factors (Hh, Wnt/β-catenin), cell cycle regulators (PML), metabotropic factors (FOXO3, Alox5), and adhesion molecules (CXCR4). In addition, surface markers specific for CML stem cells such as IL-1RAP and CD26 have been identified. New therapeutic strategies targeting these molecules in combination with TKI hold promise of achieving a more effective strategy for curing CML.

• Authors: Hirokazu Tanaka, Chikara Hirase, Itaru Matsumura
• Journal: [Rinsho ketsueki] The Japanese journal of clinical hematology (Rinsho Ketsueki) Vol. 56 Issue 2 Pg. 139-49 (Feb 2015) ISSN: 0485-1439 [Print] Japan
• PMID: 25765793 (Publication Type: English Abstract, Journal Article, Review)

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Drug Monitoring
• Drug Resistance, Neoplasm (drug effects)
• Humans
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy)
• Protein Kinase Inhibitors (therapeutic use)
• Stem Cells (metabolism)