LAUSR

&NA; Failure to eradicate hematologic cancer stem cells (hCSCs) associated with resistance to tyrosine kinase inhibitors such as imatinib mesylate (IM) in chronic myeloid leukemia (CML) patients is a clinical challenge that highlights the need for discovering and developing therapeutic strategies that target and eliminate these hCSCs. Herein, we document the essential role of the interplay between histone deacetylases (HDACs), the polycomb group proteins, pluripotency transcription factors and the cell cycle machinery in the viability, oncogenicity and therapy evasion of IM‐resistant CD34+/CD38‐ CML stem cells (CML‐SCs). Using the proteotranscriptomic analyses of wild type (WT), CD34+/CD38+ and CD34+/CD38− K562 or KU812 cells, we showed that CD34+/CD38− SC‐enriched cells expressed significantly higher levels of CD44, CD133, SOX2, Nanog, OCT4, and c‐Myc mRNA and/or protein, compared to the WT or CD34+/CD38+ cells. This overexpression of stemness factors in the CD34+/CD38− cells positively correlates with enhanced expression of HDACs 1–6, cyclins D1/D3, CDK 2, 4 and 6, while inversely correlating with p18, p21 and p27. Enhanced co‐expression of MDR1, survivin, and Bcl‐2 proteins, supposedly involved in IM‐resistance and CML‐SC survival, was detected in both CD34+/CD38− and CD34+/CD38+ cells. Importantly, we demonstrate that in synergism with IM, SAHA reverses the tumor‐promoting proteotranscriptomic profile noted above and elicits marked inhibition of the CML‐SCs by up‐regulating hsa‐miR‐196a expression. This hsa‐miR‐196a‐mediated SC‐limiting effect of SAHA is dose‐dependent, low‐dosed, cell cycle‐modulating and accompanied by leukemic SC apoptosis. Interestingly, this anti‐SC therapeutic activity of SAHA in vitro was reproduced in vivo using the NOD‐SCID mice models. Graphical abstract Figure. No Caption available. Highlightshsa‐miR‐196a mediates inhibition of CML stem cells.Potentiate the anticancer effect of Imatinib mesylate by suberanilohydroxamic acid.Synergism with Imatinib mesylate and suberanilohydroxamic acid reverses the tumor‐promoting proteotranscriptomic profile.