Human Solid Tumors Research Articles

Abstract 5679: Tetra-specific antibody GNC-035: guidance and navigation control (GNC) molecule development for treatment of ROR1+ malignancies

Abstract Cancer-intrinsic immune escape mechanisms and immune cell suppression can progressively diminish the curative potential of currently available T cell-based therapies. Barriers to successful T cell checkpoint therapies may be addressed by redirection of T cells toward tumor antigens using T cell engagers that function independently of MHC presented T cell epitopes. Here we demonstrate that an octavalent, tetraspecific Guidance and Navigation Control (GNC) antibody, GNC-035, binds to ROR1, CD3, PD-L1, and 4-1BB and mediates redirected T cell cytolysis of human solid tumor and leukemia and lymphoma cell lines in a ROR1 specific manner. Experiments using GNC-035 to redirect T cell cytotoxicity toward ROR1+ cancer cell targets show the T cells in PBMC are highly functionalized by pre-exposure to GNC-035. This pre-exposure of PBMC to GNC-035 results in greater tumor cell killing efficacy compared to concurrent exposure of tumor cells in the presence of T cell effectors. This result suggests that the systemic delivery of GNC-035 can condition the T cell compartment to increase the therapeutic impact of T cells migrating to solid tumors, with or without preexisting infiltrating T cells. This beneficial conditioning of T cells by pre-exposure to GNC-035 is not observed with pre-exposure to CD3xROR1 bi-specific T cell engager controls. To evaluate the potential for GNC-035 to mediate cytokine release syndrome, the molecule is evaluated in soluble formats in the presence of PBMC and the ROR1+ A549 cancer cells, or HUVEC cells. Under these conditions, the cytolysis of A549 target cells is detectable after exposure to GNC-035 at 100 fM concentrations as well as the release of IFN-γ and certain other inflammatory cytokines at 24 or 48 hours post-treatment. However, consistent with Blinatumomab treatment, PBMC exposed to soluble GNC-035 for 24 or 48 hours on a monolayer of HUVEC cells, produced significantly greater amounts of IFN-γ and IL-6 at concentrations greater than 10 pM. These results indicate GNC-035 has a therapeutic window of activity that is ROR1 dependent, spanning cytolytic activity, and IFN-γ release without a production of IL-6 and which is wider than that indicated by Blinatumomab in PBMC. Collectively, the GNC-035 represents a class of multi-specific and multi-modal immune cell engagers with potential to mediate ROR1+ cancer regression, overcome TCR-based immune escape and reverse T cell immune suppression in tumor microenvironment. The clinical phase I-b study of GNC-035 is under way in breast cancer and hematologic cancers and the available data exhibit strong signals of efficacy with acceptable tolerability. Citation Format: Jahan Salar Khalili, Sa Xiao, Yi Zhu. Tetra-specific antibody GNC-035: guidance and navigation control (GNC) molecule development for treatment of ROR1+ malignancies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5679.

A Concerted Redox- and Light-Activated Agent for Controlled Multimodal Therapy against Hypoxic Cancer Cells.

Hypoxia represents a remarkably exploitable target for cancer therapy, is encountered only in solid human tumors, and is highly associated with cancer resistance and recurrence. Here, a hypoxia-activated mitochondria-accumulated Ru(II) polypyridyl prodrug functionalized with conjugated azo (Az) and nitrogen mustard (NM) functionalities, RuAzNM, is reported. This prodrug has multimodal theranostic properties toward hypoxic cancer cells. Reduction of the azo group in hypoxic cell microenvironments gives rise to the generation of two primary amine products, a free aniline mustard, and the polypyridyl RuNH2 complex. Thus, the aniline mustard triggers generation ofreactive oxygen species (ROS) and mtDNA crosslinking. Meanwhile, the resultant biologically benign phosphorescent RuNH2 gives rise to a diagnostic signal and signals activation of the phototherapy. This multimodal therapeutic effect eventually elevates ROS levels, depletes reduced nicotinamide adenine dinucleotide (NADH) and adenosine triphosphate (ATP), and induces mitochondrial membrane damage, mtDNA damage, and ultimately cell apoptosis. This unique strategy allows controlled multimodal theranostics to be realized in hypoxic cells and multicellular spheroids, making RuAzNM a highly selective and effective cancer-cell-selective theranostic agent (IC50 = 2.3µm for hypoxic HepG2 cancer cells vs 58.2µm for normoxic THL-3 normal cells). This is the first report of a metal-based compound developed as a multimodal theranostic agent for hypoxia.

LncRNA Linc00173 may be a potential prognostic biomarker in human solid tumors: a meta-analysis and bioinformatics analysis.

Despite advances in diagnostic techniques and treatments, cancer remains one of the leading causes of death worldwide.Therefore, finding new biomarkers and therapeutic targets is crucial for improving the diagnosis and treatment of human cancer.LncRNA Linc00173 is a newly identified tumor marker, and in this study, we aimed to explore the relationship between Linc00173 and clinicopathological features and patient prognosis. By using The Cochrane Library, EMbase, Web of Science, PubMed, OVID, we conducted a complete and thorough literature search from its inception to November 10, 2022.Meta-analysis was performed using Stata SE16.0 software. Nine studies involving 1102 patients were included.Meta-analysis showed that the overexpression of Linc00173 was significantly associated with poorer OS (HR = 1.76,95%CI:1.36-2.26, P < 0.001) and shorter DFS (HR = 1.89, 95%CI:1.49-2.40,P < 0.001),and was significantly associated with gender (male) (OR = 1.31,95% CI:1.01-1.69, P = 0.042), tumor size (large) (OR = 1.34,95% CI:1.01-1.78, P = 0.045), and lymph node metastasis (positive) (OR = 1.72,95% CI:1.03-2.88, P = 0.038). Overexpression of Linc00173 is associated with poor prognosis in cancer patients and is a potential prognostic biomarker and therapeutic target.

Selective carbonic anhydrase IX and XII inhibitors based around a functionalized coumarin scaffold.

Inhibition of specific carbonic anhydrase (CA) enzymes is a validated strategy for the development of agents to target cancer. The CA isoforms IX and XII are overexpressed in various human solid tumors wherein they play a critical role in regulating extracellular tumor acidification, proliferation, and progression. A series of novel sulfonamides based on the coumarin scaffold were designed, synthesized and characterized as potent and selective CA inhibitors. Selected compounds show significant activity and selectivity over CA I and CA II to target the tumor-associated CA IX and CA XII with high inhibition activity at the single digit nanomolar level. Twelve compounds were identified to be more potent compared with acetazolamide (AAZ) control to inhibit CA IX while one was also more potent than AAZ to inhibit CA XII. Compound 18f (Ki's = 955 nM, 515 nM, 21 nM and 5 nM for CA's I, II, IX, and XII, respectively) is highlighted as a novel CA IX and XII inhibitor for further development.

Metabolic reprogramming via an engineered PGC-1α improves human chimeric antigen receptor T-cell therapy against solid tumors

BackgroundCellular immunotherapies for cancer represent a means by which a patient’s immune system can be augmented with high numbers of tumor-specific T cells. Chimeric antigen receptor (CAR) therapy involves genetic...

Connecting the macro- and micro-scale properties in human solid tumors: hydraulic conductivity

Connecting the macro- and micro-scale properties in human solid tumors: hydraulic conductivity

Notch signaling, hypoxia, and cancer.

Notch signaling is involved in cell fate determination and deregulated in human solid tumors. Hypoxia is an important feature in many solid tumors, which activates hypoxia-induced factors (HIFs) and their downstream targets to promote tumorigenesis and cancer development. Recently, HIFs have been shown to trigger the Notch signaling pathway in a variety of organisms and tissues. In this review, we focus on the pro- and anti-tumorigenic functions of Notch signaling and discuss the crosstalk between Notch signaling and cellular hypoxic response in cancer pathogenesis, including epithelia-mesenchymal transition, angiogenesis, and the maintenance of cancer stem cells. The pharmacological strategies targeting Notch signaling and hypoxia in cancer are also discussed in this review.

Up-regulated GRB7 protein in gastric cancer cells correlates with clinical properties and increases proliferation and stem cell properties.

It has been reported that GRB7 is closely related to a variety of human solid tumors, but its role in gastric cancer has not been reported yet. The purpose of this study was to investigate the expression level and intracellular effects of GRB7 in human gastric cancer. Real-time fluorescent quantitative PCR and Western blot were used to detect the expression of GRB7 in gastric cancer cell lines. The immunohistochemical staining and SPSS analysis verified the GRB7 protein expression. Stable gastric cancer cell lines, MTT experiments, clone formation experiments, cell cycle flow cytometry experiments, sphere formation experiments and lateral subpopulation cell sorting experiments were conducted to investigate the role of GRB7 in gastric cancer cells. We found that the expression of GRB7 in gastric cancer cell lines was higher than that of the corresponding normal gastric epithelial cells, and correspondingly higher in gastric cancer tissues than its paired adjacent tissues. GRB7 protein was expressed more highly in cancer tissues than in adjacent tissues. GRB7 protein expression levels were positively correlated with the clinical stage of gastric cancer patients, and negatively correlated with the survival prognosis of patients. GSEA analysis of GRB7 mRNA levels in gastric cancer tissues and normal gastric epithelial tissues from public databases showed that GRB7 may affect cell proliferation and related processes of intracellular stem cells. GRB7 can promote the proliferation of gastric cancer cells and is positively related to the self-renewal ability of gastric cancer stem cells. This study shows that GRB7 molecules highly expressed in gastric cancer tissues can promote the proliferation of gastric cancer cells and increase the proportion of gastric cancer stem cells, so it is expected to become a diagnostic molecule or potential therapeutic target for gastric cancer.

Human Solid Tumors and Clinical Relevance of The Enhanced Permeation and Retention Effect: A ‘Golden Gate’ for Nanomedicine in Preclinical Studies?

Nanocarriers passively accumulate in solid tumors through irregular wide fenestrations in neovasculature and increased retention due to poor lymphatic drainage, a phenomenon termed the enhanced permeation and retention (EPR) effect. Although several preclinical reports have described the role of EPR in nanomedicine, its role in human solid tumor is obscure. There are several distinct factors for tumors in mice versus humans, including size, heterogeneity and nanomedicine pharmacokinetics. This reviewfocuses on preclinical and clinical studies demonstrating the role of the EPR effect and passive targeting. The article illustrates the gaps thatlimit clinical effectiveness of the EPR effect and elaborates strategies to boost its efficiency, relaying future clinical outcomes for designing clinically applicable EPR-based nanomedicine.

The link between T cell activation and development of functionally useful tumour-associated high endothelial venules.

High endothelial venules (HEVs) are specialized postcapillary venules that specifically serve to recruit circulating lymphocytes to secondary lymphoid organs (SLOs) where cognate antigens can be encountered, and immune responses can be initiated. The presence of HEV-like vessels in primary human solid tumours and their association with lymphocyte infiltration and favourable clinical outcomes and response to immunotherapy have provided a rationale for therapeutically inducing these vessels in tumours for immunotherapeutic benefit. Here we specifically discuss evidence for a link between T-cell activation and development of useful tumour-associated HEV (TA-HEV). We discuss the molecular and functional features of TA-HEV, highlighting the benefits for promoting tumour immunity and the important unanswered questions that need to be addressed before TA-HEV induction can be optimized for immunotherapeutic benefit.

Tetranuclear Ru2Cu2 and Ru2Ni2 complexes with nanomolar anticancer activity.

Complexes [{RuCp(PPh3)2-μ-dmoPTA-1κP:2κ2-N,N'-CuCl}2-μ-Cl-μ-OCH3](CF3SO3)2·(CH3OH)4 (1) and [{RuCp(PPh3)2-μ-dmoPTA-1κP:2κ2-N,N'-NiCl}2-μ-Cl-μ-OH](CF3SO3)2 (2) have been synthesized and characterized. Their antiproliferative activities were assessed against six human solid tumours showing nanomolar GI50 values. The effects of 1 and 2 on SW1573 cells colony formation, HeLa cells action mechanism and their interaction with the pBR322 DNA plasmid were evaluated.

Cancer immunotherapies transition endothelial cells into HEVs that generate TCF1+ T lymphocyte niches through a feed-forward loop.

The lack of Tcell infiltrates is a major obstacle to effective immunotherapy in cancer. Conversely, the formation of tumor-associated tertiary-lymphoid-like structures (TA-TLLSs), which are the local site of humoral and cellular immune responses against cancers, is associated with good prognosis, and they have recently been detected in immune checkpoint blockade (ICB)-responding patients. However, how these lymphoid aggregates develop remains poorly understood. By employing single-cell transcriptomics, endothelial fate mapping, and functional multiplex immune profiling, we demonstrate that antiangiogenic immune-modulating therapies evoke transdifferentiation of postcapillary venules into inflamed high-endothelial venules (HEVs) via lymphotoxin/lymphotoxin beta receptor (LT/LTβR) signaling. In turn, tumor HEVs boost intratumoral lymphocyte influx and foster permissive lymphocyte niches for PD1- and PD1+TCF1+ CD8 Tcell progenitors that differentiate into GrzB+PD1+ CD8T effector cells. Tumor-HEVs require continuous CD8 and NK cell-derived signals revealing that tumor HEV maintenance is actively sculpted by the adaptive immune system through a feed-forward loop.

Increased tumor glycolysis is associated with decreased immune infiltration across human solid tumors.

Response to immunotherapy across multiple cancer types is approximately 25%, with some tumor types showing increased response rates compared to others (i.e. response rates in melanoma and non-small cell lung cancer (NSCLC) are typically 30-60%). Patients whose tumors are resistant to immunotherapy often lack high levels of pre-existing inflammation in the tumor microenvironment. Increased tumor glycolysis, acting through glucose deprivation and lactic acid accumulation, has been shown to have pleiotropic immune suppressive effects using in-vitro and in-vivo models of disease. To determine whether the immune suppressive effect of tumor glycolysis is observed across human solid tumors, we analyzed glycolytic and immune gene expression patterns in multiple solid malignancies. We found that increased expression of a glycolytic signature was associated with decreased immune infiltration and a more aggressive disease across multiple tumor types. Radiologic and pathologic analysis of untreated estrogen receptor (ER)-negative breast cancers corroborated these observations, and demonstrated that protein expression of glycolytic enzymes correlates positively with glucose uptake and negatively with infiltration of CD3+ and CD8+ lymphocytes. This study reveals an inverse relationship between tumor glycolysis and immune infiltration in a large cohort of multiple solid tumor types.

Prognostic value and immunological role of FOXM1 in human solid tumors.

FOXM1 acts as an oncogenic transcription factor and is involved in multiple hallmarks of human malignancies. Recent studies have demonstrated that FOXM1 is upregulated and correlated with poor prognosis in a majority of cancers. However, there are few pan-cancer analyses of FOXM1. This study aimed to investigate the expression profiles and clinical significance of FOXM1 in 31 types of solid tumors. We explored the expression profiles and the prognostic value of FOXM1 in pan-cancer across The Cancer Genome Atlas (TCGA). We further used lung adenocarcinoma (LUAD) tissues combined with quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) for experimental validation of FOXM1 expression. Besides, we verified the function of FOXM1 in a lung cancer cell line. Gene set enrichment analysis (GSEA) was conducted to explore signaling pathways related to FOXM1 expression. We observed that up-regulated FOXM1 was significantly related to poor survival in most tumors. Furthermore, there are significant correlations between FOXM1 expression and the infiltrating levels of different types of immune cells, TMB, MSI and immune checkpoint genes in a variety of cancers. Additional analysis based on IMvigor 210 cohort confirmed that patients with high level of FOXM1 exhibited a superior response to anti-PD-L1 therapy, and had a prolonged OS. In conclusion, this study indicated that FOXM1 could serve as a prognostic biomarker for most types of cancers and played a crucial role in the tumor immune microenvironment.

BIOM-61. SYSTEMATIC REVIEW OF BIOLOGIC CORRELATES OF FRAILTY IN SOLID TUMORS: IMPLICATIONS FOR BRAIN TUMORS

Abstract BACKGROUND Cancer and cancer treatments contribute to accelerated aging and frailty, which is present in over 50% of adult cancer survivors and increases vulnerability to poor outcomes. Biomarkers of frailty would allow for early identification and timely interventions. The purpose of this review is to synthesize the current literature examining biomarkers of frailty across solid tumor patients, including primary brain tumors (PBT). METHODS The systematic review was conducted using preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines. PubMed, Web of Science, and Embase, were searched by the medical librarian (D.C.) of all reports from the inception to December 08, 2021. Inclusion criteria were: a) English language, b) biomarkers of aging hallmarks, c) association between biomarkers and frailty. Studies were limited to human solid tumors. Two reviewers (D.S. and B.P.S.) independently screened titles, abstracts, and full-text articles using Covidence platform with conflict resolution by the third researcher (T.S.A.). Included studies were independently evaluated for quality assessment using NIH tools for Observational Cohort, Cross-Sectional and Case-Control studies. RESULTS In total, 915 reports were screened and 15 full-text articles were included for the review. Studies were most commonly in breast tumors with no PBTs identified. Most were cross-sectional using small sample sizes. Fried, Balducci, and Leuven Oncogeriatric Frailty tools and cytokines (i.e. Interleukin-6 and C-reactive protein) were commonly used. Increased inflammatory response was the prevalent identified mechanism. Threats to internal validity of the studies were the use of unvalidated cut-off scores or modification of existing tools in about 50% of studies. Only six studies were rated as good using quality assessment ratings. CONCLUSIONS Varied use of frailty measures and nonspecific blood biomarkers limited conclusions for mechanisms of frailty in cancer survivors. There are missed opportunities in neuro-oncology; inclusion of frailty assessment and biomarkers is instrumental to advancing science in PBTs.

FOXC2 as a prognostic marker and a potential molecular target in patients with human solid tumors.

Forkhead Box Protein C2 (FOXC2) belongs to the Forkhead/Wing-helix family. The regulatory role of this transcription factor in physiological function and carcinogenic activity has been proven in subsequent investigations. However, there is still scarcity of evidence on the relationship between FOXC2 expression and prognosis in human solid tumors. We conducted this meta-analysis to evaluate the role of FOXC2 as a prognosis factor and a possible target marker in human solid tumors. PubMed, Web of Science, Embase, and the Cochrane library database were all searched methodically. Eligible publications on FOXC2 in human solid tumors were gathered and reviewed. The effect sizes were calculated using pooled hazard ratios (HRs) or odds ratios (ORs) with the corresponding 95% confidence interval (CI). Statistical analysis was conducted with Stata SE12.0. This meta-analysis comprised 3,267 patients from 20 studies covering a variety of solid tumors. Increased FOXC2 expression was related to shorter overall survival (OS) (HR = 2.05, 95% CI: 1.73-2.42). High expression of FOXC2 is associated with lymph node metastases (OR = 3.33, 95% CI: 2.65-4.19), TNM stage (OR = 3.09, 95% CI: 2.00-4.78), and age (OR = 1.26, 95% CI: 1.06-1.50), according to the pooled ORs. However, no significant association was observed between the high expression of FOXC2 and sex, tumor size or tumor differentiation. Increased expression of FOXC2 is associated with unfavored OS, lymph node metastases, TNM stage, and age. FOXC2 is a promising prognostic marker and a novel target marker in human solid tumors.

Prognostic and Immunological Roles of Cell Cycle Regulator CDCA5 in Human Solid Tumors.

There have been several studies evaluating the prognostic significance of cell division cycle associated 5 (CDCA5). However, few reports analyzed the correlation between CDCA5 and prognosis of diverse cancers based on large clinical data. We thus comprehensively analyzed CDCA5 expression and clinical significance using The Cancer Genome Atlas (TCGA) data from 31 types of solid tumors. The expression profiles of CDCA5 were investigated across pan-cancer samples from the TCGA. Cox regression and Kaplan-Meier analysis was performed to determine CDCA5's prognostic value. CDCA5 expression was further validated by quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) in lung adenocarcinoma (LUAD). We found that CDCA5 was significantly overexpressed in 22 types of tumors. Up-regulated CDCA5 was significantly related to poor survival in 13 types of tumors. Furthermore, CDCA5 expression was significantly associated with immune cell infiltration. Tumor mutation burden (TMB), microsatellite instability (MSI), and immune checkpoint expression were significantly correlated with CDCA5 expression. Additional analysis of IMvigor 210 cohort validated that patients with high level of CDCA5 had superior response to anti-PD-L1 therapy. Our findings suggested that CDCA5 could provide prognostic information in most types of cancers and contributed to tumor immune microenvironment.

Protein tyrosine kinase 6 regulates activation of SRC kinase

Expression of Protein tyrosine kinase 6 (PTK6) is upregulated in several human solid tumors, and it has oncogenic roles in prostate and breast cancer. PTK6 and SRC kinase are distantly related, share many substrates, and often regulate the same signaling pathways, but whether they interact to regulate signaling is not well understood. We characterized crosstalk between PTK6 and SRC and show that PTK6 can directly phosphorylate SRC to promote its activation. Stable knockdown of PTK6 in multiple cancer cell lines leads to decreased activating phosphorylation of SRC. We show that coexpression of kinase-dead SRC and active PTK6 in mouse embryonic fibroblasts lacking Src, Yes, and Fyn results in activating phosphorylation of SRC. However, there is no reciprocal effect, because active SRC does not promote activating phosphorylation of PTK6. Overexpression of active PTK6 maintained activation of epidermal growth factor receptor (EGFR), AKT, and FAK, but not SHP2 and ERK1/2 in cells with knockdown of SRC. Both PTK6 and SRC are regulated by EGFR, and its inhibition with erlotinib downregulated PTK6 and to a lesser degree SRC activation in LNCaP cells that overexpress active PTK6. Erlotinib treatment also led to AKT inhibition, but overexpression of active PTK6 prevented this. Our data demonstrate overlapping and unique functions for PTK6 and SRC. Finally, we show that PTK6 and SRC are coexpressed in subsets of human prostate and breast cancer cells, and active PTK6 and active SRC colocalize in prostate cancer, supporting a role for PTK6 in promoting SRC activity in cancer.

PLEKHH2 binds β-arrestin1 through its FERM domain, activates FAK/PI3K/AKT phosphorylation, and promotes the malignant phenotype of non-small cell lung cancer

PLEKHH2 is an important FERM domain containing-protein. However, the role of PLEKHH2 in human solid tumors has not been reported yet. We report that PLEKHH2 showed enhanced cytoplasmic expression in non-small cell lung cancer (NSCLC). Its overexpression was positively correlated with high TNM stage, low differentiation, lymphatic node metastasis, and poor prognosis. In A549 and H1299 cells, high expression of PLEKHH2 significantly promoted cell proliferation, migration, invasion, and increased the expression of proliferation- and invasion-related proteins. It also enhanced the phosphorylation of FAK and promoted the activity of the PI3K/AKT pathway. Immunofluorescence and co-immunoprecipitation analyses were performed to elucidate the molecular mechanism underlying PLEKHH2-mediated regulation of proliferation and invasion in lung cancer cells. Upon transfection of full length PLEKHH2 or its FERM domain, we observed enhanced binding of PLEKHH2 to β-arrestin1, whereas FAK- β-arrestin1 binding was diminished and this led to an increase in FAK phosphorylation. PLEKHH2-mutant plasmids without the FERM domain could not effectively promote its binding to β-arrestin1, activation of FAK phosphorylation, PI3K/AKT activation, or the malignant phenotype. Our findings suggested that PLEKHH2 is an important oncogene in NSCLC. PLEKHH2 binding to β-arrestin1 through the FERM domain competitively inhibits β-arrestin1 binding to FAK, which causes the dissociation of FAK from the FAK-β-arrestin1 complex. Furthermore, the dissociation of FAK promotes its autophosphorylation, activates the PI3K/AKT signaling pathway, and subsequently promotes lung cancer cell proliferation, migration, and invasion. These results provide evidence for the potential use of PLEKHH2 inhibition as an anticancer therapy.

Lessons to cancer from studies of leukemia and hematopoiesis

The starting point to describing the origin and nature of any cancer must be knowledge about how the normal counterpart tissue develops. New principles to the nature of hematopoietic stem cells have arisen in recent years. In particular, hematopoietic stem cells can “choose” a cell lineage directly from a spectrum of the end-cell options, and are, therefore, a heterogeneous population of lineage affiliated/biased cells. These cells remain versatile because the developmental trajectories of hematopoietic stem and progenitor cells are broad. From studies of human acute myeloid leukemia, leukemia is also a hierarchy of maturing or partially maturing cells that are sustained by leukemia stem cells at the apex. This cellular hierarchy model has been extended to a wide variety of human solid tumors, by the identification of cancer stem cells, and is termed the cancer stem cell model. At least, two genomic insults are needed for cancer, as seen from studies of human childhood acute lymphoblastic leukemia. There are signature mutations for some leukemia’s and some relate to a transcription factor that guides the cell lineage of developing hematopoietic stem/progenitor cells. Similarly, some oncogenes restrict the fate of leukemia stem cells and their offspring to a single maturation pathway. In this case, a loss of intrinsic stem cell versatility seems to be a property of leukemia stem cells. To provide more effective cures for leukemia, there is the need to find ways to eliminate leukemia stem cells.