title: A molecular and functional analysis of large granular lymphocyte expansions in patients with chronic myelogenous leukemia treated with tyrosine kinase inhibitors.
abstract: Tyrosine kinase inhibitor (TKI) therapy has become the standard treatment for chronic myelogenous leukemia (CML). Off-target kinase inhibition has been implicated in the appearance of unique adverse effects, such as colitis and pleural effusions. In addition, some patients present oligoclonal expansions of large granular lymphocytes (LGLs). We sought to further investigate this phenomenon in 64 patients treated with five different TKIs. Clonal expansions of cytotoxic T lymphocytes (CTLs) were identified in all TKI-treated patient groups, but only in dasatinib-treated patients were these expansions characterized as LGLs. Survival factors known to be important in LGL leukemia (interleukin-15 [IL-15] transpresentation, plasma platelet-derived growth factor [PDGF]-BB levels, nuclear factor-κB [NF-κB] and T-bet activation) were found to be associated with TKI-induced LGL expansions. Interestingly, patients with LGL expansions had increased cytotoxicity against non-transformed endothelial cells, which may play a role in observed autoimmune-like side effects. Our results indicate that patients with CML treated with TKIs can develop T cell expansions, which can in certain cases be related to some adverse effects.
authors.affiliation: Department of Immunology and Experimental Therapeutics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Powers
authors.forename: Jason A
authors.initials: JA
authors.lastname: Dubovsky
authors.forename: P K
authors.initials: PK
authors.lastname: Epling-Burnette
authors.forename: Lynn
authors.initials: L
authors.lastname: Moscinski
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.forename: Satu
authors.initials: S
authors.lastname: Mustjoki
authors.forename: Eduardo M
authors.initials: EM
authors.lastname: Sotomayor
authors.forename: Javier A
authors.initials: JA
authors.lastname: Pinilla-Ibarz
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D020825:T-Box Domain Proteins / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000378:metabolism; D055815:Young Adult; D000098815:T-bet Transcription Factor
chemical_list: D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor