Table 1.

 The biology and TKI‐resistance in CML stem cells based on mouse genetic studies

Disrupted molecule	CML stem cells	Inhibitor	Possible combined therapy	Reference
Pml	Defective ability of CML stem cells to develop CML at third transplantation	Arsenic trioxide	Arsenic trioxide and Ara‐C improve survival of CML‐affected mice	12
β‐Catenin	Defective ability of CML stem cells to develop CML at second transplantation	–	–	11
Alox5	Defective ability of CML stem cells to develop CML at second transplantation	Zileuton	Zileuton and imatinib improve survival of CML‐affected mice	45
Smo	Impairment of development of CML and depletion of CML stem cells	Cyclopamin	Cyclopamin and nilotinib prolong survival of CML‐affected mice	13, 21
Foxo3a	Defective ability of CML stem cells to develop CML at third transplantation	TGF‐β inhibitor	TGF‐β inhibitor and imatinib improve survival of CML‐affected mice, and suppress infiltration of CML cells in lung	14

Arsenic trioxide can reduce PML expression. Zileuton is an inhibitor of 5‐lipoxygenase. Cyclopamin stabilizes Smo in an inactive form. TGF‐β inhibitor suppresses TGF‐β–Foxo signaling. Alox5, arachidonate 5‐lipoxygenase; CML, chronic myeloid leukemia; Foxo3a, forkhead box class O 3a; PML, promyelocytic leukemia; TGF‐β, transforming growth factor‐β.