Therapeutic Strategies for Leukemic Stem Cells: History
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Contributor:
Xingjian Zhai
,
Xiaoyan Jiang

Notoriously known for their capacity to reconstitute hematological malignancies in vivo, leukemic stem cells (LSCs) represent key drivers of therapeutic resistance and disease relapse, posing as a major medical dilemma. Despite having low abundance in the bulk leukemic population, LSCs have developed unique molecular dependencies and intricate signaling networks to enable self-renewal, quiescence, and drug resistance. The abundance of molecular and phenotypical aberrations associated with LSCs offers a wealth of promising therapeutic targets. Therapeutic designs have focused on drugging surface biomarkers selectively overexpressed on LSCs, antagonizing the protective bone marrow (BM) microenvironment niche to dismantle LSC dormancy, blocking signal transduction to re-sensitize resistant LSCs to available chemotherapeutics, and even expediting the drug supply pipeline through drug repurposing. Evidently, growing insight into the biological properties and prognostic values of LSCs have prompted the implementation of many clinical trials and have laid critical groundwork for the development of more effective, personalized, scalable, and less-toxic therapeutic strategies.

  • leukemic stem cells
  • Immunotherapies
  • Antigen
  • combination therapy
  • small molecules

1. The Discovery and Cellular Properties of Leukemic Stem Cells (LSCs)

1.1. Historical Perspectives of LSCs

Stem cell biology was a boldly novel discipline in the early 20th century, beginning with the proof of existence of bone marrow (BM) hematopoietic stem cells (HSCs) by James Till and Ernest McCulloch in the 1960s after successfully reconstituting blood cells on heavily irradiated mice [1]. On a societal level, at the time, Till and McCulloch’s discovery also contributed to the theoretical framework supporting the clinical implementation of BM transplantation for those exposed to severe nuclear radiation during the Cold War [2]. In the decades that followed, expansion of cellular and molecular characterization of the physiological properties of HSCs scientifically and militarily led to the establishment of an intricate blood cell differentiation hierarchy [3] and, more importantly, the development of technologies such as fluorescence-activated cell sorting [4] and advances in tissue culture assays, including the long-term culture-initiating-cell (LTC-IC) assay that allows the differential clonal output potential of single HSCs to be examined; these all accelerated HSC research [3][5].
About 30 years after the discovery of HSCs, in the context of oncogenesis, the concept of the existence of a select subpopulation of leukemic cells not only capable of sustained self-renewal but also able to repopulate and give rise to human leukemias was demonstrated in vivo in acute myeloid leukemia (AML) by John Dick and colleagues [6][7], as well as in chronic myeloid leukemia (CML) by Connie Eaves and colleagues [8][9][10]. These cells with strong leukemia-initiating capacity, termed leukemic stem cells (LSCs), are found to be immunophenotypically enriched within the Lin−CD34+CD38− BM cell fraction, despite the high degree of surface and intracellular marker heterogeneity therein [11][12][13]. The experimental basis for such seminal discoveries involved using limiting dilution of fractionated cell pools harboring distinct surface markers, followed by engraftment into immunocompromised murine hosts. These techniques, though time-consuming, effectively isolated cell population enriched for LSCs, allowed relative quantification of LSC frequency, and even served as a contemporary in vivo gold-standard approach for functional validation of LSC activity [14]. With the advent of next-generation sequencing, high-throughput multi-omics technologies, and sophisticated murine models developed in the 21st century, scientists are now able to further interrogate the nature and evolutionary trajectory of LSCs, sprouting the seed for an era of advanced stem cell research. Indeed, recent mounting evidence corroborates that LSCs are heavily involved in refractory hematological malignancies, particularly AML and CML. 

1.2. Surface Antigens of AML LSCs

Despite recent advancements made in characterizing LSCs, it is worth noting that LSCs should not be perceived to have well-defined, uniform biomarkers. Rather, LSC surface markers can be fluidic and even context-dependent. Dick and colleagues’ seminal discovery in 1997 uncovered that cells expressing surface markers CD34+CD38− were able to differentiate in vivo in severe-combined-immunodeficiency-disease (SCID) mice into leukemic AML blasts; however, this description was broad and preliminary, as studies later revealed this same set of surface marker is also shared by normal HSCs and progenitor cells, sparking interest in the search of cellular markers that specifically encapsulate LSCs [15][16][17]. Moreover, early characterization of AML LSCs was predominantly antibody-based; however, such practices may lead to biases resulting from differing reactivities and specificities of the antibodies used and the harsh assay environment associated with cell sorting/fractionation, as not all cell types could be sorted with the same efficiency in vitro and in vivo [18][19]. Nowadays, recognizing these potential pitfalls, research efforts have concentrated on examining surface antigens that appear to be aberrantly regulated or differentially expressed on LSCs as opposed to their healthy stem and progenitor cell counterparts. One promising marker is CD33, which is highly expressed in AML patients, and its expression along with T cell immunoglobulin and mucin protein (TIM3) specifically denotes AML cells as opposed to normal hematopoietic tissues [20][21]. Another marker that is reported to be preferentially overexpressed in CD34+CD38− AML cells is CD123, and its expression serves as a clinical marker for adverse patient outcome; it is potentially mediated by mechanisms involving STAT5 activation [22][23][24][25]. Furthermore, CD47, which upon interaction with SIRPα on circulating macrophages and dendritic cells inhibits phagocytosis to facilitate immune evasion of AML cells, is overexpressed in CD34+CD38− LSCs, conferring a survival advantage to AML stem cells [26][27][28]. Using signal-sequence-trap technology to identify surface antigen expression milieu, followed by quantitative real-time polymerase chain reaction (qRT-PCR) validation across Lin−CD34+CD38− AML samples and normal BM-derived HSC/progenitor cells, Hosen and coworkers found CD96 to be preferentially upregulated in AML cells and demonstrated LSC activity among CD34+CD38−CD96+ AML cells through successful engraftment of these cells into irradiated immunocompromised mice [29]. Furthermore, transcriptomic analysis done on purified HSCs from myelodysplastic syndrome (MDS) patients and age-matched cord blood cell HSC controls identified selective overexpression of CD99 on LSCs, and that CD99 is at a particularly high level at relapse when compared to samples obtained at time of diagnosis, suggesting a potential link between CD99 expression and the chemo-resistant properties of LSCs in general [30]. Furthermore, a study conducted by Heo and colleagues reported prominent enrichment of the CD45dimCD34+CD38−CD133+ cells in BM of AML patients, and that this unique signature is associated with poor prognosis; however, functional validation of LSC activities of these cells is still needed [31]. Another factor that complicates the already heterogenous landscape of AML LSC surface antigen expression is the stage during which leukemic transformation occurs, as recent evidence reported transformation may also take place in mature granulocyte–macrophage precursors without expressing CD34, specifically in those samples with NPM1 mutation [32][33][34]. In other instances, leukemic-initiating cells are found to exist in the CD38+ progenitor cell population [35]. These novel insights may challenge the way in which researchers purify and interpret the surface antigen milieu of AML LSCs. In a nutshell, AML LSCs harbor an extremely complex surface antigen expression profile, and further consensus is needed to define these molecular markers. Of equal importance is the mechanistic understanding underlying such surface markers in relation to stemness and clinical drug resistance.

1.3. Surface Antigens of CML LSCs

The first evidence of a highly primitive type of leukemic cells present in CML patients was reported in 1992 using techniques such as LTC-IC assay followed by limiting dilution assays of patient CML blood and BM samples [36][37]. A later study published in 1999 from the same research group established the quiescent nature of CML LSCs after isolating a quiescent cell fraction among CD34+ CML LSCs using nucleic-acid-binding agents Hoechst 33342 and Pyronin Y, and subsequently confirming the engraftment capability of these quiescent CML LSCs on immunodeficient mice [38]. This dormant state was later discovered to be an important feature of drug-resistant CML LSCs, as they contribute to the root cause of drug resistance and disease relapse in CML patients [39][40]. Since then, many studies have aimed to characterize surface biomarkers selectively present on CML LSCs; however, just like the dilemmas encountered in defining the surface marker landscape of AML LSCs, evidence in CML LSCs appears to be controversial due, at least in part, to the lack of standardized in vitro and in vivo techniques employed and the molecular heterogeneity intrinsic to the functioning of CML LSCs throughout different stages of disease progression [41]. Nevertheless, studies to date have mainly focused on examining the surface marker expression of CD34+CD38− CML cells in the chronic phase, a comparatively stable stage of CML pathogenesis. According to Herrmann and coworkers, CD34+CD38− CML patient cells in the chronic phase are reported to have a roughly 10-fold higher expression of CD33 compared to normal CD34+CD38− stem cells by flow cytometric analysis, even though CD33 remains comparable at the transcript level [42]. Interestingly, IL-1 receptor accessory protein (IL1RAP), which is found to be upregulated in CD34+ and CD34+CD38− CML cells, appears to increase as patients transition from the chronic phase to accelerated and blast crisis phases [43]. Furthermore, using gene array, qPCR, and flow cytometric analyses, Hermann et al. reported that CD34+CD38−CD26+ but not CD34+CD38−CD26− LSCs obtained from chronic-phase CML patients contained BCR/ABL1 mRNA, exhibited repopulating capability in NSG mice, and were highly expressed in imatinib-nonresponder patients, suggesting that CD26 is a highly specific CML LSC biomarker and a potential therapeutic target [44][45]. Complementing this line of evidence, a more recent study using single-cell gene expression analysis in conjunction with immunophenotypic screening revealed a distinct signature of Lin-CD34+CD38−/lowCD45RA−cKIT−CD26+ as being associated with a particular CML LSC compartment that is relatively insensitive to tyrosine kinase inhibitor (TKI) treatment [46]. Furthermore, a study published in 2020 comparing a total of 878 BM or blood samples from 274 patients with AML, 97 patients with CML, and 288 controls also revealed an aberrant profile of CD25+CD26+/CD56+/CD93+/IL1RAP+ antigens among CD34+CD38− CML cells [11]. Indeed, characterization of the surface marker landscape of CML LSCs not only aids in the phenotypic purification of these intriguing cells, but also paves the way for the identification of specific, actionable, and prognostic biomarkers on CML LSCs for therapeutic design and prevention of disease relapses. As exciting as these discoveries may seem, further studies are still needed to identify CML LSC surface antigens potentially driving disease progression from chronic to accelerated and blast crisis phases and/or conferring TKI resistance.

1.4. Clinical Challenges of LSCs

Owing to their unique molecular properties, including self-renewal, phenotypic plasticity, and the wondrous ability to differentiate and repopulate new tissues, LSCs are highly versatile entities, insidiously perpetuating therapeutic resistance [47][48]. Indeed, genetic variants known to evade therapeutic treatments are enriched in stem-like cells found across almost all forms of leukemia [49][50][51][52][53]. Among the molecular aberrations present in cancer stem cells, drug-induced senescence and quiescence represent predominant causes of patient relapse, as most antineoplastics target processes associated with actively dividing bulk cancer cells, not those in the quiescent state [54][55]. As LSCs represent just a rare fraction of the total bulk cancer cells, patients undergoing chemotherapy can be considered to have reached therapeutic endpoints when, in fact, those LSCs may still remain alive. More so, several groups have also reported that cancer stem cells can become “trained” to respond to chemotherapeutic insults either through crosstalk with the tumor microenvironment or acquisition of adaptive genomic circuitry to mitigate drug-mediated cytotoxicity or to bypass drug-targeted pathways, fortifying their ability to withstand therapeutic challenges [56][57][58]. This creates a clinical dilemma where drug resistance and relapses are not only permitted, but are sometimes even inadvertently encouraged once patients go through round after round of therapy. These complications, coupled with the heterogenous surface marker expression of LSCs, nonspecific cytotoxicity of existing antineoplastics, and inter-patient sensitivity to standardized treatments, collectively stagnate the overall survival of leukemia patients, especially that of elderly individuals.

2. Surface Antigen-Based Immunotherapies

Interrogation of LSC surface antigen milieu has encouraged the development of distinct functional categories of antibodies, namely mono-specific and bi-specific antibodies, as well as antibody-drug conjugates (ADCs). Mono-specific antibodies against prominent LSC markers are relatively uncommon. This can presumably be due to several reasons, including but not limited to the fact that there is likely no singular “panacea” LSC surface marker whose targeting will disarm all LSC phenotypical and functional characteristics and exert broad-spectrum antileukemic effects for all patients. To resolve this dilemma, current therapeutic efforts center on drugging multiple LSC surface markers at once in the form of bi-specific antibodies and ADCs. Nevertheless, a few clinically employed mono-specific antibodies that are also known to target LSC surface antigens include 213Bi-lintuzumab (anti-CD33) [59], Talacotuzumab (anti-CD123) [60], Magrolimab (anti-CD47) [61][62], and daclizumab (anti-CD25) [63][64], with some of them demonstrating exceptional anti-leukemic effects against residual and resistant hematological cancer cells. However, it is crucial to acknowledge that the identification and practicality of targeting LSC surface antigens, at least via mono-specific antibodies, remains largely empirical. Bi-specific antibodies, on the other hand, possess greater flexibility in accommodating substrates from either the same target or distinct targets. Flotetuzumab, a bi-specific antibody that recognizes CD123 and CD3, in addition to having the potential to target leukemic blasts and LSCs overexpressing CD123, can also utilize CD3 to activate T cells and redirect their cytotoxicity towards CD123+ AML cells, rendering it a salvage immunotherapy for refractory AML patients [65][66]. A few other bi-specific antibodies, including AMG330 (anti-CD33 and anti-CD3) [67] and blinatumomab (anti-CD19 and anti-CD3) [68], have also been uncovered to elicit T-cell mediated immunity to exert sustained anti-leukemic effects. Furthermore, as another therapeutic modality, ADCs are typically composed of a cytotoxic payload chemically connected to a monoclonal antibody via a biodegradable linker, whereby the antibody component mediates the specific delivery of the payload into target cells to minimize unintentional cytotoxicity. A classic example is gemtuzumab ozogamicin (GO) [69][70], which consists of calicheamicin linked to an anti-CD33 antibody and has entered multiple phase III clinical trials for adult and pediatric AML patients harboring diverse cytogenetic phenotypes, such as nucleophosmin1 (NPM1)-mutated [71] and lysine methyltransferase 2A (KMT2A)-rearranged AML subtypes [72][73]. Importantly, it has been shown that GO is effective in managing minimal residual disease and drastically reduces chemo-residual leukemic-initiating cells upon incorporation into conventional induction chemotherapy [74][75]. Recently, SGN-CD33A, a humanized ADC composed of the DNA cross-linking agent pyrrolobenzodiazepine dimer and anti-CD33, was developed with more enhanced therapeutic efficacy than that of GO, especially for AML subtypes associated with poor prognosis and entailing a multi-drug resistant phenotype [76]. Another example of AML LSC- and leukemic blast-specific ADC is CLT030, whereby a DNA-binding payload is covalently linked to anti-CLL1, creating a site-specific avenue for drug delivery. As a result, the administration of CLT030 leads to decreased LSC colony formation and even presents a more favorable toxicity profile than that of CD33-ADC sharing the identical payload as CCL1-ADC [77].

3. Small-Molecule Inhibitors

LSC-driven hematological malignancies present multi-dimensional molecular abnormalities in their transcriptome, epigenome, proteome, and metabolome. Many of these alterations can then be harnessed as the basis for therapeutic design of small-molecule inhibitors. For instance, recently, Jiang and colleagues reported the potent anti-leukemic effects of the highly selective AXL kinase inhibitor SLC-391 on MLL-fusion AML stem and progenitor cells in vitro and in vivo [78]. Additionally, jumonji domain modulator #7 (JDM-7) binds and inhibits histone lysine demethylase JMJD1C and effectively downregulates LSC self-renewal gene HOXA9 to selectively decrease colony formation of leukemic cells in vitro in MLL-rearranged AML [79]. Intriguingly, small-molecule inhibitors are also designed to disarm leukemic niche signaling. For example, Dynole 34-2, which inhibits Dynamin GTPase activity, blocks receptor-mediated endocytosis critical for niche-mediated growth-factor signaling in pre-LSCs [80]. Furthermore, targeting the epigenetic m6A modification in AML by inhibiting the catalytic activity of the METTL3 methyltransferase by the small-molecule inhibitor STM2457 impairs engraftment potential in murine models of AML [81]. In IM-resistant CML, pharmacological inhibition of ubiquitin-specific peptidase 47 (USP47) with P22077 reduces the percentage of CD34+CD38− cells in secondary BM transplantation and inhibits colony-forming activity of CD34+ cells from IM-resistant CML patients while sparing normal CD34+ cells [82]. To meet the burning clinical need of eradicating LSCs, research on drug repurposing is also rapidly expanding. For example, proscillaridin A, predominantly indicated for heart failure, has been empirically demonstrated to kill MYC-overexpressing LSCs in both T-ALL and AML models, potentially through downregulating acetylation of MYC target genes [83]. Another interesting case of drug repurposing is that of salinomycin. As an antimicrobial drug, salinomycin is found to confer cytotoxicity against a broad spectrum of cancer stem cells [84]. In MLL-rearranged AML, sub-micromolar treatment of salinomycin on human and mouse primary leukemia cells led to reduced colony formation while sparing normal samples, indicating anti-LSC activity of salinomycin [85]. Intriguingly, powerful in silico analysis of AML LSC gene expression signatures crossed with drug–gene interaction datasets has yielded diverse cohorts of repositionable drugs, potentially increasing the diversity and accessibility of a drug repertoire that inhibits LSCs to better manage residual malignancies [86].

4. Combination Therapies

Combination therapies represent a major research hotspot. The recognition that cancer cells are often more susceptible to disruption of multiple pathways at once and the possibility of combining several targets to more precisely capture a specific oncogenic signature to minimize off-target effects has led to the advent of numerous strategic combination regimens. Among several recently developed combination therapies, oxidative metabolism-based therapeutics have garnered astounding popularity due to the shared dependence of AML and CML LSCs on OXPHOS for survival. To highlight a few discoveries, in AML, the BCL-2 inhibitor Venetoclax synergizes with ribonucleoside analog 8-chloro-adenosine (8-Cl-Ado) to decrease OXPHOS of CD34+CD38− LSC-enriched cells [87]. Furthermore, Venetoclax in combination with the hypomethylating agent Azacytidine results in decreased electron transport chain complex II activity, suppressing OXPHOS and consequently leading to the death of AML LSCs [88]. A recurring theme herein is the incorporation of the BCL-2 inhibitor Venetoclax into combination regimens against AML LSCs. Indeed, clinical evaluation of AML patient LSC profiles has indicated that elderly AML patients may particularly benefit from Venetoclax combination therapy [89]. Apart from AML, in CML, combined blockade of BCL-2 by Venetoclax and BCR-ABL tyrosine kinase using a TKI effectively eradicates CML LSCs in vitro and in vivo [90]. Interestingly, combination therapy consisting of the integrin-linked kinase (ILK) inhibitor QLT0267 and DA effectively inhibited the growth of primitive CML cells by downregulating oxidative metabolism and mitochondrial dynamics while sensitizing refractory patient LSCs to TKI therapy in vitro and in a PDX model [91]. In line with this, tigecycline, a mitochondrial protein translation inhibitor, in conjunction with IM, selectively eradicates CML LSCs both in vitro and in vivo [92]. Furthermore, using an advanced drug/proliferation screen, Lai et al. uncovered a pro-survival role for protein phosphatase 2A (PP2A) in TKI-nonresponder cells, and that the inhibition of PP2A impaired survival of these cells and sensitized them to TKIs, inducing a dramatic loss of several key proteins, particularly β-catenin [93]. Remarkably, the clinically validated PP2A inhibitors LB100 and LB102, in combination with TKIs, act synergistically to inhibit the growth of CML LSCs [93] and BCR-ABL+ ALL patient cells [94].

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines10081841

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