Immunotherapy-resistant acute lymphoblastic leukemia cells exhibit reduced CD19 and CD22 expression and BTK pathway dependency

被引：6

作者：

Aminov, Sarah ^{[1
]}

Giricz, Orsi ^{[1
]}

Melnekoff, David T. ^{[2
]}

Sica, R. Alejandro ^{[1
]}

Polishchuk, Veronika ^{[1
]}

Papazoglu, Cristian ^{[1
]}

Yates, Bonnie ^{[3
]}

Wang, Hao-Wei ^{[4
]}

Sahu, Srabani ^{[1
]}

Wang, Yanhua ^{[5
]}

Gordon-Mitchell, Shanisha ^{[1
]}

Leshchenko, Violetta V. ^{[2
]}

Schinke, Carolina ^{[1
]}

Pradhan, Kith ^{[1
]}

Aluri, Srinivas ^{[1
]}

Sohn, Moah ^{[2
]}

Barta, Stefan K. ^{[6
]}

Agarwal, Beamon ^{[7
]}

Goldfinger, Mendel ^{[1
]}

Mantzaris, Ioannis ^{[1
]}

Shastri, Aditi ^{[1
]}

Matsui, William ^{[8
]}

Steidl, Ulrich ^{[1
]}

Brody, Joshua D. ^{[2
,11
]}

Shah, Nirali N. ^{[3
,12
]}

Parekh, Samir ^{[2
,10
]}

Verma, Amit ^{[1
,9
]}

机构：

[1] Montefiore Einstein Comprehens Canc Ctr, Blood Canc Inst, Dept Oncol, Bronx, NY USA

[2] Icahn Sch Med Mt Sinai, Hematol & Med Oncol, New York, NY USA

[3] NCI, Ctr Canc Res, Pediat Oncol Branch, Bethesda, MD USA

[4] NCI, Lab Pathol, Ctr Canc Res, Bethesda, MD USA

[5] Albert Einstein Coll Med, Dept Pathol, Bronx, NY USA

[6] Hosp Univ Penn, Dept Med, Div Hematol Oncol, Philadelphia, PA USA

[7] GenomeRxUS LLC, Philadelphia, PA USA

[8] Univ Texas Austin, Dell Med Sch, Dept Oncol, Austin, TX USA

[9] Albert Einstein Coll Med, Dept Oncol, 1300 Morris Pk Ave,Chanin Bldg,Room 302B, Bronx, NY 10461 USA

[10] Icahn Sch Med Mt Sinai, Dept Hematol & Med Oncol, 1470 Madison Ave,5th Floor, New York, NY 10029 USA

[11] Icahn Sch Med Mt Sinai, Dept Hematol & Med Oncol, 1470 Madison Ave,3rd Floor, New York, NY 10029 USA

[12] NCI, Pediat Oncol Branch, NCI Bldg 10 CRC,Room 1,Room 1 5752, Bethesda, MD 20814 USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2024年 / 134卷 / 08期

关键词：

CAR T-CELLS; ANTI-CD19; STEM;

D O I：

10.1172/JCI175199

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

While therapies targeting CD19 by antibodies, chimeric antigen receptor T cells (CAR -T), and T cell engagers have improved the response rates in B cell malignancies, the emergence of resistant cell populations with low CD19 expression can lead to relapsed disease. We developed an in vitro model of adaptive resistance facilitated by chronic exposure of leukemia cells to a CD19 immunotoxin. Single -cell RNA-Seq (scRNA-Seq) showed an increase in transcriptionally distinct CD19lo populations among resistant cells. Mass cytometry demonstrated that CD22 was also decreased in these CD19lo-resistant cells. An assay for transposase-accessible chromatin with sequencing (ATAC-Seq) showed decreased chromatin accessibility at promoters of both CD19 and CD22 in the resistant cell populations. Combined loss of both CD19 and CD22 antigens was validated in samples from pediatric and young adult patients with B cell acute lymphoblastic leukemia (B -ALL) that relapsed after CD19 CAR-T-targeted therapy. Functionally, resistant cells were characterized by slower growth and lower basal levels of MEK activation. CD19lo resistant cells exhibited preserved B cell receptor signaling and were more sensitive to both Bruton's tyrosine kinase (BTK) and MEK inhibition. These data demonstrate that resistance to CD19 immunotherapies can result in decreased expression of both CD19 and CD22 and can result in dependency on BTK pathways.

引用

页数：10

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