Clonal evolution including partial loss of human leukocyte antigen genes favoring extramedullary acute myeloid leukemia relapse after matched related allogeneic hematopoietic stem cell transplantation.
BACKGROUND
Relapse of acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT) leaves few therapeutic options, and mechanisms of immune escape of recurring leukemic cells remain poorly understood. Recently, acquired loss of mismatched human leukocyte antigen (HLA) was demonstrated in patients with AML undergoing haploidentical allogeneic HSCT and was suggested not to occur in HLA-matched HSCT. We hypothesized that this mechanism applies to extramedullary AML relapse which occurs frequently after allogeneic HSCT and might also not be restricted to haploidentical HSCT.


METHODS
DNA from extramedullary AML relapse after HSCT was compared with bone marrow at diagnosis with array comparative genomic hybridization to investigate relapse-specific genomic aberrations in relapsing AML after allogeneic HSCT. Formalin-fixed, paraffin-embedded tissues from the same points of time were assessed for HLA, major histocompatibility complex class I chain-related gene A, and TAP2 immunohistochemistry staining to assess cell surface expression of deleted loci encoded on chromosome 6p.


RESULTS
Array comparative genomic hybridization revealed a partial loss of chromosome 6p in extramedullary myeloid sarcoma relapse of AML after sustained complete remission was achieved through matched related allogeneic HSCT. Among others, a deleted region 6p21.32-p21.33, which included several HLA class I genes, was detected.


CONCLUSIONS
These results suggest that the loss of HLA class I haplotype also occurs in AML relapse after HLA-matched related HSCT. Partial loss of several HLA class I genes and subsequent reduced presentation of minor histocompatibility antigens and reduced ligation of activating natural killer-cell receptors may explain the loss of graft-versus-leukemia response and extramedullary AML relapse in tissue with reduced immunologic surveillance.
Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus, Dresden, Germany. friedrich.stoelzel@uniklinikum-dresden.de
Friedrich
F
Stölzel
Karl
K
Hackmann
Friederike
F
Kuithan
Brigitte
B
Mohr
Monika
M
Füssel
Uta
U
Oelschlägel
Christian
C
Thiede
Christoph
C
Röllig
Uwe
U
Platzbecker
Johannes
J
Schetelig
Thomas
T
Illmer
Markus
M
Schaich
Barbara
B
Seliger
Arndt
A
Hartmann
Gustavo
G
Baretton
Christian
C
Zietz
Gerhard
G
Ehninger
Evelin
E
Schrock
Martin
M
Bornhäuser
D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000032:analysis; D000328:Adult; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D001706:Biopsy; D001943:Breast Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D060965:Clonal Evolution / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D020544:Graft vs Leukemia Effect / Q000235:genetics; D006680:HLA Antigens / Q000235:genetics*; D006239:Haplotypes; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D015395:Histocompatibility Antigens Class I / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000601:surgery*; D018570:Risk Assessment; D012307:Risk Factors; D023981:Sarcoma, Myeloid / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D013997:Time Factors; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D019139:Tumor Escape / Q000235:genetics*
D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D014408:Biomarkers, Tumor; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; C099187:MHC class I-related chain A; C071692:TAP2 protein, human