Abstract
Chronic myeloid leukemia (CML) is a classical example of stem cell cancer since it arises in a multipotent hematopoietic stem cell upon the acquisition of the t(9;22) chromosomal translocation, that converts it into a leukemic stem cell (LSC). The resulting BCR-ABL1 fusion gene encodes a deregulated tyrosine kinase that is recognized as the disease driver. Therapy with tyrosine kinase inhibitors (TKIs) eliminates progenitor and more differentiated cells but fails to eradicate quiescent LSCs. Thus, although many patients obtain excellent responses and a proportion of them can even attempt treatment discontinuation (treatment free remission [TFR]) after some years of therapy, LSCs persist, and represent a potentially dangerous reservoir feeding relapse and hampering TFR. Over the past two decades, intensive efforts have been devoted to the characterization of CML LSCs and to the dissection of the cell-intrinsic and -extrinsic mechanisms sustaining their persistence, in an attempt to find druggable targets enabling LSC eradication. Here we provide an overview and an update on these mechanisms, focusing in particular on the most recent acquisitions. Moreover, we provide a critical appraisal of the clinical relevance and feasibility of LSC targeting in CML.
Highlights
Why Aren’t We Happy Yet with Clinical Results in CML?Chronic myeloid leukemia (CML) is one of the first human malignancies whose molecular pathogenesis could be fully unraveled, between the 1960s and the 1990s, well before the advent of omics [1]
The t(9;22)(q34;q11) chromosomal translocation, that is consistently detectable in the bone marrow cells of virtually all the patients who are diagnosed with CML, gives rise on chromosome 22 derivative to a fusion gene, BCR-ABL1, that encodes a protein with deregulated tyrosine kinase activity
They profoundly modified the natural history of the disease, that used to inexorably progress from a relatively indolent chronic phase (CP) that may last for years, where proliferation is enhanced but terminal differentiation is maintained, to the blastic phase (BP), that fully resembles an acute leukemia and has a dismal outcome [4]
Summary
Chronic myeloid leukemia (CML) is one of the first human malignancies whose molecular pathogenesis could be fully unraveled, between the 1960s and the 1990s, well before the advent of omics [1]. Pellicano et al [75] have shown that BCR-ABL1 kinase-dependent upregulation of hsa-mir183 results in the downregulation of its direct target Early Growth Response 1 (EGR1) transcription factor, and, as a consequence, upregulation of the cell cycle regulator E2F1, that is known to control both cell proliferation and p53-dependent/independent apoptosis The latter was found to play a pivotal role in controlling LSC (but not normal HSC) survival and proliferation, since E2F1 inhibition led to a decrease in colony-forming potential, cellcycle arrest, and induction of p53-mediated apoptosis. The CHOICES (CHlOroquine and Imatinib Combination to Eliminate Stem cells) study was activated as early as in 2009, and results have just recently been published [97] It was an international randomized phase II trial aimed to evaluate the safety and efficacy of a combination of imatinib and hydroxychloroquine (an antimalarial drug that was found to be an autophagy inhibitor) versus imatinib alone for CML patients with detectable residual disease.
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