CHIP and adverse events. A, Percentage of patients on each treatment that had an adverse event on therapy, split by cohort and treatment. B, Proportions of patients with adverse events split by CHIP status. Lighter shades indicate no adverse event, and darker shades indicate an adverse event. P values were determined by Fisher exact tests.

Before diagnosis, a pre-leukemic state precedes leukemia, where a single mutated hematopoietic stem cell (HSC) with a competitive growth advantage expands clonally (termed clonal hematopoiesis (CH)). Autosomal mosaic chromosome alterations (mCAs) are common CH drivers but are unexplored mechanistically. Chromosome 13q deletion (13q-) is one of the most common mCAs, increasing leukemia risk 29.5-fold and chronic lymphocytic leukemia (CLL) 185-fold. We informatically determined that a 260kb region containing two lincRNAs, DLEU1 and DLEU2 is the 13q minimum deleted region (MDR). With CRISPR, the 13q MDR was deleted in human cord blood hematopoietic stem and progenitor cells (HSPCs). Then, detailed in vitro single-cell erythro-myeloid (EM) and B cell stromal differentiation assays and in vivo xenograft assays determined the effects of 13q- on HSC function. In vitro studies with 1,385 colonies showed a significantly increased CD14+ monocyte and decreased B cell output in MDR knock-out (KO) long-term (LT-) HSC-derived colonies. However, detailed analysis of the B cell lineage showed MDR KO increased proportion of primitive CD10+ B cells followed by decreased proportion of more mature CD19+ B cells, pointing to a downstream differentiation block; this was seen in LT-, short-term (ST-) HSC, and multi-lymphoid progenitors (MLPs) derived colonies. MDR KO also increased the number of LT-HSC-derived colonies expressing CD34+. Together, MDR KO in HSPCs increases monocyte output, retains the primitiveness of HSCs, and delays B cell maturation in vitro. 13q- CH humanized models were established by xenotransplanting MDR KO LT-HSCs or CD34+CD38- HSPCs into 174 NSG, NSG-SGM3, and NSG-Quad mice. Comparing the proportion of cells with MDR KO before and after 10-20 weeks of transplantation revealed a doubling in the percentage of KO cells in the human graft at endpoint, indicating a competitive growth or output advantage conferred by 13q- in HSCs. Supporting this, MDR KO cells generated larger CD45+ human grafts than control in injected femurs and peripheral lymphoid organs such as spleens and livers. There were 10% greater MDR KO cell prevalence in male recipients, correlating to higher male prevalence of autosomal mCA in CH and CLL, suggesting the male environment enhanced advantages in MDR KO HSCs. Aligning with in vitro studies, both monocytes and more primitive CD10+CD20- pro-B cells were increased and more mature CD10+/-CD20+ B cells were decreased in MDR KO xenografts. Moreover, a decrease in neutrophils and splenomegaly were observed, but with no evidence of CLL. To examine mature myeloid subsets in more detail, we adopted NSG-Quad mice. These express transgenic huCSF1 that promotes monocyte mobilization and macrophage differentiation. Liver and lung homogenates from NSG-Quad showed a significant, male-specific reduction in tissue resident macrophages upon MDR KO. Together, 13q- endows a competitive growth advantage in HSPCs, perturbs monocyte, neutrophil, and tissue resident macrophages output, and promotes primitiveness of B cells. Although extending outside the MDR, the lincRNA DLEU2 contains miR-15a and miR-16-1, two intronic miRNAs proposed to drive CLL in mouse models. To identify potential genes responsible for the MDR phenotypes, we repeated all the in vitro and xenotransplantation assays using miR-15a/16-1 KO human HSPCs. Most findings phenocopied the MDR results, suggesting that miR-15a/16-1 contributes to 13q- CH. However, the magnitude of the effect was less than MDR, suggesting that not all the impact of MDR can be explained by miR-15a/16-1. This data also points to a potential regulatory element within the MDR that impacts DLEU2/miR-15a/16-1, which is our active objective to uncover. Here we establish that a large chromosomal alteration 13q- provides a competitive growth advantage to human HSC and alters their differentiation output. Mechanistic studies into how 13q hijacks normal stemness programs to give a growth advantage are ongoing, and this could inform potential therapeutic targets for 13q- CH and CLL. Broadly, our 13q example offers a roadmap for modeling other mCAs and evaluating their effect on human HSC. These will be valuable for studying mCA-driven CH and the malignant and non-malignant diseases that derive from them.

Prevalence of CHIP variants across cohorts and CHIP association with age. A, Percentage of patients with CHIP variants in each cohort. Insert shows the breakdown by tumor type in the PREDiCT-l cohort. B, Number of patients with a CHIP variant in each gene; DNMT3A, TET2, and ASXL1. C, Protein position of coding variants by gene. Each lollipop represents a patient, multiple dots show patients with the same variant position, and red outlines show variants of high impact (frameshift or stop gain). Orange bars along the length of the genes show functional domains. D, Percentage of patients with CHIP variants by age group. E, Age difference between patients with CHIP (CHIP+) and without CHIP (CHIP−). P value was determined by the Wilcoxon rank sum test.

VAF of all CHIP variants split by cohort

Clinical Characteristics of B-ALL Patient Samples.

Clonal hematopoiesis (CH) arises when a single mutated hematopoietic stem cell (HSC) acquires a competitive growth advantage and undergoes clonal expansion. Autosomal mosaic chromosome alterations (mCAs) are common CH drivers, of which 13q deletion (13q−) is the most prevalent. However, the mechanistic link between mCAs and CH is unexplored due to a lack of human models. A 260kb region containing only two lncRNAs, DLEU1 and DLEU2, was found to comprise the 13q minimum deleted region (MDR). Human cord blood HSCs with CRISPR-induced 13q MDR or control deletion were subjected to single-cell in vitro erythromyeloid and B-cell differentiation assays. Our analysis of 1385 colonies showed that MDR loss increased CD14+ monocytes and primitive CD10+ B cells but decreased B-cell maturation. Engineered HSCs were also transplanted into 174 immunodeficient mice for 10–20 weeks. Cells with MDR loss doubled in proportion relative to unedited cells at end point, indicating a competitive growth advantage. There were 29% greater MDR-deleted cells in male recipients, correlating to higher male prevalence of autosomal mCAs in CH and chronic lymphocytic leukemia (CLL). Both monocytes and CD10+CD20- pro-B cells were increased, congruent with our in vitro results. We further examined mature myeloid progeny in xenograft recipients expressing transgenic huCSF1, which promotes monocyte mobilization and macrophage differentiation. Loss of 13q MDR led to a significant, male-specific reduction in tissue-resident macrophages within the livers and lungs. Here, we established the first human mCA-driven model of CH, showing 13q− drives clonal expansion and alters lymphoid and myeloid differentiation, which alludes to premalignancy. Ongoing mechanistic studies could inform therapeutic targets for 13q− CH and CLL. Our study also offers a blueprint for investigating other mCAs that drive CH and malignancy.

CHIP and treatment outcomes. Kaplan–Meier curves showing the difference in outcome between patients with (CHIP+) and without CHIP (CHIP−) and outcomes on different therapies. PFS is shown on the left two columns for all three cohorts, and OS is on the right two columns for CO.26 (top row) and PA.7 (middle row). Hazard ratios displayed are derived from univariable Cox proportional hazards models, and interaction P values are from multivariable models (see “Materials and Methods”).

Ten-Eleven Translocation-2 (TET2) mutations drive the expansion of mutant hematopoietic stem cells (HSCs) in clonal hematopoiesis (CH). However, the precise mechanisms by which TET2 mutations confer a competitive advantage to HSCs remain unclear. Here, through an epigenetic drug screen, we discover that inhibition of disruptor of telomeric silencing 1-like (DOT1L), a H3K79 methyltransferase, selectively reduces the fitness of Tet2 knockout (Tet2KO) hematopoietic stem and progenitor cells (HSPCs). Mechanistically, we find that TET2 deficiency increases H3K79 dimethylation and expression of Mpl, which encodes the thrombopoietin receptor (TPO-R). Correspondingly, TET2 deficiency is associated with a higher proportion of primitive Mpl-expressing (Mpl+) cells in the HSC compartment. Importantly, inhibition of Mpl expression or the signaling downstream of TPO-R is sufficient to reduce the competitive advantage of murine and human TET2-deficient HSPCs. Our findings demonstrate a critical role for aberrant TPO-R signaling in TET2 mutation-driven CH and uncover potential therapeutic strategies against this condition.

Progression free survival for patients on PREDiCT-l, split by tumor type. Therapy received is indicated in each title above each Kaplan Meier curve.

Abstract Clonal hematopoiesis of indeterminate potential (CHIP) is the clonal expansion of hematopoietic stem cells from somatic mutations. It is a common incidental finding in cell-free DNA (cfDNA). We investigated the incidence of CHIP in cfDNA from patients with solid tumors and explored its association with treatment outcomes and adverse events. We reviewed cfDNA results from a local prospective solid tumor cohort (PREDiCT-l) and two randomized trials: Canadian Cancer Trials Group CO.26 [durvalumab + tremelimumab (D + T) or best supportive care in metastatic colorectal cancer] and Canadian Cancer Trials Group PA.7 (gemcitabine and nab-paclitaxel ± D + T in metastatic pancreatic adenocarcinoma). CHIP+ was defined as any mutation in DNMT3A, TET2, or ASXL1 with a variant allele frequency ≥2%. Presumed germline variants (variant allele frequency >40%) were removed. The first line of treatment after cfDNA was reviewed for grade ≥3 and dose-limiting toxicities. The prevalence of CHIP in the 465 included patients was 10% to 30%, and it was more common as age increased (P = 0.003). DNMT3A was the gene most frequently mutated in all cohorts. Patients with CHIP in PA.7 treated with immunotherapy showed an improved progression-free survival versus CHIP− [HR = 0.55 (0.28–1.07); P = 0.079, P-interaction = 0.098 (multivariable)]. However, patients with CHIP treated with chemotherapy in PREDiCT-l showed a trend toward worse progression-free survival [HR = 1.82 (0.98–3.38); P = 0.059]. There was no difference in adverse event rates between CHIP ± groups for those treated with chemotherapy or immunotherapy. CHIP is common in patients with solid tumors. Although not appearing to affect rates of adverse events, CHIP may affect outcomes from immunotherapy or chemotherapy. Significance: Liquid biopsy is increasingly being used in oncology for tumor molecular characterization. CHIP is a common incidental finding in cfDNA, and its prevalence increases with age. This study builds on growing evidence of common CHIP variants in patients with solid tumors. The results suggest a possible clinical impact of CHIP on treatment outcomes from immunotherapy or chemotherapy. This may have implications for treatment selection for patients with solid tumors.

Clonal hematopoiesis (CH)-the expansion of somatically mutated hematopoietic cells-is common in solid cancers. CH is associated with systemic inflammation, but its impact on tumor biology is underexplored. Here, we report the effects of CH on the tumor microenvironment (TME) using 1,550 treatment-naive patient samples from the Clinical Proteomics Tumor Analysis Consortium (CPTAC) cohort. CH is present in 18.3% of patients, with one-third of CH mutations also detectable in tumor-derived DNA from the same individual (CH-Tum), reflecting CH-mutant leukocyte infiltration. Across cancers, the presence of CH-Tum is associated with worse survival outcomes. Molecular analyses reveal an association between CH-Tum and an immune-rich, inflammatory TME that is notably distinct from age-related gene expression changes. These effects are most prominent in glioblastoma, where CH correlates with pronounced macrophage infiltration, inflammation, and an aggressive, mesenchymal phenotype. Our findings demonstrate that CH shapes the TME, with potential applications as a biomarker in precision oncology.

Functional cellular heterogeneity in tumours often underlies incomplete response to therapy and relapse. Previously, we demonstrated that the growth of the paediatric brain malignancy, sonic hedgehog subgroup medulloblastoma, is rooted in a dysregulated developmental hierarchy, the apex of which is defined by characteristically quiescent SOX2+ stem-like cells. Integrating gene expression and chromatin accessibility patterns in distinct cellular compartments, we identify the transcription factor Olig2 as regulating the stem cell fate transition from quiescence to activation, driving the generation of downstream neoplastic progenitors. Inactivation of Olig2 blocks stem cell activation and tumour output. Targeting this rare OLIG2-driven proliferative programme with a small molecule inhibitor, CT-179, dramatically attenuates early tumour formation and tumour regrowth post-therapy, and significantly increases median survival in vivo. We demonstrate that targeting transition from quiescence to proliferation at the level of the tumorigenic cell could be a pivotal medulloblastoma treatment strategy. Previous work shows that a small population of quiescent SOX2+ medulloblastoma (MB) stem cells can drive tumour growth in early tumorigenesis and relapse. Here, the authors identify OLIG2 as a transcriptional mediator of the transition from quiescent to rapidly proliferating progenitor states and therapeutically target this axis in preclinical models of MB.

All CHIP variants identified in the study

2567 Background: Clonal hematopoiesis (CH) is caused by somatic mutations that provide a fitness advantage in hematopoietic stem cells, contributing to inflammation and disease. CH is common in solid tumor patients, and has shown context-dependent associations with survival; however, its contribution to the tumor microenvironment (TME) remains unclear. Here, we employ proteogenomic methods to define CH-associated alterations in the TME. Methods: We tested 1,550 patients across 10 primary, treatment-naïve cancers in the Clinical Proteomic Tumor Analysis Consortium cohort. CH calls were derived from peripheral blood and tumour whole exome sequencing (WES) data, and CH was defined as the presence of a somatic driver mutation at variant allele frequency (VAF) ≥2% in blood. Overall survival (OS) analysis was conducted using Cox proportional hazard models, controlled for age, sex, tumor type, metastatic status, and smoking. Tumor bulk RNA-sequencing and mass spectrometry proteomics data were processed for differential expression and gene set enrichment analyses. Abundance of immune cell populations was estimated with CibersortX. Results: 349 CH mutations were identified in 283 patients (18.3%). CH was strongly associated with age and mutations were mostly found in the epigenetic regulators DNMT3A(37.8%, n=132) and TET2(20.6%, n=72). CH was most prevalent in ovarian cancer (30%, n=27/90) and colorectal cancer (CRC; 28.3%, n=30/106). 103 blood CH mutations were also detected in tumor WES (CHTum), with presence in the tumor associated with higher tumor immune infiltration and peripheral blood VAF ≥10%. CHTum, but not CH, was associated with worse OS (CHTum HR = 1.74 [1.13-2.69]; CH HR = 1.12 [0.83-1.50]). CHTum was also associated with a reduced likelihood of patients being classified as tumor free at follow up (OR = 0.39 [0.19-0.82]). We did not identify a pan-cancer proteogenomic signature of CH in the TME. At the tumor-specific level, we consistently observed associations between CH and its subtypes with dysregulated inflammation, with high transcriptomic-proteomic concordance. In CRC, TET2-mutant CH was associated with greater infiltration of CD4+ T cells, monocyte/macrophages, NK cells, and B cells, alongside an inflammatory response characterized by IL6/JAK/STAT3 signalling, TNF signalling via NFκB, and IL2/STAT5 signalling. Conclusions: CH is common, even prior to therapy, in solid tumor patients and the infiltration of CH-mutant immune clones into the TME is linked with poor outcomes. Beyond confounding molecular tumor diagnostics, CH in the TME also dysregulates the anti-tumor immune response, highlighting the value of a blood reference in precision oncology. The lack of a pan-cancer CH signature in the TME supports a tumor-specific influence of CH. Further study is needed for mechanistic discovery and biomarker development to realize the potential of CH in immuno-oncology and improve patient outcomes.

Background: Clonal hematopoiesis (CH) drives systemic inflammation and chronic disease with aging. In solid tumor patients, CH is common and has context-dependent effects on survival outcomes. CH mutations promote both pro- and anti-tumor immune phenotypes in solid tumor models, although implications in human cancer are still unclear. We present a multi-omics characterization of CH in the tumor microenvironment (TME) to evaluate the biomarker potential of CH in oncology. Methods: This study used the data of 1,550 patients from the Clinical Proteomics Tumor Analysis Consortium (CPTAC) and 8,927 patients from The Cancer Genome Atlas (TCGA) cohorts. Patients were treatment-naïve and mainly had local disease. Somatic variants in peripheral blood and tumor whole exome sequencing (WES) were detected using GATK-Mutect2, and CH status was ascertained as described previously (PMID: 36652671). Cox proportional hazard models controlled for age, sex, tumor type, metastatic status, and smoking were used to assess overall survival (OS). Differential expression analysis was conducted using DESeq2 and limma for tumor bulk RNA-seq and mass spectrometry proteomics data, followed by gene set enrichment analysis. Immune cell abundance was estimated using CIBERSORTx. Results: 349 CH mutations were identified in 18.3% of patients in CPTAC, and CH was strongly associated with age (p=1.6x10-11). CH mutations were most frequent in epigenetic regulators DNMT3A and TET2 (37.8%, n=132; 20.6%, n=72). In 103 patients with CH, the mutation called in peripheral blood WES was also present in tumor WES (CH-Tum). CH-Tum was associated with higher tumor immune infiltrate (p= 0.003) and peripheral blood VAF ≥10% (p=8.6x10-10). In TCGA, the prevalence of CH was 8.74% (n=780/8,927); however, CH detection was related to WES depth. CPTAC had significantly higher average depth than TCGA (248x vs 94x, p=0), and higher coverage of the most common CH drivers (DNMT3A 215x vs. 77x, p=0; TET2 312x vs 44x, p=0). In CPTAC, CH-Tum, but not CH, was associated with worse OS (CH-Tum HR = 1.74 [1.13-2.69]; CH HR = 1.12 [0.83-1.50]). CH-Tum was also associated with a reduced likelihood of patients being classified as tumor free at follow up (OR = 0.39 [0.19-0.82]). Across cancers, CH-Tum was associated with elevated expression of inflammatory markers like IL1A and the S100 alarmins, enrichment of HALLMARK pathways including IL6-JAK-STAT signalling, angiogenesis, and the epithelial mesenchymal transition (EMT) in tumor RNA-seq. Furthermore, gene sets predictive of immune checkpoint inhibitor response were upregulated in tumors from patients with CH. CH-Tum correlated with higher macrophage, neutrophil, and regulatory T cell signatures within the tumor. Gene expression changes and clinical outcomes related to CH varied between cancer types. Glioblastoma multiforme (GBM) stood out with prominent enrichment of numerous inflammatory pathways and macrophage infiltration, accompanied by worse OS with CH-Tum (HR = 3.63 [1.21-10.9]). There was a nominal trend towards GBM cases with CH-Tum adopting the aggressive, immune-rich mesenchymal phenotype (OR=6.55 [0.70-61.1]), as well as significant enrichment of glioma stem cell signatures. Even within the mesenchymal GBM cases, CH-Tum was associated with enrichment of inflammatory signalling, angiogenesis, and mitogenic signalling, trending strongly towards worse OS in multivariate analysis (HR=3.82 [0.99-14.7]). Conclusion: CH is common in treatment-naïve solid cancer patients, and the infiltration of CH-mutant leukocytes into the TME is associated with poor prognosis across cancers. CH-Tum is correlated with more pronounced inflammatory dysregulation, altered immune infiltrates, and cancer hallmarks like angiogenesis and EMT, suggesting that clonal burden in the blood may not be the sole determinant of non-hematologic outcomes with CH. Rather, the degree of mutant cell infiltration of the tumor - or any tissue - may be a paradigm for understanding the connection between CH and chronic disease. Heterogeneity of outcomes across different cancer types also supports a role for the local microenvironment in dictating the effects of CH, as suggested by the exacerbation of immune-rich, mesenchymal GBM phenotypes observed with CH-Tum. As more is uncovered about CH in the solid tumor context, CH-Tum presents a promising new biomarker for improving outcomes in the era of immuno-oncology.

Clonal hematopoiesis is common in solid tumour patients, who frequently have loss of function mutations in TET2. TET2 restricts innate and adaptive immunity, so we hypothesized that TET2-mutant clonal hematopoiesis (TET2-CH) is associated with immunotherapy response. To test this hypothesis, syngeneic colorectal cancer-bearing mice with Tet2-heterozygous null (Tet2-het) or wild type hematopoiesis were treated with anti-PD-1 immunotherapy. Treatment responses were greater and tumors were smaller in Tet2-het mice. The Tet2-effect required phagocytes, CD4, and CD8 T cells, but not NK cells. scRNA-seq revealed how Tet2-mutations reshape the tumor-infiltrating cell (TIL) landscape with immunotherapy by inducing anti-tumour states and restricting pro-tumour cell states. Tet2-mutant monocytes upregulated T cell costimulatory genesets and we found enhanced communication between Tet2-het antigen presenting and T cells. Combined sc-genotyping and RNA-seq of primary TET2-CH patient leukocytes showed that, like mouse TILs, human TET2-mutant monocytes upregulated costimulatory and inflammatory programs associated with immunotherapy response. TET2-mutant CD8 T cells were rare but strikingly enriched for memory programs and TCR signaling, yet suppressed an exhaustion signature. Melanoma patient RNA-seq showed TET2-CH+ tumours are enriched for antigen presentation/costimulation and T cell memory versus exhaustion. TET2-CH+ melanomas also had increased immune infiltrate, T cells and dendritic cells, and re-analysis of 200 immunotherapy-treated melanoma patients showed those with TET2-CH were 6-fold more likely to benefit from immunotherapy. Therefore, across mouse tumours, human leukocytes and tumours, somatic TET2-mutations activate transcriptional programs in myeloid and T cells associated with anti-tumour immunity, which correlate with enhanced immunotherapy response in melanoma.

Somatic mutations inactivating TET2 are among the most common drivers of clonal hematopoiesis (CH). While TET2 inactivation is associated with monocyte-derived inflammation and improved chimeric antigen-receptor-T cell function, its impact on immunotherapy response is unknown. In our mouse model, hematopoietic Tet2 mutation enhanced immune checkpoint blockade (ICB) response. Enhanced ICB response with Tet2 mutation required phagocytes, CD4 and CD8 T cells. Mechanistically, in Tet2 -mutant tumor-infiltrating leukocytes (TILs), ICB preferentially induced anti-tumor states and restricted cell states linked to tumor progression. Tet2 -mutant monocytes activated costimulatory programs, while Tet2 -mutant T cells showed enhanced T cell memory signatures, lesser exhaustion and decreased regulatory phenotype. Our murine data was clinically relevant, since we found that melanomas from patients with TET2 driver mutation-CH (TET2-CH) showed enhanced immune infiltration, T cell activation, and T cell memory programs. In melanoma patients treated with ICB, TET2-CH was associated with 6-fold greater odds of clinical benefit. Collectively, our data establishes that hematopoietic Tet2 inactivation primes leukocytes for anti-tumor states associated with immunotherapy response and provides a potential biomarker for personalized therapy. ### Competing Interest Statement RJV and JED are co-inventors of a patent Clonal Hematopoiesis as a Biomarker. J.E.D. receives revenue from patents licenced to Trillium Therapeutics Inc/Pfizer and receives a commercial research grant from Celgene/BMS.

3521 Background: CHIP is the clonal expansion of hematopoietic stem cells following acquisition of somatic mutations. It is a common incidental finding in cell-free DNA (cfDNA). We investigated the incidence of CHIP in cfDNA from patients with solid tumors and explored its association with outcomes and adverse events (AEs). Methods: We reviewed cfDNA results from a local prospective solid tumor cohort (PREDICT-L) and two randomized trials: CCTG CO.26 (durvalumab + tremelimumab [D+T] or best supportive care [BSC] in metastatic colorectal cancer [mCRC]) and CCTG PA.7 (gemcitabine and nab-paclitaxel [GN] +/- D+T in metastatic pancreatic adenocarcinoma [mPDAC]). CHIP+ was defined as any mutation in DNMT3A, TET2, ASXL1or ATM with a variant allele frequency (VAF) 2% or higher. Variants were considered germline if the VAF was >40%, or were annotated as germline by respective assays. The first line of treatment after cfDNA was reviewed for grade 3 or higher and dose-limiting AEs. Results: The prevalence of CHIP was 10%-21% and was more common in older patients (p=0.003). There was no association between CHIP and sex (p=0.80) or ECOG status (p=0.31). The VAF of CHIP variants was similar across all panels, and DNMT3A was the gene most frequently mutated in all cohorts. Patients with CHIP in PA.7 treated with immunotherapy (IO) had improved progression-free survival (PFS) versus patients without CHIP (p=0.036, p-interaction=0.061 [multivariable]). However, patients with CHIP treated with chemotherapy (Chemo) showed a trend towards worse overall survival (OS) in the PREDICT-L cohort (p=0.057). There was no significant difference in the rates of AEs between the CHIP+ versus CHIP- groups for those treated with Chemo or IO. Conclusions: CHIP is common in patients with solid tumors. Although not appearing to impact rates of AEs, CHIP may impact outcomes from Chemo or IO. [Table: see text]

PDF file - 180K, HoxA10 leukemia targets in Glioma NS cells

dPDX and dRI-PDX leukemia-initiating cell frequencies