About

Carolyn A. Felix, M.D., is a Professor of Pediatrics (Oncology) and an Attending Physician at the Children's Hospital of Philadelphia, affiliated with the Perelman School of Medicine at the University of Pennsylvania. Her research focuses on unraveling the causes and consequences of MLL (KMT2A) translocations, which are underlying aberrations in ultra-high-risk and often fatal pediatric leukemias, particularly infant leukemias and therapy-related secondary leukemias caused by topoisomerase II (TOP2) poisons. Her long-term goal is to bridge basic science and clinical applications to develop more efficacious, less toxic, targeted treatments and preventive strategies for these patients. Dr. Felix's laboratory has made significant contributions to understanding the DNA damage leading to MLL translocations, discovering that similar translocations occur prenatally in infant twins and early during primary cancer treatment in therapy-related cases. Her work has shown that TOP2 poisons damage DNA at translocation breakpoints, and her team has developed methodologies to detect and characterize these translocations. She has also explored the role of maternal-fetal exposures to TOP2 poisons and genetic variations in detoxifying pathways that confer susceptibility to leukemia. Her research employs innovative next-generation sequencing strategies and zebrafish models to study leukemogenesis, pinpoint the leukemia cell of origin, and identify new therapeutic targets. Additionally, her work investigates novel therapeutic approaches, such as using obatoclax mesylate to induce cell death in infant leukemia cells and ribavirin to inhibit EIF4E, aiming to improve treatment outcomes and reduce toxicities associated with conventional therapies.

Research topics

• Biology
• Genetics
• Molecular biology
• Medicine
• Cancer research

Selected publications

• <i>KMT2A</i> partner genes in infant acute lymphoblastic leukemia have prognostic significance and correlate with age, white blood cell count, sex, and central nervous system involvement: a Children’s Oncology Group P9407 trial study

  Haematologica · 2023-03-02 · 4 citations

  letterOpen accessSenior author

  Not available.

  PublisherOA PDFDOI

• Leukemia‐associated transcription factor <i>mllt3</i> is important for primitive erythroid development in zebrafish embryogenesis

  Developmental Dynamics · 2022-04-16 · 5 citations

  articleSenior author

  BACKGROUND: MLLT3 (AF9) is a nuclear transcription factor crucial for hematopoietic stem cell and progenitor cell maintenance, but its role during embryonic hematopoiesis remains uncertain. Here, we examine the role of mllt3 in developmental hematopoiesis during embryogenesis using zebrafish. RESULTS: Cloning, sequencing, phylogenetic, and synteny analyses showed high evolutionary conservation between important functional domains of the zebrafish orthologue of mllt3 and MLLT3 in humans. Quantitative reverse transcription-PCR and in situ hybridization analyses revealed that mllt3 is maternally supplied and zygotically expressed throughout embryonic development, and that expression is highest between 10 and 24 hours post-fertilization (hpf) coincident with enrichment in the intermediate cell mass (ICM) and posterior blood island, which are the sites of the primitive and transient definitive hematopoiesis in zebrafish, respectively. Further, we found co-expression of mllt3 with the early hematopoietic progenitor markers tal1, gata2, and gata1a in the posterior ICM. By investigating zebrafish hematopoietic mutants, we discovered that mllt3 is involved in erythroid precursor formation. By 48-72 hpf, mllt3 expression proved to be restricted to non-hematopoietic tissues including head structures, pronephric tubules, and liver primordium. CONCLUSIONS: These findings establish a link between mllt3 and primitive erythropoiesis and provide the basis for future functional investigations.

  PublisherDOI

• Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner Syndrome

  Molecular Genetics and Metabolism · 2021-04-01 · 1 citations

  article
  PublisherDOI

• <i>KMT2A‐MAML2</i> rearrangement emerged and regressed during neuroblastoma therapy without leukemia after 12.8‐year follow‐up

  Pediatric Blood & Cancer · 2021-09-22 · 1 citations

  articleOpen access1st authorCorresponding

  Twelvepatients without therapy-related leukemia were studied after completing TOP2 poison chemotherapy in a high-risk neuroblastoma regimen. One patient harbored an inv(11) that was a KMT2A rearrangement. The KMT2A-MAML2 transcript was expressed at low level. The patient was prospectively followed. The inv(11) was undetectable in ensuing samples. Leukemia never developed after a 12.8-year follow-up period. Enriched etoposide-induced TOP2A cleavage in the relevant MAML2 genomic region supports a TOP2A DNA damage mechanism. After completing TOP2 poison chemotherapies, covert KMT2A-R clones may occur in a small minority of patients; however, not all KMT2A rearrangements herald a therapy-related leukemia diagnosis.

  PublisherOA PDFDOI

• Single-cell multiomics reveals increased plasticity, resistant populations, and stem-cell–like blasts in <i>KMT2A</i>-rearranged leukemia

  Blood · 2021-12-05 · 111 citations

  articleOpen access

  KMT2A-rearranged (KMT2A-r) infant acute lymphoblastic leukemia (ALL) is a devastating malignancy with a dismal outcome, and younger age at diagnosis is associated with increased risk of relapse. To discover age-specific differences and critical drivers that mediate poor outcome in KMT2A-r ALL, we subjected KMT2A-r leukemias and normal hematopoietic cells from patients of different ages to single-cell multiomics analyses. We uncovered the following critical new insights: leukemia cells from patients <6 months have significantly increased lineage plasticity. Steroid response pathways are downregulated in the most immature blasts from younger patients. We identify a hematopoietic stem and progenitor-like (HSPC-like) population in the blood of younger patients that contains leukemic blasts and form an immunosuppressive signaling circuit with cytotoxic lymphocytes. These observations offer a compelling explanation for the ability of leukemias in young patients to evade chemotherapy and immune-mediated control. Our analysis also revealed preexisting lymphomyeloid primed progenitors and myeloid blasts at initial diagnosis of B-ALL. Tracking of leukemic clones in 2 patients whose leukemia underwent a lineage switch documented the evolution of such clones into frank acute myeloid leukemia (AML). These findings provide critical insights into KMT2A-r ALL and have clinical implications for molecularly targeted and immunotherapy approaches. Beyond infant ALL, our study demonstrates the power of single-cell multiomics to detect tumor intrinsic and extrinsic factors affecting rare but critical subpopulations within a malignant population that ultimately determines patient outcome.

  PublisherOA PDFDOI

• Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann‐Steiner syndrome

  American Journal of Medical Genetics Part A · 2021-03-30 · 72 citations

  articleOpen access

  Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS.

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• Targeting EIF4E signaling with ribavirin in infant acute lymphoblastic leukemia

  Oncogene · 2018-11-26 · 39 citations

  articleSenior author
  PublisherDOI

• Genome-wide TOP2A DNA cleavage is biased toward translocated and highly transcribed loci

  Genome Research · 2017-04-06 · 59 citations

  articleOpen accessSenior author

  Type II topoisomerases orchestrate proper DNA topology, and they are the targets of anti-cancer drugs that cause treatment-related leukemias with balanced translocations. Here, we develop a high-throughput sequencing technology to define TOP2 cleavage sites at single-base precision, and use the technology to characterize TOP2A cleavage genome-wide in the human K562 leukemia cell line. We find that TOP2A cleavage has functionally conserved local sequence preferences, occurs in cleavage cluster regions (CCRs), and is enriched in introns and lincRNA loci. TOP2A CCRs are biased toward the distal regions of gene bodies, and TOP2 poisons cause a proximal shift in their distribution. We find high TOP2A cleavage levels in genes involved in translocations in TOP2 poison-related leukemia. In addition, we find that a large proportion of genes involved in oncogenic translocations overall contain TOP2A CCRs. The TOP2A cleavage of coding and lincRNA genes is independently associated with both length and transcript abundance. Comparisons to ENCODE data reveal distinct TOP2A CCR clusters that overlap with marks of transcription, open chromatin, and enhancers. Our findings implicate TOP2A cleavage as a broad DNA damage mechanism in oncogenic translocations as well as a functional role of TOP2A cleavage in regulating transcription elongation and gene activation.

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• Unique Familial <i>MLL(KMT2A)‐</i>Rearranged Precursor B‐Cell Infant Acute Lymphoblastic Leukemia in Non‐twin Siblings

  Pediatric Blood & Cancer · 2016-03-21 · 6 citations

  articleSenior authorCorresponding

  BACKGROUND: Infant acute lymphoblastic leukemia (ALL) has never occurred in families except for the ∼100% concordant cases in monozygous twins attributed to twin-to-twin metastases. We report the first kindred with infant ALL in non-twin siblings. The siblings were diagnosed with MLL-rearranged (MLL-R) ALL 26 months apart. The second affected sibling had an unaffected dichorionic monozygous co-twin. Both had fatal outcomes. PROCEDURES: Translocations were characterized by karyotype, FISH, multiplex FISH, and MLL breakpoint cluster region (bcr) Southern blot analysis. Breakpoint junctions and fusion transcripts were cloned by PCR. TP53 mutation and NADPH quinone oxidorecuctase 1 (NQO1) C609T analyses were performed, and pedigree history and parental occupations were ascertained. The likelihood of chance occurrence of infant ALL in non-twin siblings was computed based on a binomial distribution. Zygosity was determined by single nucleotide polymorphism (SNP) array. RESULTS: The translocations were not related or vertically transmitted. The complex karyotype of the proband's ALL had chromosome 2, 3, 4, and 11 abnormalities causing a 5'-MLL-AFF1-3' fusion and a non-productive rearrangement of 3'MLL with a chromosome 3q intergenic region. The affected twin's ALL exhibited a simple t(4;11). The complex karyotype of the proband's ALL suggested a genotoxic insult, but no exposure was identified. There was no germline TP53 mutation. The NQO1 C609T risk allele was absent. The likelihood of infant ALL occurring in non-twin siblings by chance alone is one in 1.198 × 10(9) families. CONCLUSIONS: Whether because of a deleterious transplacental exposure, novel predisposition syndrome, or exceedingly rare chance occurrence, MLL-R infant ALL can occur in non-twin siblings. The discordant occurrence of infant ALL in the monozygous twins was likely because they were dichorionic.

  PublisherDOI

• Inhibiting cytosolic translation and autophagy improves health in mitochondrial disease

  Human Molecular Genetics · 2015-06-03 · 70 citations

  articleOpen access

  Mitochondrial respiratory chain (RC) disease therapies directed at intra-mitochondrial pathology are largely ineffective. Recognizing that RC dysfunction invokes pronounced extra-mitochondrial transcriptional adaptations, particularly involving dysregulated translation, we hypothesized that translational dysregulation is itself contributing to the pathophysiology of RC disease. Here, we investigated the activities, and effects from direct inhibition, of a central translational regulator (mTORC1) and its downstream biological processes in diverse genetic and pharmacological models of RC disease. Our data identify novel mechanisms underlying the cellular pathogenesis of RC dysfunction, including the combined induction of proteotoxic stress, the ER stress response and autophagy. mTORC1 inhibition with rapamycin partially ameliorated renal disease in B6.Pdss2(kd/kd) mice with complexes I-III/II-III deficiencies, improved viability and mitochondrial physiology in gas-1(fc21) nematodes with complex I deficiency, and rescued viability across a variety of RC-inhibited human cells. Even more effective was probucol, a PPAR-activating anti-lipid drug that we show also inhibits mTORC1. However, directly inhibiting mTORC1-regulated downstream activities yielded the most pronounced and sustained benefit. Partial inhibition of translation by cycloheximide, or of autophagy by lithium chloride, rescued viability, preserved cellular respiratory capacity and induced mitochondrial translation and biogenesis. Cycloheximide also ameliorated proteotoxic stress via a uniquely selective reduction of cytosolic protein translation. RNAseq-based transcriptome profiling of treatment effects in gas-1(fc21) mutants provide further evidence that these therapies effectively restored altered translation and autophagy pathways toward that of wild-type animals. Overall, partially inhibiting cytosolic translation and autophagy offer novel treatment strategies to improve health across the diverse array of human diseases whose pathogenesis involves RC dysfunction.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01CA153348

  NIH · $2.0M · 2016

• NIH Grant R01CA077683

  NIH · $2.1M · 2010

• NIH Grant R01CA080175

  NIH · $2.4M · 2010

• NIH Grant R29CA066140

  NIH · $612k · 2000

• NIH Grant R01CA085469

  NIH · $1.8M · 2009

Frequent coauthors

• Eric Rappaport

  Children's Cancer Institute Australia

  140 shared

• Maureen D. Megonigal

  138 shared

• Peter C. Nowell̀

  Unite 2 Fight Paralysis

  131 shared

• Beverly J. Lange

  Children's Hospital of Philadelphia

  119 shared

• Diana J. Slater

  Children's Hospital of Philadelphia

  92 shared

• Douglas H. Jones

  Clearfield (United States)

  82 shared

• Gregory H. Reaman

  68 shared

• Cheryl L. Willman

  St. Jude Children's Research Hospital

  59 shared

Labs

• Carolyn A. Felix LaboratoryPI

Education

• MD

  Boston University School of Medicine

  1981