2003 – MHC II-MEDIATED CD4 T CELL ENGAGEMENT OVERCOMES THE DIFFERENTIATION BLOCK IN ACUTE MYELOID LEUKEMIA

Abstract

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by a block in differentiation and the accumulation of immature leukemic blasts. Current therapies mainly rely on eliminating these cells, rather than restoring normal differentiation. In acute promyelocytic leukemia (APL), differentiation therapy has markedly improved outcomes by directly overcoming the differentiation block. However, these approaches remain limited to a small subset of patients, underscoring the need for novel strategies that restore differentiation across AML subtypes. Building on our findings that MHC class II-mediated antigen presentation by hematopoietic stem and progenitor cells can engage CD4⁺ T cells to induce stem cell differentiation (Hernández-Malmierca et al (2022), Cell Stem Cell), we investigated whether this mechanism can be leveraged to overcome the differentiation block in AML. Using a diverse panel of AML cell lines, we show that enforced interaction between CD4⁺ T cells and leukemic blasts via a crosslinking strategy induces differentiation in multiple AML subtypes. Notably, CD4⁺ T cell engagement elicits context-dependent and heterogeneous T cell states, which are linked to differences in leukemic cell differentiation and survival, suggesting that the qualitative nature of the CD4⁺ T cell response shapes therapeutic outcome. Mechanistically, our data support a multilayered mode of action in which CD4⁺ T cells exert antileukemic effects through direct cell–cell interactions and soluble factors. Finally, we validate MHC II-mediated crosslinking-induced differentiation in primary patient samples, showing that this mechanism is preserved in a physiologically relevant setting and highlighting its translational potential. These findings establish MHC II-mediated CD4⁺ T cell engagement as a promising strategy to overcome the differentiation block in AML.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by a block in differentiation and the accumulation of immature leukemic blasts. Current therapies mainly rely on eliminating these cells, rather than restoring normal differentiation. In acute promyelocytic leukemia (APL), differentiation therapy has markedly improved outcomes by directly overcoming the differentiation block. However, these approaches remain limited to a small subset of patients, underscoring the need for novel strategies that restore differentiation across AML subtypes. Building on our findings that MHC class II-mediated antigen presentation by hematopoietic stem and progenitor cells can engage CD4⁺ T cells to induce stem cell differentiation (Hernández-Malmierca et al (2022), Cell Stem Cell), we investigated whether this mechanism can be leveraged to overcome the differentiation block in AML. Using a diverse panel of AML cell lines, we show that enforced interaction between CD4⁺ T cells and leukemic blasts via a crosslinking strategy induces differentiation in multiple AML subtypes. Notably, CD4⁺ T cell engagement elicits context-dependent and heterogeneous T cell states, which are linked to differences in leukemic cell differentiation and survival, suggesting that the qualitative nature of the CD4⁺ T cell response shapes therapeutic outcome. Mechanistically, our data support a multilayered mode of action in which CD4⁺ T cells exert antileukemic effects through direct cell–cell interactions and soluble factors. Finally, we validate MHC II-mediated crosslinking-induced differentiation in primary patient samples, showing that this mechanism is preserved in a physiologically relevant setting and highlighting its translational potential. These findings establish MHC II-mediated CD4⁺ T cell engagement as a promising strategy to overcome the differentiation block in AML.