Minor histocompatibility protein HMHA1 (HMHA1)

Minor histocompatibility protein HMHA1, also known as ARHGAP45, is a Rho GTPase-activating protein (RhoGAP) that regulates the actin cytoskeleton, cell spreading, and migration by inactivating Rho-family GTPases such as Rac1 and RhoA. It is characterized by its restricted expression in hematopoietic cells and its aberrant expression in various solid tumors, including breast and lung cancers, while remaining absent in normal non-hematopoietic tissues. This tissue-specific distribution makes HMHA1 a prime target for immunotherapy, particularly in allogeneic hematopoietic stem cell transplantation (SCT). The HA-1 antigen is a polymorphic peptide derived from HMHA1 and presented by HLA-A*02:01; a mismatch between a donor (HA-1 negative) and a recipient (HA-1 positive) can trigger a potent graft-versus-leukemia (GVL) effect. Therapeutic approaches under investigation include HA-1-specific TCR-engineered T-cell therapies (e.g., MDG1021, TSC-100) and peptide-based vaccines designed to eradicate residual leukemic cells or solid tumors. These strategies aim to exploit the lineage-restricted expression of HMHA1 to achieve tumor-specific killing while minimizing the risk of systemic toxicity or graft-versus-host disease.

Other names

ARHGAP45HA-1HLA-HA1Rho GTPase activating protein 45KIAA0223Histocompatibility (minor) HA-1

Adoptive T-cell therapy (TCR-T) or vaccination targeting the HA-1 peptide (VLHDDLLEA) presented by HLA-A*02:01 on the surface of hematopoietic and tumor cells to induce cytotoxic T-lymphocyte (CTL) mediated lysis and a graft-versus-leukemia (GVL) effect.