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Active Rac1-Mediated Bone Marrow Retention Enhances CD33 CAR-T Cell Efficacy Against CD33+ Leukemia Cells.

Shangshang Wang1,2, Le Li1,2, Haiyan Xing1,2

  • 1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|April 10, 2026
PubMed
Summary
This summary is machine-generated.

Engineering T cells with active Rac1 enhances their ability to target and eliminate chemo-resistant acute myeloid leukemia (AML) cells within the bone marrow, improving therapeutic outcomes.

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Area of Science:

  • Immunology
  • Cell Biology
  • Oncology

Background:

  • The bone marrow (BM) niche protects leukemia cells, causing therapeutic resistance and relapse in acute myeloid leukemia (AML).
  • This microenvironment hinders T cell infiltration, limiting CAR-T therapy efficacy in myeloid malignancies.

Purpose of the Study:

  • To enhance T cell migration and anti-leukemia activity in the bone marrow by engineering T cells to express constitutively active Rac1 (Rac1V12).

Main Methods:

  • Primary human T cells and CD33 CAR-T cells were engineered to express Rac1V12.
  • In vitro cytotoxicity assays and in vivo xenograft models were used to evaluate efficacy.
  • Immunological memory phenotype and tonic signaling were assessed mechanistically.

Main Results:

  • Rac1V12 expression enhanced T cell and CD33 CAR-T cell migration and bone marrow residence in vivo.
  • Engineered CAR-T cells showed increased cytotoxicity against leukemia cells in vitro and superior leukemia suppression in vivo.
  • Rac1V12 CAR-T cells exhibited an enhanced memory phenotype and reduced tonic signaling, promoting persistence and anti-tumor efficacy.

Conclusions:

  • Active Rac1-engineered CD33 CAR-T cells offer a promising strategy for targeting bone marrow leukemia.
  • This approach has the potential to eradicate acute myeloid leukemia cells and overcome therapeutic resistance.