Chronic myelogenous leukemia, a still unsolved problem: pitfalls and new therapeutic possibilities

Abstract

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of hematopoietic stem cells. At the molecular level, the disorder results from t(9;22)(q34;q11) reciprocal translocation between chromosomes, which leads to the formation of an oncogenic BCR-ABL gene fusion. Instead of progress in the understanding of the molecular etiology of CML and the development of novel therapeutic strategies, clinicians still face many challenges in the effective treatment of patients. In this review, we discuss the pathways of diagnosis and treatment of patients, as well as the problems appearing in the course of disease development. We also briefly refer to several aspects regarding the current knowledge on the molecular basis of CML and new potential therapeutic targets.

Keywords: BCR–ABL; CML; TKI; TKI withdrawal; autophagy; chronic myeloid leukemia; stem cells; tyrosine kinase inhibitors.

Figure 1

Schematic representation of the ABL, BCR, and BCR–ABL genes and encoded proteins. Notes: Upper panel: location of the ABL and BCR loci on 9 and 22 chromosomes, respectively, and the BCR–ABL fusion gene on the Philadelphia (Ph) chromosome. Both 9+ and Ph (formally 22−) chromosomes are a result of reciprocal translocation between long arms of 9 and 22 chromosomes. Middle panel: the exon–intron structure of the ABL (officially ABL1; HGNC:76) and BCR (previously BCR1; HGNC:1014) genes and their predicted transcripts. Exons are shown as boxes denoted a1a to a11 for ABL and e1 to e23 for BCR, while introns are marked by bent lines. Left right arrows indicate the most frequent regions of break points in both genes. The protein-coding regions (CDS) of the genes are shown underneath. Lower panel: the normal as well as fusion proteins encoded by wild-type ABL and BCR genes and by oncogenic variants of the BCR–ABL fusion gene, respectively. In chronic myeloid leukemia, the p210 variant is present, p190 is generally associated with acute lymphoblastic leukemia, while p230 with chronic neutrophilic leukemia.

Figure 2

Most important upstream signaling in the regulation of autophagy and apoptosis processes. Notes: Growth factors and nutrients stimulate the PI3K and Ras pathways, and their downstream effectors, such as Akt and Erk kinases, directly inactivate TSC1/2 complex by its phosphorylation and in this way activate mTORC1, which negatively regulates autophagy through inhibitory phosphorylation of Ulk1 and Ulk2 kinases. However, mTORC1 signaling can be suppressed by AMPK. The AMPK pathway is activated by the tumor suppressor LKB1 during energetic stress resulting from low energy and oxygen levels. The active TSC1/2 complex switches autophagy off by inactivation of Rheb and mTORC. Moreover, AMPK directly associates with Ulk1 to activate autophagy in response to multinutrient deprivation. Cells exposed to long-term stress factors can succumb to cell death. During apoptosis, proapoptotic proteins such as Bax and Bak can be activated. These proteins are responsible for the disruption of the MOMP and the release of other proapoptotic proteins including cytochrome c that in turn activates effector caspases. Activation of both processes can be initiated by accumulation of ROS. ROS can activate autophagy through Beclin-1 and hVps34. Increased levels of ROS can lead to genomic instability through direct damage to DNA. This can activate p53 proteins that lead to the induction of the processes of both autophagy and apoptosis., Abbreviations: AMPK, AMP-activated protein kinase; mTORC1, mammalian targets of rapamycin complex 1; ATM, ataxia telangiectasia-mutated kinase; ERK, extracellular signal–regulated kinase.