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Blood Adv DOI:10.1182/bloodadvances.2019000445

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

Publication TypeJournal Article
Year of Publication2019
AuthorsJan, M, Leventhal, MJ, Morgan, EA, Wengrod, JC, Nag, A, Drinan, SD, Wollison, BM, Ducar, MD, Thorner, AR, Leppanen, S, Baronas, J, Stevens, J, Lane, WJ, Kekre, N, Ho, VT, Koreth, J, Cutler, CS, Nikiforow, S, Alyea, EP, Antin, JH, Soiffer, RJ, Ritz, J, R Lindsley, C, Ebert, BL
JournalBlood Adv
Volume3
Issue14
Pages2199-2204
Date Published2019 Jul 23
ISSN2473-9537
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.

DOI10.1182/bloodadvances.2019000445
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/31324640?dopt=Abstract

Alternate JournalBlood Adv
PubMed ID31324640
PubMed Central IDPMC6650729
Grant ListP01 CA066996 / CA / NCI NIH HHS / United States
P50 CA206963 / CA / NCI NIH HHS / United States
R01 HL082945 / HL / NHLBI NIH HHS / United States