Targeting Chronic Myeloid Leukemia Stem Research Articles

Shedding Light on Targeting Chronic Myeloid Leukemia Stem Cells.

Chronic myeloid leukemia stem cells (CML LSCs) are a rare and quiescent population that are resistant to tyrosine kinase inhibitors (TKI). When TKI therapy is discontinued in CML patients in deep, sustained and apparently stable molecular remission, these cells in approximately half of the cases restart to grow, resuming the leukemic process. The elimination of these TKI resistant leukemic stem cells is therefore an essential step in increasing the percentage of those patients who can reach a successful long-term treatment free remission (TFR). The understanding of the biology of the LSCs and the identification of the differences, phenotypic and/or metabolic, that could eventually allow them to be distinguished from the normal hematopoietic stem cells (HSCs) are therefore important steps in designing strategies to target LSCs in a rather selective way, sparing the normal counterparts.

Targeting chronic myeloid leukemia stem cells: can transcriptional program be a druggable target for cancers?

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm resulting from acquisition of constitutively active BCR-ABL protein tyrosine kinase in a hematopoietic stem cell (HSC). Though tyrosine kinase inhibitors (TKIs) have changed a fatal disease into manageable disease, most patients cannot discontinue TKI treatment due to persistence of TKI-resistant leukemia stem cells (LSCs). Much effort has been made to find out factors or pathways specifically operating in LSCs to selectively target LSCs, with some promising results at least in preclinical models. In this article, we briefly review the role of Wnt/β-catenin signaling and its related factors in CML LSCs, especially focusing on Tcf1/Lef1 transcription factors, major effectors of Wnt/β-catenin pathway, of which transcriptional program have recently been shown to be targetable with prostaglandin E1.

Targeting chronic myeloid leukemia stem cells with the hypoxia-inducible factor inhibitor acriflavine

AbstractChronic myeloid leukemia (CML) is a hematopoietic stem cell (HSC)-driven neoplasia characterized by expression of the constitutively active tyrosine kinase BCR/Abl. CML therapy based on tyrosine kinase inhibitors (TKIs) is highly effective in inducing remission but not in targeting leukemia stem cells (LSCs), which sustain minimal residual disease and are responsible for CML relapse following discontinuation of treatment. The identification of molecules capable of targeting LSCs appears therefore of primary importance to aim at CML eradication. LSCs home in bone marrow areas at low oxygen tension, where HSCs are physiologically hosted. This study addresses the effects of pharmacological inhibition of hypoxia-inducible factor-1 (HIF-1), a critical regulator of LSC survival, on the maintenance of CML stem cell potential. We found that the HIF-1 inhibitor acriflavine (ACF) decreased survival and growth of CML cells. These effects were paralleled by decreased expression of c-Myc and stemness-related genes. Using different in vitro stem cell assays, we showed that ACF, but not TKIs, targets the stem cell potential of CML cells, including primary cells explanted from 12 CML patients. Moreover, in a murine CML model, ACF decreased leukemia development and reduced LSC maintenance. Importantly, ACF exhibited significantly less-severe effects on non-CML hematopoietic cells in vitro and in vivo. Thus, we propose ACF, a US Food and Drug Administration (FDA)-approved drug for nononcological use in humans, as a novel therapeutic approach to prevent CML relapse and, in combination with TKIs, enhance induction of remission.

CBP/Catenin antagonists: Targeting LSCs' Achilles heel.

Cancer stem cells (CSCs), including leukemia stem cells (LSCs), exhibit self-renewal capacity and differentiation potential and have the capacity to maintain or renew and propagate a tumor/leukemia. The initial isolation of CSCs/LSCs was in adult myelogenous leukemia, although more recently, the existence of CSCs in a wide variety of other cancers has been reported. CSCs, in general, and LSCs, specifically with respect to this review, are responsible for initiation of disease, therapeutic resistance and ultimately disease relapse. One key focus in cancer research over the past decade has been the development of therapies that safely eliminate the LSC/CSC population. One major obstacle to this goal is the identification of key mechanisms that distinguish LSCs from normal endogenous hematopoietic stem cells. An additional daunting feature that has recently come to light with advances in next-generation sequencing and single-cell sequencing is the heterogeneity within leukemias/tumors, with multiple combinations of mutations, gain and loss of function of genes, and so on being capable of driving disease, even within the CSC/LSC population. The focus of this review/perspective is on our work in identifying and validating, in both chronic myelogenous leukemia and acute lymphoblastic leukemia, a safe and efficacious mechanism to target an evolutionarily conserved signaling nexus, which constitutes a common "Achilles heel" for LSCs/CSCs, using small molecule-specific CBP/catenin antagonists.

Targeting Chronic Myeloid Leukemia Stem Cells through Pharmacological Inhibition of HIF-1α

Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell (HSC) disorder due to the 9;22(q34.1;q11.2) reciprocal chromosomal translocation, which results in the generation of BCR/abl "fusion" oncogene and the expression of the BCR/Abl oncoprotein, a constitutively-active tyrosine kinase (TK). To date, chronic-phase CML patients are treated with TK inhibitors (TKi) such as imatinib- mesylate (IM) and dasatinib. However, to eradicate CML, it is necessary to eliminate Leukemia Stem Cells (LSC), which are largely insensitive to TKi. Thus, TKi, rather than curing CML definitively, induce a state of minimal residual disease (MRD) apparently sustained by LSC persistence. Therefore, the identification of non-TKi drugs capable to target and eradicate LSC responsible for MRD and therefore the risk of relapse of disease is of primary importance.LSC, as well as normal HSC, in vivo reside in low oxygen tension areas of the bone marrow (BM) called "HSC niche". Several previous studies from our group and others demonstrate that low oxygen tension maintains the survival and stem cell potential of HSC and LSC, favoring their self-renewal. Interestingly, we also found that the expression of BCR/Abl oncoprotein is suppressed in low oxygen, which well explains the refractoriness of LSC to TKi, provided they manage to survive in the absence of BCR/Abl signaling.Hypoxia-Inducible Factor-1α (HIF-1α) is a key regulator of cell adaptation to low oxygen and of LSC maintenance. This study addresses the in vitro and in vivo effects of the pharmacological inhibition of HIF-1α on the maintenance of CML stem cell potential.After screening several HIF-1α inhibitors, we found that Acriflavine (ACF) induced apoptosis and DNA damage in CML cells and identified ACF as a very effective inhibitor of CML cell survival and growth in low oxygen, as regards the number of viable cells in culture and colony formation efficiency of CML cell lines or human or murine primary cells. Interestingly, ACF did not affect the colony formation efficiency of normal human hematopoietic cells. We also demonstrated in this study that IM and ACF exhibited an at least additive effect as far as the reduction of the total number of viable cells in low oxygen is concerned. Moreover, we demonstrated that low-oxygen incubation of CML cells increased the expression of genes related to stem cell potential, such as Nanog, Sox2 and Oct4, and that ACF treatment reduced their expression. These results on one hand confirmed that hypoxia selects cells with SC potential, on the other hand they demonstrated that ACF treatment reduces their maintenance.Moreover, we evaluated the maintenance of CML stem cell potential using a stem cell assay, demonstrating that ACF suppressed the stem cell potential of CML cell lines or primary cells. On the contrary, IM or Dasatinib, were unable to affect the stem cell potential of CML cells also when administered to primary samples neither TKi-treated before nor carrying primary mutations of BCR/Abl kinase domain. This is in agreement with what observed before by us and others and confirms the refractoriness of LSC to TKi.The effects of ACF in vivo were evaluated using a murine CML model where the disease was induced by a BCR/abl-carrying retrovirus. A 10 day-long ACF treatment was sufficient to attenuate CML development in mice, as evidenced by lower spleen weight, fewer leukemia cells in peripheral blood and BM, and a markedly reduced leukemia cell infiltration into the lungs. Moreover, it was possible to confirm in vivo the effects of ACF on LSC observed in vitro. ACF treatment indeed reduced the maintenance of the Long-Term LSC-containing LSK cell subset (CD34- LSK) in the BM of CML mice. Interestingly and in keeping with the less-severe addiction of HSC to HIF-1α deficiency, we found that non-CML cells were significantly less sensitive to ACF treatment than CML cells. This points to a good therapeutic index of ACF in discriminating leukemic from normal hematopoietic cells.On the basis of all above, the ACF/TKi combination may represent a novel therapeutic approach to target at one time CML cell bulk and LSC, in order to induce remission and prevent MRD of CML. Interestingly, ACF is an already FDA-approved drug for non-oncological uses in humans. DisclosuresNo relevant conflicts of interest to declare.

Emerging Therapeutic Strategies for Targeting Chronic Myeloid Leukemia Stem Cells

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder. Current targeted therapies designed to inhibit the tyrosine kinase activity of the BCR-ABL oncoprotein have made a significant breakthrough in the treatment of CML patients. However, CML remains a chronic disease that a patient must manage for life. Although tyrosine kinase inhibitors (TKI) therapy has completely transformed the prognosis of CML, it has made the therapeutic management more complex. The interruption of TKI treatment results in early disease progression because it does not eliminate quiescent CML stem cells which remain a potential reservoir for disease relapse. This highlights the need to develop new therapeutic strategies for CML to achieve a permanent cure, and to allow TKI interruption. This review summarizes recent research done on alternative targeted therapies with a particular focus on some important signaling pathways (such as Alox5, Hedgehog, Wnt/b-catenin, autophagy, and PML) that have the potential to target CML stem cells and potentially provide cure for CML.

Targeting Chronic Myeloid Leukemia Stem Cells

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder that is characterized by the presence of the fusion oncogene BCR-ABL that encodes the tyrosine kinase BCR-ABL. Constitutive expression of BCR-ABL leads to the unregulated production of mature myeloid cells in the bone marrow and their subsequent release into the blood. Untreated, CML will progress from a chronic to accelerated phase over a number of years before quickly proceeding to a terminal blast crisis phase, reminiscent of acute leukemia. The advent of tyrosine kinase inhibitors has led to much improved management of the disease, but these drugs do not provide a cure as they are unable to eradicate the most primitive, quiescent fraction of CML stem cells. This review looks at recent research into targeting CML stem cells and focuses on major signalling pathways of interest.

Novel Combination Treatments Targeting Chronic Myeloid Leukemia Stem Cells

Chronic myeloid leukemia (CML) is currently considered incurable in most patients. Stem cell transplantation, an accepted curative option for which extensive experience has been gained, is limited by high morbidity and mortality rates, particularly in older patients. Tyrosine kinase inhibitors targeting BCR-ABL are widely used and induce remission in a high proportion of patients, but resistance and incomplete response to these agents portends eventual relapse and disease progression. Although BCR-ABL inhibitors eradicate most CML cells, they are largely ineffective against the reservoir of quiescent leukemic stem cells (LSCs). Thus a strong medical need exists for therapies that effectively eradicate LSCs and is currently a focus of extensive research. To date, evidence obtained from in vitro studies, animal models, and clinical CML specimens suggests that an effective approach may be to partner existing BCR-ABL inhibitors with compounds targeting key stem cell molecular effectors, including Wnt/β-catenin, hedgehog pathway components, histone deacetylase (HDAC), transforming growth factor-β (TGF-β), Janus kinase 2, promyelocytic leukemia protein, and arachidonate 5-lipoxygenase (ALOX5). Novel combinations may sensitize LSCs to BCR-ABL inhibitors, thereby overcoming resistance and creating the possibility of improving disease outcome beyond the current standard of care.

Targeting Chronic Myeloid Leukemia Stem Cells

Chronic myeloid leukemia (CML) arises as a consequence of a chromosomal translocation giving rise to the Philadelphia chromosome and Bcr-Abl oncogene. CML is a clonal disease of stem cell origin and an excellent example of a malignancy in which tumor-initiating cells may hold the key to disease eradication. The known molecular basis of CML has enabled the development of Abl-specific tyrosine kinase inhibitors, such as imatinib mesylate. However, the success of tyrosine kinase inhibitors, as rationally designed first-line therapies, has been tempered by problems of disease persistence and resistance. Residual disease has been shown to be enriched within the stem cell compartment and to persist at stable levels for up to 5 years of complete cytogenetic response. This finding has led to further searches for novel strategies aimed at eliminating these cells; such strategies may be essential in achieving cure. The most significant recent findings are discussed in this review.

The Challenges of Targeting Chronic Myeloid Leukemia Stem Cells

Chronic myeloid leukemia (CML) is sustained by a clonally amplified population of Bcr-Abl–positive pluripotent stem cells. Persistence of a large, functionally intact yet suppressed residual normal hematopoietic stem cell population in most patients with CML has made it possible to aim at the development of curative therapies. However, achieving this goal requires the identification of agents that will eradicate the leukemic stem cell population. Several potent Bcr-Abl–targeted drugs have now been introduced into clinical practice with remarkable effects. Nevertheless, accumulating data indicate that the leukemic CML stem cells in patients with chronic phase CML are less responsive to these agents than the bulk of the neoplastic cells. In this article, we review emerging evidence that CML stem cells have a number of unusual properties that underlie their relative insensitivity to treatment, including those that specifically target the Bcr-Abl oncoprotein. The biology of the neoplastic stem cells in patients with CML is clearly important to the future attainment of cures and might also prove a paradigm relevant to other types of malignancies that are sustained by transformed stem cell populations.