Table I.

Deregulated microRNA (miRNA) expression in chronic myeloid leukemia.

miRNAs	Cell type	Mechanism	mRNA targets	Notes	BCR–ABL1 kinase-dependent?
miR-203 is down-regulated in Ph1 cells [102]	Primary Ph1 B-ALL and CML cells, K562, KCL-22	Promoter methylation	c-ABL, BCR–ABL1	Loss of miR-203 leads to increased levels of BCR–ABL1	Heavy methylation in BCR–ABL1-expressing cells
miR-7, miR-23a, miR-26a, miR-29a, miR-29c, miR-30b, miR-30c, miR-100, miR-126#, miR-134, miR-141, miR-183, miR-196b, miR-199a, miR-224, miR-326, miR-422b, and miR-520a are down-regulated in IM-resistant patients; miR-191 is up-regulated [110]	BM MNCs from IM-sensitive and -insensitive patients; none presented common mutations associated with resistance to IM (e.g. T315I, Y253H, Y253F, E225K, and E255V)	Unidentified	Predicted ABCC5 (miR-199a), ABCA1 (miR-183), and ABCB6 (miR-29c), members of the ATP binding cassette (ABC) family of transmembrane transporters that have been implicated in resistance to chemotherapy	Study implicates these miRNAs in resistance to IM	Without the presence of common mutations associated with resistance to IM, it is likely that these patients have higher levels of BCR–ABL1 kinase activity; therefore, the deregulation of these miRNAs between IM-sensitive and -insensitive patients is likely BCR–ABL1-dependent
let-7 family members are down-regulated in CML-BC [116]	Peripheral blood MNCs from paired patients with CML-CP and CML-BC, K562, LAMA-84	Increased expression of Lin28	c-MYC, K-Ras	Increased proliferation resulting from higher levels of c-MYC and K-Ras	BCR–ABL1 dependence suggested by increased levels of Lin28 being present in CML-BC, presumably where BCR–ABL1 activity is higher
miR-328 is down-regulated in CML-BC [108]	BM CD34+ CML-CP and CMP-BC, Lin− WT and SCLtTA-BCR–ABL1 mice, 32D, 32D-BCR–ABL1, K562 ± IM	BCR–ABL1-MAPK-dependent inhibition of C/EBPA translation	PIM1	Enhanced survival and arrest in differentiation (miR-328 promotes C/EBPA translation by binding to hnRNP E2)	IM treatment of K562 and Lin− from transgenic mice restores levels of miR-328
miR-17–92 cluster is up-regulated in CML-CP compared with CML-BC [73]	CD34+ from normal, CML-CP, and CML-BC, K562 ± IM, LAMA-84, EM-2	Unidentified	E2F1, PTEN, and TGFβ (previously described by others, references in text)	Increased proliferation and sensitivity to IM	Deregulated miR-17–92 cluster identified following treatment of K562 with IM and shRNA
miR-150 and miR-151 are down-regulated in Ph1 MNCs and CD34+ while miR-96 is up-regulated; up-regulation of miR-17–92 cluster not observed [111]	BM MNCs and CD34+ from normal patients and patients with CML	Unidentified	Unidentified	Deregulated expression of these miRNAs in both CD34+ and MNCs strongly implicates them in pathogenesis by BCR–ABL1	Study demonstrates altered expression of these miRNAs is BCR–ABL1-dependent and not cell-type specific
miR-196b is down-regulated and miR-708, miR-181a, b, c, d are up-regulated [117]	Ph1 B-ALL and normal CD34+ from patients with childhood ALL	Unidentified	Unidentified	Expression of these miRNAs are dependent on leukemic subtypes	Expression profiles specific to oncogene responsible for disease
Increased expression of miR-150 and miR-146a, reduced expression of miR-142–3p and miR-199b-5p following IM treatment [122]	PB MNCs from newly diagnosed patients with CML-CP, IM-treated CML-CP, and CML-BC	Unidentified	c-MYB, a previously described target of miR-150	Following IM treatment, miRNA expression profiles in PB MNCs returned to that of normal donors	Deregulated expression of these miRNAs dependent on BCR–ABL1 kinase activity as its impairment restored normal miRNA levels

Ph¹, Philadelphia chromosome; IM, imatinib; CML-BC, chronic myeloid leukemia-blast crisis; CML-CP, chronic myeloid leukemia-chronic phase; MNC, mononuclear cell; B-ALL, B-cell acute lymphoblastic leukemia; BM, bone marrow; MAPK, mitogen activated protein kinase; TGFβ, transforming growth factor β; hnRNP, heterogeneous nuclear ribonucleoprotein.