In an effort to develop pharmacological inhibition of the TMIGD2 oncogenic signaling pathway in AML, we generated distinct anti-TMIGD2 mAbs, which provided therapeutic effect in AML patient-derived xenograft (PDX) models of refractory/relapsed AML without derailing normal hematopoiesis, and simultaneously maintained HHLA2/TMIGD2-mediated co-stimulatory signaling on T and NK cells. The gene discussed is HHLA2; the disease is acute myeloid leukemia.