In Search of CML Stem Cells’ Deadly Weakness

Abstract

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder that is characterized by the presence of a fusion oncogene, BCR-ABL, which encodes a protein with constitutive tyrosine kinase activity. This activity causes excessive production of myeloid cells and their premature release into the circulation. The discovery of tyrosine kinase inhibitors marked a major advance in CML therapy, but these drugs cannot eradicate the disease because they are unable to kill the most primitive, quiescent leukemic stem cells. This review discusses current research in CML and attractive targets that have emerged with potential for eradicating the disease. Several new targets have recently been investigated as potential modulators in myeloid leukemia pathogenesis, including the multiple gene regulators miRNAs, the apparently leukemia-specific cell surface marker IL1RAP, transcription factors such as BMI1 and FOXOs, the tumor suppressors PML and PP2A, and the tyrosine kinase JAK2.

PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells

“…The notion that TKIs do not kill quiescent CML HSCs (5) because BCR-ABL1 activity is dispensable for their survival (7,8) suggests that other aberrantly regulated signals control leukemic stem cell persistence (5,(33)(34)(35). Our present findings support the hypothesis that BCR-ABL1 expression per se is required for survival of CML HSCs.…”

“…However, only a few patients in CMR do not relapse after discontinuation of TKI (e.g., imatinib) therapy (3). Persistence of cells from the original BCR-ABL1 + clone in TKI-treated patients, but not in allogeneic transplanted patients in CMR (4), suggests the existence of nonproliferating (quiescent) CML HSCs with innate TKI resistance (5), for which BCR-ABL1 kinase activity appears dispensable (5)(6)(7)(8). However, how these cells persist in TKI-responsive patients, and whether BCR-ABL1 expression is required for their survival/ self-renewal, remain unknown.…”

CDK6 as a key regulator of hematopoietic and leukemic stem cell activation

“…In CML, quiescent LSCs represent the leukemic stem cell compartment and are protected from conventional chemotherapy and tyrosine kinase inhibitors, allowing them to survive for many years and posing a significant challenge to therapeutic attempts. 52,53 Imatinib represents a major breakthrough in therapy, although it only targets the peripheral symptoms of leukemia. The idea of inhibiting CDK6 may seem provocative, but our data show that it warrants further investigation.…”

Recent advances in acute myeloid leukemia stem cell biology

“…38,40 In accordance with this, in chronic myeloid leukemia (CML), the initiating chromosomal translocation t(9;22) leading to formation of the BCR-ABL fusion gene occurs in an HSC. 41 However, transition of the disease to myeloid blast crisis occurs as a result of additional events accumulated in GMP, including activation of β-catenin, which confer selfrenewal activity to this compartment. 42 …”