期刊
BLOOD
卷 140, 期 1, 页码 38-44出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2021014840
关键词
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资金
- European Research Council [CoG-2014-646903, PoC-2018-811220]
- Spanish Ministry of Economy and Competitiveness [SAF2016-80481R, PID2019-108160RB-I00]
- ISCIII (ISCIII/FEDER) [PI17/01028, PI20/00822]
- Spanish Association against Cancer (AECC)
- FERO Foundation
- ISCIII-RICORS within the Next Generation EU program (Plan de Recuperacion, Transformacion y Resiliencia)
- Cancer Research UK
- Children and Young People's Cancer Innovation Award [DRCPGM\100058]
- Wellcome Trust Clinical Research Career Development Fellowship [216632/Z/19/Z]
- ISCIII [PI19/011183]
- AGAUR/Generalitat de Catalunya [SGR288]
- MRC Discovery award [MRCDA 0816-11]
- MRC [MR/M00919X/1]
- Joint MRC/Wellcome Trust [MR/R006237/1]
- MRC WIMM Single Cell Facility
- Wellcome Trust [216632/Z/19/Z] Funding Source: Wellcome Trust
CD19-directed immunotherapies have greatly improved the treatment of B-cell acute lymphoblastic leukemia (B-ALL). However, many patients still experience relapse. This study reveals the presence of pre-leukemic CD34(+)CD19(-)CD22(+) cells, which may contribute to phenotypic escape after CD19-directed immunotherapies.
CD19-directed immunotherapies have revolutionized the treatment of advanced B-cell acute lymphoblastic leukemia (B-ALL). Despite initial impressive rates of complete remission (CR) many patients ultimately relapse. Patients with B-ALL successfully treated with CD19-directed T cells eventually relapse, which, coupled with the early onset of CD22 expression during B-cell development, suggests that preexisting CD34(+)CD22(+)CD19(-) (pre)-leukemic cells represent an early progenitor origin-related mechanism underlying phenotypic escape to CD19-directed immunotherapies. We demonstrate that CD22 expression precedes CD19 expression during B-cell development. CD34(+)CD19(-)CD22(+) cells are found in diagnostic and relapsed bone marrow samples of similar to 70% of patients with B-ALL, and their frequency increases twofold in patients with B-ALL in CR after CD19 CAR T-cell therapy. The median of CD34(+)CD19(-)CD22(+) cells before treatment was threefold higher in patients in whom B-ALL relapsed after CD19-directed immunotherapy (median follow-up, 24 months). Fluorescence in situ hybridization analysis in flow-sorted cell populations and xenograft modeling revealed that CD34(+)CD19(-)CD22(+) cells harbor the genetic abnormalities present at diagnosis and initiate leukemogenesis in vivo. Our data suggest that preleukemic CD34(+)CD19(-)CD22(+) progenitors underlie phenotypic escape after CD19-directed immunotherapies and reinforce ongoing clinical studies aimed at CD19/CD22 dual targeting as a strategy for reducing CD19(-) relapses. The implementation of CD34/CD19/CD22 immunophenotyping in clinical laboratories for initial diagnosis and subsequent monitoring of patients with B-ALL during CD19-targeted therapy is encouraged.
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