Updated project metadata. HSP90 inhibitors (HSP90i) have not entered routinely in the clinics, primarily due to the associated resistance via heat shock response (HSR) induction and dose limiting toxicity. In this study, we employed genetic KO and knockdown (KD) models of HSP90 isoforms (α and β) for extensive multi-omics-based in vitro and in vivo characterization and identified HSP90α as the primary driver of malignancy of the two isoforms in BCR-ABL1+ leukemia cells. Notably, combinatorial ex vivo drug sensitivity screenings identified CDK7 inhibitors (CDK7i) as drugs synergizing with HSP90α inhibition.Histone deacetylase 6 (HDAC6) has emerged as a promising therapeutic target in cancer due to its immunomodulatory effects. While its prognostic significance remains debated, we demonstrate that HDAC6 loss significantly impairs myeloid leukemia progression in vivo, despite having no functional impact on leukemia cell proliferation in vitro. Global proteome and secretome profiling of HDAC6-knockout (KO) cells revealed upregulation of several immune-related modulators.