Chronic myeloid leukemia: mechanisms of blastic transformation

Abstract

The BCR-ABL1 oncoprotein transforms pluripotent HSCs and initiates chronic myeloid leukemia (CML). Patients with early phase (also known as chronic phase [CP]) disease usually respond to treatment with ABL tyrosine kinase inhibitors (TKIs), although some patients who respond initially later become resistant. In most patients, TKIs reduce the leukemia cell load substantially, but the cells from which the leukemia cells are derived during CP (so-called leukemia stem cells [LSCs]) are intrinsically insensitive to TKIs and survive long term. LSCs or their progeny can acquire additional genetic and/or epigenetic changes that cause the leukemia to transform from CP to a more advanced phase, which has been subclassified as either accelerated phase or blastic phase disease. The latter responds poorly to treatment and is usually fatal. Here, we discuss what is known about the molecular mechanisms leading to blastic transformation of CML and propose some novel therapeutic approaches.

Figures

Figure 1. BCR-ABL1–dependent pathways to blastic transformation.

Schematic representation of the potential BCR-ABL1–dependent molecular mechanisms leading to CML disease progression.The relatively high BCR-ABL1 expression/activity in CML-CP CD34+CD38– stem cells and/or CD34+ early progenitors compared with more committed progenitors, which is further markedly increased in CML-BP CD34+ progenitors results in the following: enhancement of proliferation/survival pathways; increased genomic instability; and activation of pathways leading to a block in myeloid differentiation, acquisition of the ability to self renew, and inhibition of tumor suppressors with broad cell regulatory functions. BAD, BCL2 antagonist of cell death; DNA-PKcs, DNA-dependent protein kinase, catalytic subunit; FOXO, forkhead box O; IK6, Ikaros 6; miR-328, microRNA-328; MLH1, mutL homolog 1; PMS2, postmeiotic segregation increased 2; RAD51, RecA homolog in Escherichia coli; RAD52, RAD52 homolog (Saccharomyces cerevisiae); Shh, Sonic Hedgehog; wnt/β-catenin, wingless-int1/beta-catenin.

Figure 2. BCR-ABL1 and PP2A interplay.

(A) In CML-BP and Ph-positive ALL CD34+ progenitors, p210 and p190 BCR-ABL1 oncoproteins inhibit PP2A activity by inducing hnRNP-A1, which, in turn, enhances expression of SET. In BCR-ABL–positive myeloid progenitor cells, suppression of PP2A phosphatase activity is required for sustained activation of mitogenic and survival signals. (B) Restored PP2A activity, achieved by treatment with PP2A activators (e.g., Forskolin or FTY720), impairs in vitro and in vivo wild-type and T315I BCR-ABL1 leukemogenesis by antagonizing the effects of BCR-ABL1 on its downstream signal transducers (not shown) and promoting SHP-1–mediated BCR-ABL1 inactivation and proteasome-dependent degradation.

Figure 3. BCR-ABL1 regulates DNA damage and DNA repair, the 2 major components of genomic instability.

BCR-ABL1–positive leukemia cells accumulate more DNA lesions, such as 7,8-dihydro-8-oxo-2′-deoxyguanosine (8-oxoG), and DNA DSBs induced by ROS, AID, and genotoxic agents (e.g., γ-radiation, cisplatin, mitomycin C, hydroxyurea, and UV light) in comparison with normal cells. In addition, BCR-ABL1 inhibits MMR and stimulates mutagenic NER to generate point mutations including those causing TKI resistance. Moreover, BCR-ABL1 activates unfaithful DSB repair mechanisms, HRR, NHEJ, and SSA, which contribute to chromosomal aberrations. The effect of BCR-ABL1 on base excision repair (BER) and O(6)-methylguanine–DNA methyltransferase (MGMT) is not known. Altogether, elevated levels of DNA damage combined with inefficient/unfaithful DNA repair cause genomic instability in CML-CP and facilitate CML-BP.