title: Correlation between deletion of the CDKN2 gene and tyrosine kinase inhibitor resistance in adult Philadelphia chromosome-positive acute lymphoblastic leukemia.
abstract: BACKGROUND
  Frequency relapses are common in Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL) following tyrosine kinase inhibitors (TKIs). CDKN2A/B is believed to contribute to this chemotherapy resistance.
  
  
  METHODS
  To further investigate the association between CDKN2 status and TKI resistance, the prevalence of CDKN2 deletions and its correlation with a variety of clinical features was assessed in 135 Ph-positive ALL patients using interphase fluorescence in situ hybridization (I-FISH).
  
  
  RESULTS
  Results showed that no difference occurred between patients with CDKN2 deletion (44/135) and wild-type patients in sex, age, and complete remission (CR) rate following induction chemotherapy combined with tyrosine kinase inhibitors (TKIs). However, CDKN2 deletion carriers demonstrated higher white blood cell (WBC) count, enhanced rates of hepatosplenomegaly (P = 0.006), and upregulation of CD20 expression (P = 0.001). Moreover, deletions of CDKN2 resulted in lower rates of complete molecular response (undetectable BCR/ABL), increased cumulative incidence of relapse, short overall survival (OS), and disease-free survival (DFS) time (P < 0.05) even though these patients received chemotherapy plus TKIs followed by allogenic hematopoietic stem cell transplantation (Allo-HSCT). In the case of 44 patients who presented with CDKN2 deletion, 18 patients were treated with dasatinib treatment, and another 26 patients were treated with imatinib therapy, and our study found that there were no differences associated with OS (P = 0.508) and DFS (P = 0.555) between the two groups.
  
  
  CONCLUSIONS
  CDKN2 deletion is frequently acquired during Ph-positive ALL progression and serves as a poor prognostic marker of long-term outcome in Ph-positive ALL patients with CDKN2 deletion even after the second-generation tyrosine kinase inhibitor treatment.
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors.forename: Na
authors.initials: N
authors.lastname: Xu
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors.forename: Yu-ling
authors.initials: YL
authors.lastname: Li
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Cao
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors.forename: Zi-yuan
authors.initials: ZY
authors.lastname: Lu
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors.forename: Ji-xian
authors.initials: JX
authors.lastname: Huang
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors.forename: Zhi-ping
authors.initials: ZP
authors.lastname: Fan
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors.forename: Fen
authors.initials: F
authors.lastname: Huang
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors.forename: Hong-sheng
authors.initials: HS
authors.lastname: Zhou
authors.affiliation: Guangzhou Air Force Headquarters Hospital, No. 475, Huanshi East Road, Yuexiu District, Guangzhou, 510071, China.
authors.forename: Song
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Hematology, The Second People's Hospital of Guangdong Province, Guangzhou, 510317, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Hematology, Hospital of Guizhou Province, Guizhou, 550002, China.
authors.forename: Hong-qian
authors.initials: HQ
authors.lastname: Zhu
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors.forename: Qi-fa
authors.initials: QF
authors.lastname: Liu
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. doctorliuxiaoli@yeah.net.
authors.forename: Xiao-li
authors.initials: XL
authors.lastname: Liu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018951:Antigens, CD20 / Q000235:genetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D003131:Combined Modality Therapy; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D000069439:Dasatinib / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D015973:Gene Expression Regulation, Leukemic; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000628:therapy; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014184:Transplantation, Homologous; D055815:Young Adult
chemical_list: D018951:Antigens, CD20; C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; D000069439:Dasatinib
keywords: Acute lymphoblastic leukemia; CD20; CDKN2; Deletion; Philadelphia chromosome; Tyrosine kinase inhibitors