Real-World Use of Ubrogepant as Acute Treatment for Migraine with an Anti-Calcitonin Gene-Related Peptide Monoclonal Antibody: Results from COURAGE.

INTRODUCTION: Although acute and preventive treatments for migraine are commonly given in combination, data on the real-world effectiveness of ubrogepant as an acute treatment when used with an anti-calcitonin gene-related peptide (CGRP) monoclonal antibody (with or without onabotulinumtoxinA) are limited. This analysis sought to evaluate the real-world effectiveness, treatment satisfaction, and optimization of ubrogepant for the acute treatment of migraine when used in combination with an anti-CGRP monoclonal antibody, with or without concomitant onabotulinumtoxinA. METHODS: This prospective, multiple-attack, open-label, observational study (COURAGE) assessed meaningful pain relief (MPR), return to normal function (RNF), treatment satisfaction, and acute treatment optimization of ubrogepant (50 or 100 mg) when combined with an anti-CGRP monoclonal antibody, onabotulinumtoxinA, or both in adult users of Migraine Buddy, a migraine tracking application. RESULTS: In the ubrogepant and anti-CGRP monoclonal antibody arm (n = 245), following the first ubrogepant-treated attack, 61.6% (151/245) and 80.4% (197/245) of ubrogepant-treated participants achieved MPR at 2 and 4 h post-dose, respectively, and 34.7% (85/245) and 55.5% (136/245) achieved RNF at 2 and 4 h post-dose, respectively. Across up to 10 ubrogepant-treated attacks (N = 1153), MPR was achieved in 51.3% (592/1153) and 73.5% (847/1153) at 2 and 4 h post-dose, respectively. RNF was achieved by 32.2% (371/1153) and 53.2% (613/1153) at 2 and 4 h post-dose. After 30 days, 72.7% (168/231) of participants reported satisfaction (using a 7-point scale) with ubrogepant when used in combination with an anti-CGRP monoclonal antibody, and 79.7% (184/231) of participants achieved acute treatment optimization (defined as moderate-maximum treatment efficacy using the Migraine Treatment Optimization Questionnaire-4). CONCLUSION: Real-world ubrogepant use with an anti-CGRP monoclonal antibody was associated with MPR, RNF, satisfaction, and acute treatment optimization.

Simultaneous Comparisons of 25 Acute Migraine Medications Based on 10 Million Users' Self-Reported Records From a Smartphone Application.

BACKGROUND AND OBJECTIVES: Many acute treatment options exist for migraine. However, large-scale, head-to-head comparisons of treatment effectiveness from real-world patient experience reports are lacking. METHODS: This is a retrospective analysis of 10,842,795 migraine attack records extracted from an e-diary smartphone application between June 30, 2014, and July 2, 2020. We analyzed 25 acute medications among 7 classes-acetaminophen, nonsteroid anti-inflammatory drugs (NSAIDs), triptans, combination analgesics, ergots, antiemetics, and opioids. Gepants and ditan were not included in this analysis. Different doses and formulations of each medication, according to the generic names, were combined in this analysis. We used a 2-level nested logistic regression model to analyze the odds ratio (OR) of treatment effectiveness of each medication by adjusting concurrent medications and the covariance within the same user. Subgroup analyses were conducted for users in the United States, the United Kingdom, and Canada. RESULTS: Our final analysis included 4,777,524 medication-outcome pairs from 3,119,517 migraine attacks among 278,006 users. Triptans (mean OR 4.8), ergots (mean OR 3.02), and antiemetics (mean OR 2.67) were the top 3 classes of medications with the highest effectiveness, followed by opioids (mean OR 2.49), NSAIDs (other than ibuprofen, mean OR 1.94), combination analgesics (acetaminophen/acetylsalicylic acid/caffeine) (OR 1.69, 95% CI 1.67-1.71), others (OR 1.49, 95% CI 1.47-1.50), and acetaminophen (OR 0.83, 95% CI 0.83-0.84), using ibuprofen as the reference. Individual medications with the highest ORs were eletriptan (OR 6.1, 95% CI 6.0-6.3), zolmitriptan (OR 5.7, 95% CI 5.6-5.8), and sumatriptan (OR 5.2, 95% CI 5.2-5.3). The ORs of acetaminophen, NSAIDS, combination analgesics, and opioids were mostly around or less than 1, suggesting similar or lower reported effectiveness compared with ibuprofen. The ORs for 24 medications, except that of acetylsalicylic acid, achieved statistical significance with p < 0.0001, and our nested logistic regression model achieved an area under the curve (AUC) of 0.849. Country-specific subgroup analyses revealed similar ORs of each medication and AUC (United States 0.849, United Kingdom 0.864, and Canada 0.842), demonstrating the robustness of our analysis. DISCUSSION: Using a big data approach, we analyzed patient-generated real-time records of 10 million migraine attacks and conducted simultaneous head-to-head comparisons of 25 acute migraine medications. Our findings that triptans, ergots, and antiemetics are the most effective classes of medications align with the guideline recommendations and offer generalizable insights to complement clinical practice. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with migraine, selected acute medications (e.g., triptans, ergots, antiemetics) are associated with higher odds of user-rated positive response than ibuprofen.

3D spray-coated gradient profile ceramic membranes enables improved filtration performance in aerobic submerged membrane bioreactor.

Rational design of cross-sectional microstructure in ceramic membranes has shown to improve membrane filtration efficacy without affecting rejection performance. In this work, we adopted 3D spray-coating technique to generate multi-layered membrane layers on macro-porous flat-sheet ceramic supports. The thickness of each layer was controlled by spray-coating cycles, and a gradient membrane layer was rationalized by successively coating three ceramic slurries containing alumina powders of gradually refined particle sizes, followed by co-sintering. Gradient membrane layers on both sides of the various sized flat-sheet ceramic supports were fabricated. Compared to the non-gradient counterpart, the gradient membranes showed both higher pure water flux (at the same TMP) and lower membrane resistance, which clearly evidenced the benefits of gradient profile in the membrane layer. Further, their performance in aerobic membrane bioreactors (AeMBR) was comparably studied for the first time. The treatment performance was not significantly affected by the types of membranes used, while the gradient membrane showed better filtration performance (i.e., a slower rise in TMP). Although the fouling mechanisms were revealed to be similar, the fouling layer in the gradient membrane was composed of a higher percentage of smaller foulants compared to that of the non-gradient counterpart. The observed differences were closely correlated to the larger internal pore structure in the gradient membrane. The present work provides a feasible 3D spray-coating technique for the fabrication of gradient flat-sheet ceramic membranes, and clarifies the benefits in AeMBR for domestic wastewater treatment.

Impact of COVID-19 pandemic on migraine management in the United States: insights from migraine tracking app users.

BACKGROUND: The nature of COVID-19 pandemic measures has altered the clinical management of migraine, and has also created barriers to evaluate the impact of such measures of migraine patients. Using the Migraine Buddy smartphone application, we assessed the impact of the COVID-19 pandemic on migraine in users residing in the United States. METHODS: Migraine Buddy is a smartphone application by individuals to record their migraine headache episodes, characteristics, and coping mechanisms. For this study, anonymized self-reported data from 163,176 adult Migraine Buddy users in the United States between January 2020 and May 2020, were analyzed for migraines associated with stress. A stress-related migraine is defined as one in which stress or anxiety was reported as a trigger or symptom. A questionnaire on the impact of COVID-19 on migraine and its management was also completed by 923 users from the United States in the app between April 2020 and May 2020. RESULTS: 88% of the Migraine Buddy database extract and 84% of the respondents are female, with a mean age of 36.2 years. The proportion of stress-related migraine attacks peaked at 53% on March 21 to 23, although the number of migraine attacks decreased. This followed the declaration of the COVID-19 national emergency on March 13 and a spike in the number of COVID-19 cases in the United States. Questionnaire respondents felt that the following added more stress: social isolation (22.6%), information overdose (21.2%), access to essentials (food, medication, etc.) (18.7%), and financial concerns (17.8%). To help manage migraine during COVID-19, respondents suggested stress and diet coaching programs and resources (medical articles, etc.) (34.0%), having the option for home delivery of medication (30.6%) and tele-consulting (25.5%). CONCLUSION: Here, we report the change in the proportion of self-reported stress-related migraine in relation to evolution of the COVID-19 pandemic, as well as its impact of migraine management. Our data will help increase the understanding of patients' needs and help with planning and execution of mitigating strategies.

BRCA1 Promoter Methylation Is Linked to Defective Homologous Recombination Repair and Elevated miR-155 to Disrupt Myeloid Differentiation in Myeloid Malignancies.

PURPOSE: Defective homologous recombination (HR) has been reported in multiple myeloid disorders, suggesting a shared dysregulated pathway in these diverse malignancies. Because targeting HR-defective cancers with PARP inhibition (PARPi) has yielded clinical benefit, improved understanding of HR defects is needed to implement this treatment modality. EXPERIMENTAL DESIGN: We used an ex vivo irradiation-based assay to evaluate HR repair, HR gene promoter methylation, and mRNA expression in primary myeloid neoplastic cells. In vitro BRCA1 gene silencing was achieved to determine the consequences on HR repair, sensitivity to PARPi, and expression of miR-155, an oncogenic miRNA. RESULTS: Impaired HR repair was frequently detected in myeloid neoplasm samples (9/21, 43%) and was linked to promoter methylation-mediated transcriptional repression of BRCA1, which was not observed for other members of the HR pathway (BRCA2, ATM, ATR, FANC-A). In vitro BRCA1 knockdown increased sensitivity to PARP inhibition, and BRCA1 expression is inversely correlated with miR-155 expression, a finding reproduced in vitro with BRCA1 knockdown. Increased miR-155 was associated with PU.1 and SHIP1 repression, known myeloid differentiation factors that are frequently downregulated during leukemic transformation. CONCLUSIONS: This study demonstrates frequent defective HR, associated with BRCA1 epigenetic silencing, in a broad range of myeloid neoplasms. The increased prevalence of BRCA1 promoter methylation, resulting in repressed BRCA1, may have an additional role in leukemogenesis by increasing miR-155 expression, which then inhibits transcription factors associated with normal myeloid differentiation. Further study of HR defects may facilitate the identification of HR-defective myeloid neoplasms sensitive to PARPi.

A Phase 1 Study of the PARP Inhibitor Veliparib in Combination with Temozolomide in Acute Myeloid Leukemia.

PURPOSE: In preclinical studies, the PARP inhibitor veliparib enhanced the antileukemic action of temozolomide through potentiation of DNA damage. Accordingly, we conducted a phase 1 study of temozolomide with escalating doses of veliparib in patients with relapsed, refractory acute myeloid leukemia (AML) or AML arising from aggressive myeloid malignancies. EXPERIMENTAL DESIGN: Patients received veliparib [20-200 mg once a day on day 1 and twice daily on days 4-12 in cycle 1 (days 1-8 in cycle ≥2)] and temozolomide [150-200 mg/m2 daily on days 3-9 in cycle 1 (days 1-5 in cycle ≥2)] every 28 to 56 days. Veliparib pharmacokinetics and pharmacodynamics [ability to inhibit poly(ADP-ribose) polymer (PAR) formation and induce H2AX phosphorylation] were assessed. Pretreatment levels of MGMT and PARP1 protein, methylation of the MGMT promoter, and integrity of the Fanconi anemia pathway were also examined. RESULTS: Forty-eight patients were treated at seven dose levels. Dose-limiting toxicities were oral mucositis and esophagitis lasting >7 days. The MTD was veliparib 150 mg twice daily with temozolomide 200 mg/m2 daily. The complete response (CR) rate was 17% (8/48 patients). Veliparib exposure as well as inhibition of PAR polymer formation increased dose proportionately. A veliparib-induced increase in H2AX phosphorylation in CD34+ cells was observed in responders. Three of 4 patients with MGMT promoter methylation achieved CR. CONCLUSIONS: Veliparib plus temozolomide is well tolerated, with activity in advanced AML. Further evaluation of this regimen and of treatment-induced phosphorylation of H2AX and MGMT methylation as potential response predictors appears warranted. Clin Cancer Res; 23(3); 697-706. ©2016 AACR.

Poly (ADP-Ribose) Polymerase Inhibitor Hypersensitivity in Aggressive Myeloproliferative Neoplasms.

PURPOSE: DNA repair defects have been previously reported in myeloproliferative neoplasms (MPN). Inhibitors of PARP have shown activity in solid tumors with defects in homologous recombination (HR). This study was performed to assess MPN sensitivity to PARP inhibitors ex vivo EXPERIMENTAL DESIGN: HR pathway integrity in circulating myeloid cells was evaluated by assessing the formation of RAD51 foci after treatment with ionizing radiation or PARP inhibitors. Sensitivity of MPN erythroid and myeloid progenitors to PARP inhibitors was evaluated using colony formation assays. RESULTS: Six of 14 MPN primary samples had reduced formation of RAD51 foci after exposure to ionizing radiation, suggesting impaired HR. This phenotype was not associated with a specific MPN subtype, JAK2 mutation status, or karyotype. MPN samples showed increased sensitivity to the PARP inhibitors veliparib and olaparib compared with normal myeloid progenitors. This hypersensitivity, which was most pronounced in samples deficient in DNA damage-induced RAD51 foci, was observed predominantly in samples from patients with diagnoses of chronic myelogenous leukemia, chronic myelomonocytic leukemia, or unspecified myelodysplastic/MPN overlap syndromes. CONCLUSIONS: Like other neoplasms with HR defects, MPNs exhibit PARP inhibitor hypersensitivity compared with normal marrow. These results suggest that further preclinical and possibly clinical study of PARP inhibitors in MPNs is warranted. Clin Cancer Res; 22(15); 3894-902. ©2016 AACR.

DREAMing: a simple and ultrasensitive method for assessing intratumor epigenetic heterogeneity directly from liquid biopsies.

Many cancers comprise heterogeneous populations of cells at primary and metastatic sites throughout the body. The presence or emergence of distinct subclones with drug-resistant genetic and epigenetic phenotypes within these populations can greatly complicate therapeutic intervention. Liquid biopsies of peripheral blood from cancer patients have been suggested as an ideal means of sampling intratumor genetic and epigenetic heterogeneity for diagnostics, monitoring and therapeutic guidance. However, current molecular diagnostic and sequencing methods are not well suited to the routine assessment of epigenetic heterogeneity in difficult samples such as liquid biopsies that contain intrinsically low fractional concentrations of circulating tumor DNA (ctDNA) and rare epigenetic subclonal populations. Here we report an alternative approach, deemed DREAMing (Discrimination of Rare EpiAlleles by Melt), which uses semi-limiting dilution and precise melt curve analysis to distinguish and enumerate individual copies of epiallelic species at single-CpG-site resolution in fractions as low as 0.005%, providing facile and inexpensive ultrasensitive assessment of locus-specific epigenetic heterogeneity directly from liquid biopsies. The technique is demonstrated here for the evaluation of epigenetic heterogeneity at p14(ARF) and BRCA1 gene-promoter loci in liquid biopsies obtained from patients in association with non-small cell lung cancer (NSCLC) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN), respectively.

Poly(ADP-ribose) polymerase inhibitor CEP-8983 synergizes with bendamustine in chronic lymphocytic leukemia cells in vitro.

DNA repair aberrations and associated chromosomal instability is a feature of chronic lymphocytic leukemia (CLL). To evaluate if DNA repair insufficiencies are related to methylation changes, we examined the methylation of nine promoter regions of DNA repair proteins by bisulfide sequencing in 26 CLL primary samples and performed quantitative PCR on a subset of samples to examine BRCA1 expression. We also investigated if changes in cytogenetic or expression level of DNA repair proteins led to changes in sensitivity to a novel PARP inhibitor, CEP-8983, alone and in combination with bendamustine. No changes in promoter methylation were identified in BRCA1, BRCA2, FANC-C, FANC-F, FANC-L, ATM, MGMT, hMLH1 and H2AX except for two cases of minor BRCA1 hypermethylation. CLL samples appeared to have reduced BRCA1 mRNA expression uniformly in comparison to non-malignant lymphocytes irrespective of promoter hypermethylation. CEP-8983 displayed single agent cytotoxicity and the combination with bendamustine demonstrated synergistic cytotoxicity in the majority of CLL samples. These results were consistent across cytogenetic subgroups, including 17p deleted and previously treated patients. Our results provide rationale for further exploration of the combination of a PARP inhibitor and DNA damaging agents as a novel therapeutic strategy in CLL.

Whole-exome sequencing of pancreatic neoplasms with acinar differentiation.

Pancreatic carcinomas with acinar differentiation, including acinar cell carcinoma, pancreatoblastoma and carcinomas with mixed differentiation, are distinct pancreatic neoplasms with poor prognosis. Although recent whole-exome sequencing analyses have defined the somatic mutations that characterize the other major neoplasms of the pancreas, the molecular alterations underlying pancreatic carcinomas with acinar differentiation remain largely unknown. In the current study, we sequenced the exomes of 23 surgically resected pancreatic carcinomas with acinar differentiation. These analyses revealed a relatively large number of genetic alterations at both the individual base pair and chromosomal levels. There was an average of 119 somatic mutations/carcinoma. When three outliers were excluded, there was an average of 64 somatic mutations/tumour (range 12-189). The mean fractional allelic loss (FAL) was 0.27 (range 0-0.89) and heterogeneity at the chromosome level was confirmed in selected cases using fluorescence in situ hybridization (FISH). No gene was mutated in >30% of the cancers. Genes altered in other neoplasms of the pancreas were occasionally targeted in carcinomas with acinar differentiation; SMAD4 was mutated in six tumours (26%), TP53 in three (13%), GNAS in two (9%), RNF43 in one (4%) and MEN1 in one (4%). Somatic mutations were identified in genes in which constitutional alterations are associated with familial pancreatic ductal adenocarcinoma, such as ATM, BRCA2 and PALB2 (one tumour each), as well as in genes altered in extra-pancreatic neoplasms, such as JAK1 in four tumours (17%), BRAF in three (13%), RB1 in three (13%), APC in two (9%), PTEN in two (9%), ARID1A in two (9%), MLL3 in two (9%) and BAP1 in one (4%). Perhaps most importantly, we found that more than one-third of these carcinomas have potentially targetable genetic alterations, including mutations in BRCA2, PALB2, ATM, BAP1, BRAF and JAK1.

HMGA1: a master regulator of tumor progression in triple-negative breast cancer cells.

Emerging evidence suggests that tumor cells metastasize by co-opting stem cell transcriptional networks, although the molecular underpinnings of this process are poorly understood. Here, we show for the first time that the high mobility group A1 (HMGA1) gene drives metastatic progression in triple negative breast cancer cells (MDA-MB-231, Hs578T) by reprogramming cancer cells to a stem-like state. Silencing HMGA1 expression in invasive, aggressive breast cancer cells dramatically halts cell growth and results in striking morphologic changes from mesenchymal-like, spindle-shaped cells to cuboidal, epithelial-like cells. Mesenchymal genes (Vimentin, Snail) are repressed, while E-cadherin is induced in the knock-down cells. Silencing HMGA1 also blocks oncogenic properties, including proliferation, migration, invasion, and orthotopic tumorigenesis. Metastatic progression following mammary implantation is almost completely abrogated in the HMGA1 knock-down cells. Moreover, silencing HMGA1 inhibits the stem cell property of three-dimensional mammosphere formation, including primary, secondary, and tertiary spheres. In addition, knock-down of HMGA1 depletes cancer initiator/cancer stem cells and prevents tumorigenesis at limiting dilutions. We also discovered an HMGA1 signature in triple negative breast cancer cells that is highly enriched in embryonic stem cells. Together, these findings indicate that HMGA1 is a master regulator of tumor progression in breast cancer by reprogramming cancer cells through stem cell transcriptional networks. Future studies are needed to determine how to target HMGA1 in therapy.

DNA-intercalators causing rapid re-expression of methylated and silenced genes in cancer cells.

Epigenetic inactivation of tumor-suppressor and other regulatory genes plays a critical role in carcinogenesis. Transcriptional silencing is often maintained by DNA methyl transferase (DNMT)-mediated hypermethylation of CpG islands in promoter DNA. Nucleoside analogs including azacytidine and decitabine have been used to inhibit DNMT and re-activate genes, and are clinically used. Their shortcomings include a short half-life and a slow onset of action due to required nucleotide incorporation during DNA replication, which may limit clinical utility. It might be useful to begin to identify lead compounds having novel properties, specifically distinct and fast-acting gene desilencing. We previously identified chemicals augmenting gene expression in multiple reporter systems. We now report that a subset of these compounds that includes quinacrine re-expresses epigenetically silenced genes implicated in carcinogenesis. p16, TFPI2, the cadherins E-cadherin and CDH13, and the secreted frizzle-related proteins (SFRPs) SFRP1 and SFRP5 were desilenced in cancer cell lines. These lead compounds were fast-acting: re-expression occurred by 12-24 hours. Reactivation of silenced genes was accompanied by depletion of DNMT1 at the promoters of activated genes and demethylation of DNA. A model compound, 5175328, induced changes more rapidly than decitabine. These gene desilencing agents belonged to a class of acridine compounds, intercalated into DNA, and inhibited DNMT1 activity in vitro. Although to define the mechanism would be outside the scope of this initial report, this class may re-activate silenced genes in part by intercalating into DNA and subsequently inhibiting full DNMT1 activity. Rapid mechanisms for chemical desilencing of methylated genes therefore exist.

Klotho-beta overexpression as a novel target for suppressing proliferation and fibroblast growth factor receptor-4 signaling in hepatocellular carcinoma.

BACKGROUND: We had previously demonstrated overexpression of fibroblast growth factor receptor-4 (FGFR4) in hepatocellular carcinoma (HCC). However, additional molecular mechanisms resulting in amplified FGFR4 signaling in HCC remain under-studied. Here, we studied the mechanistic role of its co-receptor klotho-beta (KLB) in driving elevated FGFR4 activity in HCC progression. RESULTS: Quantitative real-time PCR analysis identified frequent elevation of KLB gene expression in HCC tumors relative to matched non-tumor tissue, with a more than two-fold increase correlating with development of multiple tumors in patients. KLB-silencing in Huh7 cells decreased cell proliferation and suppressed FGFR4 downstream signaling. While transient repression of KLB-FGFR4 signaling decreased protein expression of alpha-fetoprotein (AFP), a HCC diagnostic marker, prolonged inhibition enriched for resistant HCC cells exhibiting increased liver stemness. CONCLUSIONS: Elevated KLB expression in HCC tissues provides further credence to the oncogenic role of increased FGFR4 signaling in HCC progression and represents a novel biomarker to identify additional patients amenable to anti-FGFR4 therapy. The restricted tissue expression profile of KLB, together with the anti-proliferative effect observed with KLB-silencing, also qualifies it as a specific and potent therapeutic target for HCC patients. The enrichment of a liver stem cell-like population in response to extended KLB-FGFR4 repression necessitates further investigation to target the development of drug resistance.

HMGA1 drives stem cell, inflammatory pathway, and cell cycle progression genes during lymphoid tumorigenesis.

BACKGROUND: Although the high mobility group A1 (HMGA1) gene is widely overexpressed in diverse cancers and portends a poor prognosis in some tumors, the molecular mechanisms that mediate its role in transformation have remained elusive. HMGA1 functions as a potent oncogene in cultured cells and induces aggressive lymphoid tumors in transgenic mice. Because HMGA1 chromatin remodeling proteins regulate transcription, HMGA1 is thought to drive malignant transformation by modulating expression of specific genes. Genome-wide studies to define HMGA1 transcriptional networks during tumorigenesis, however, are lacking. To define the HMGA1 transcriptome, we analyzed gene expression profiles in lymphoid cells from HMGA1a transgenic mice at different stages in tumorigenesis. RESULTS: RNA from lymphoid samples at 2 months (before tumors develop) and 12 months (after tumors are well-established) was screened for differential expression of > 20,000 unique genes by microarray analysis (Affymetrix) using a parametric and nonparametric approach. Differential expression was confirmed by quantitative RT-PCR in a subset of genes. Differentially expressed genes were analyzed for cellular pathways and functions using Ingenuity Pathway Analysis. Early in tumorigenesis, HMGA1 induced inflammatory pathways with NFkappaB identified as a major node. In established tumors, HMGA1 induced pathways involved in cell cycle progression, cell-mediated immune response, and cancer. At both stages in tumorigenesis, HMGA1 induced pathways involved in cellular development, hematopoiesis, and hematologic development. Gene set enrichment analysis showed that stem cell and immature T cell genes are enriched in the established tumors. To determine if these results are relevant to human tumors, we knocked-down HMGA1 in human T-cell leukemia cells and identified a subset of genes dysregulated in both the transgenic and human lymphoid tumors. CONCLUSIONS: We found that HMGA1 induces inflammatory pathways early in lymphoid tumorigenesis and pathways involved in stem cells, cell cycle progression, and cancer in established tumors. HMGA1 also dyregulates genes and pathways involved in stem cells, cellular development and hematopoiesis at both early and late stages of tumorigenesis. These results provide insight into HMGA1 function during tumor development and point to cellular pathways that could serve as therapeutic targets in lymphoid and other human cancers with aberrant HMGA1 expression.