Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms

Yung, Yammy; Lee, Emily; Chu, Hiutung; Yip, Pui-Kwan; Gill, Harinder

doi:10.3390/ijms22020659

Cited by 9 publications

(9 citation statements)

References 325 publications

(501 reference statements)

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“…Several studies suggest that autophagy plays an important role in the maintenance of leukemia stem cells and in the resistance to TKIs in the stem cell fraction in CML in vitro [ 33 , 34 , 35 ]. However, the role of autophagy may be altered by environmental factors and it is not clear whether autophagy is also important for the maintenance of CML stem cells in vivo [ 36 , 37 ]. We plan to investigate the effect of FA-HP-β-CyD on CML stem cells in vitro and in vivo in the near future.…”

Section: Discussionmentioning

confidence: 99%

Folic Acid-Appended Hydroxypropyl-β-Cyclodextrin Exhibits Potent Antitumor Activity in Chronic Myeloid Leukemia Cells via Autophagic Cell Death

Hoshiko

Kubota

Onodera

et al. 2021

Cancers

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2-Hydroxypropyl-β-cyclodextrin (HP-β-CyD) is widely used as an enabling excipient in pharmaceutical formulations. We previously demonstrated that HP-β-CyD disrupted cholesterol homeostasis, and inhibited the proliferation of leukemia cells by inducing apoptosis and cell-cycle arrest. Recently developed drug delivery systems using folic acid (FA) and folic acid receptors (FR) are currently being used in cancer treatment. To confer tumor cell-selectivity to HP-β-CyD, we synthesized folate-appended HP-β-CyD (FA-HP-β-CyD) and evaluated the potential of FA-HP-β-CyD as an anticancer agent using chronic myeloid leukemia (CML) cells in vitro and in vivo. FA-HP-β-CyD inhibited the growth of FR-expressing cells but not that of FR-negative cells. FA-HP-β-CyD had stronger anti-leukemia and cell-binding activities than HP-β-CyD in CML cells. Unlike HP-β-CyD, FA-HP-β-CyD entered CML cells through endocytosis and induced both apoptosis and autophagy via mitophagy. FA-HP-β-CyD increased the inhibitory effects of the ABL tyrosine kinase inhibitors imatinib mesylate and ponatinib, which are commonly used in CML. In vivo experiments in a BCR-ABL leukemia mouse model showed that FA-HP-β-CyD was more effective than HP-β-CyD at a ten-fold lower dose. These results indicate that FA-HP-β-CyD may be a novel tumor-targeting agent for the treatment of leukemia.

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Section: Discussionmentioning

confidence: 99%

Folic Acid-Appended Hydroxypropyl-β-Cyclodextrin Exhibits Potent Antitumor Activity in Chronic Myeloid Leukemia Cells via Autophagic Cell Death

Hoshiko

Kubota

Onodera

et al. 2021

Cancers

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“…Increases in miR-29a cause downregulation of tumor suppressor TET2 and antioxidant-coding EPAS1, as well as overexpression of anti-apoptotic genes BCL-2 and MCL-1, resulting in greater TKI resistance in CML LSC [ 146 , 147 ]. In addition, low levels of tumor suppressor miR-142 are related to high levels of oncoproteins such as MCL-1 and c-KIT, which leads to anti-apoptotic, pro-survival, and therapy-resistant effects via reactivating PI3K/AKT, JAK/STAT, and RAS/RAF/MEK/ERK signaling in TKI-resistant LSCs [ 148 , 149 ]. The expression of miR-30a is reduced following IM therapy, favoring LSC resistance to TKIs via a mechanism that involves Beclin1 and ATG5 [ 150 ].…”

Section: Survival and Functional Resistance Of CML Lscs To Therapiesmentioning

confidence: 99%

Chronic myeloid leukemia stem cells: targeting therapeutic implications

2021

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Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm driven by BCR-ABL1 oncoprotein, which plays a pivotal role in CML pathology, diagnosis, and treatment as confirmed by the success of tyrosine kinase inhibitor (TKI) therapy. Despite advances in the development of more potent tyrosine kinase inhibitors, some mechanisms particularly in terms of CML leukemic stem cell (CML LSC) lead to intrinsic or acquired therapy resistance, relapse, and disease progression. In fact, the maintenance CML LSCs in patients who are resistance to TKI therapy indicates the role of CML LSCs in resistance to therapy through survival mechanisms that are not completely dependent on BCR-ABL activity. Targeting therapeutic approaches aim to eradicate CML LSCs through characterization and targeting genetic alteration and molecular pathways involving in CML LSC survival in a favorable leukemic microenvironment and resistance to apoptosis, with the hope of providing a functional cure. In other words, it is possible to develop the combination therapy of TKs with drugs targeting genes or molecules more specifically, which is required for survival mechanisms of CML LSCs, while sparing normal HSCs for clinical benefits along with TKIs.

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“…Similarly, several key interactions and regulators of LSC fate in the BMM have been identified and characterized (Figure 5). However, despite the striking efficacy shown in vitro and most frequently also in mouse models by several approaches aimed to specifically target CML LSCs (recently reviewed by Yung et al [127]), this has so far been translated into relatively few clinical trials (listed in Table 2). And most of these trials have, so far, exhibited relatively disappointing results, as discussed above.…”

Section: Will We Ever Be Able To Kill CML Lscs?mentioning

confidence: 99%

Targeting Leukemic Stem Cells in Chronic Myeloid Leukemia: Is It Worth the Effort?

Soverini

Santis

Monaldi

et al. 2021

IJMS

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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.

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Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms

Cited by 9 publications

References 325 publications

Folic Acid-Appended Hydroxypropyl-β-Cyclodextrin Exhibits Potent Antitumor Activity in Chronic Myeloid Leukemia Cells via Autophagic Cell Death

Folic Acid-Appended Hydroxypropyl-β-Cyclodextrin Exhibits Potent Antitumor Activity in Chronic Myeloid Leukemia Cells via Autophagic Cell Death

Chronic myeloid leukemia stem cells: targeting therapeutic implications

Targeting Leukemic Stem Cells in Chronic Myeloid Leukemia: Is It Worth the Effort?

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