Back to Search Start Over

Recurrent genetic HLA loss in AML relapsed after matched unrelated allogeneic hematopoietic cell transplantation

Authors :
Samantha D. Drinan
Jerome Ritz
William J. Lane
Scott Leppanen
Aaron R. Thorner
Vincent T. Ho
Benjamin L. Ebert
Robert J. Soiffer
Elizabeth A. Morgan
Max Jan
Jonathan Stevens
Natasha Kekre
Sarah Nikiforow
Anwesha Nag
Corey Cutler
Matthew D. Ducar
Jordan Wengrod
Joseph H. Antin
Jane Baronas
Edwin P. Alyea
Bruce M. Wollison
John Koreth
Matthew Leventhal
R. Coleman Lindsley
Source :
Blood Advances. 3:2199-2204
Publication Year :
2019
Publisher :
American Society of Hematology, 2019.

Abstract

Immune evasion is a hallmark of cancer and a central mechanism underlying acquired resistance to immune therapy. In allogeneic hematopoietic cell transplantation (alloHCT), late relapses can arise after prolonged alloreactive T-cell control, but the molecular mechanisms of immune escape remain unclear. To identify mechanisms of immune evasion, we performed a genetic analysis of serial samples from 25 patients with myeloid malignancies who relapsed ≥1 year after alloHCT. Using targeted sequencing and microarray analysis to determine HLA allele-specific copy number, we identified copy-neutral loss of heterozygosity events and focal deletions spanning class 1 HLA genes in 2 of 12 recipients of matched unrelated-donor HCT and in 1 of 4 recipients of mismatched unrelated-donor HCT. Relapsed clones, although highly related to their antecedent pretransplantation malignancies, frequently acquired additional mutations in transcription factors and mitogenic signaling genes. Previously, the study of relapse after haploidentical HCT established the paradigm of immune evasion via loss of mismatched HLA. Here, in the context of matched unrelated-donor HCT, HLA loss provides genetic evidence that allogeneic immune recognition may be mediated by minor histocompatibility antigens and suggests opportunities for novel immunologic approaches for relapse prevention.

Details

ISSN :
24739537 and 24739529
Volume :
3
Database :
OpenAIRE
Journal :
Blood Advances
Accession number :
edsair.doi.dedup.....f1604f60ff97a044e9c14b0f5c87394d
Full Text :
https://doi.org/10.1182/bloodadvances.2019000445