Faculty

Carolyn A. Felix, M.D.

faculty photo
Professor of Pediatrics (Oncology)
Department: Pediatrics
Graduate Group Affiliations

Contact information
Colket Translational Research Bldg, Room 4006
The Children's Hospital of Philadelphia
3501 Civic Center Blvd
Philadelphia, PA 19104-4318
Office: 215-590-2831
Fax: 267-426-0685
Lab: 215-590-4540
Education:
BS (Biology/Chemistry (summa cum laude))
Boston College, 1977.
NA
University of Pittsburgh School of Medicine, 1978.
MD
Boston University School of Medicine, 1981.
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Description of Research Expertise

Research Interests
Infant and chemotherapy-related leukemias with MLL (Mixed Lineage Leukemia; Myeloid Lymphoid Leukemia) gene translocations.

Key words: leukemia, infant leukemia, secondary leukemia, therapy-related leukemia,translocation, MLL, KMT2A, obatoclax, ribavirin, TOP2, EIF4E, zebrafish.

Description of Research
I am a physician scientist with clinical and translational research interests focused on unraveling the causes and consequences of MLL (KMT2A) translocations as the underlying aberrations in ultra-high-risk and often fatal pediatric subsets of leukemia that occur both in infants and as a complication of particular anticancer drugs. Our long-term objectives are to build bridges between basic science and the bedside that will accelerate more efficacious, less toxic, targeted new treatments and, ultimately, preventive strategies for these patients. New insights into the DNA damage leading to MLL translocations and risk factors for MLL leukemias have emerged from my laboratory. My research group has shown that similar translocations and other rearrangements of the MLL gene at chromosome band 11q23 are characteristic of both infant leukemias and the therapy related secondary leukemias caused by a type of chemotherapy called topoisomerase II (TOP2) poisons. The MLL gene can be fused with one of many different partner genes to form translocations. We pioneered a number of panhandle PCR methodologies to detect the translocations and characterize the DNA sequences that form the breakpoint junctions, and we discovered many of the partner genes of MLL. In AML in infant twins we showed that MLL translocations and, therefore the DNA damage leading to them, occur in the prenatal period. In the chemotherapy-related cases we showed that the translocations can be present early during the primary cancer treatment. The activity of the TOP2 protein involves cutting and re-joining DNA. TOP2 poisons damage DNA by corrupting this activity, either by causing increased cutting or decreased DNA re-joining. Work in my laboratory using a biochemical assay first suggested that DNA damage from TOP2 at/near the translocation breakpoints, is involved in the chromosomal breakage that leads to translocations. Not only are chemotherapeutic TOP2 poisons associated with secondary MLL leukemia, but also our research has suggested that maternal-fetal exposures to TOP2 poisons in dietary or environmental substances are important in the infant cases. In related work, we discovered that genetic variations in TOP2 poison detoxifying pathways (NQO1 and CYP3A4, respectively) confer susceptibility to infant and treatment-related leukemias with MLL translocations. In the infant cases, the prenatal period when the translocation must occur holds possibilities for prevention if there are relevant exposures in high-risk individuals. In the treatment-related cases, the identification of high-risk individuals could also lead to chemotherapy alterations with preventive potential. Thus in one ongoing project we are taking these studies to the next level by employing a new next generation sequencing strategy that we invented for the detection and mapping of TOP2 cleavage complexes germane to translocations in hematopoietic cells to the human genome.
In a different aspect of our work, the in utero origin of the translocations in the infant cases has led to studies in which we are creating MLL translocation models in the zebrafish embryo as a powerful developmental tool to recapitulate leukemogenesis in infants, pinpoint the leukemia cell of origin and uncover new therapeutic targets. The transparency and ex vivo development of the zebrafish embryo enables in vivo access to early embryonic timepoints that are not accessible in mammals. Already we reported that zebrafish have an mll gene that encodes all of the functional domains of the human protein, and we are now discovering that the expression of novel target genes is controlled by mll during the earliest stages of development of the blood cell lineages.
Conventional treatments for patients with MLL-rearranged leukemias are associated with excessive toxicities and frequent relapses, and we are using multifaceted approaches to discover better therapeutic options. We reported that despite their long appreciated refractoriness to conventional treatments, upon ex vivo treatment with a small molecule inhibitor (obatoclax mesylate), primary acute lymphoblastic leukemia cells from infants were sensitive to activation of three pathways to cell death (apoptosis, autophagy, necroptosis). Deciphering the actionable therapeutic targets leading to this triple mode of killing has high translational importance. Because infant leukemias have frequent elevation of the eukaryotic translation initiation factor EIF4E, a direction we are now pursuing is the use of ribavirin to inhibit EIF4E in mechanism-based targeted agent combinations.
Thus my research program represents a cross-cultivation of complementary scientific disciplines spanning basic research, preclinical analyses and clinical applications that are relevant to MLL leukemia diagnosis, prognosis, monitoring, treatment and prevention.

Description of Clinical Expertise

Pediatric leukemias, infant leukemias, therapy-related secondary leukemias

Selected Publications

Urtishak Karen A, Edwards Alena Y Z, Wang Li-San, Hudome Amanda, Robinson Blaine W, Barrett Jeffrey S, Cao Kajia, Cory Lori, Moore Jonni S, Bantly Andrew D, Yu Qian-Chun, Chen I-Ming L, Atlas Susan R, Willman Cheryl L, Kundu Mondira, Carroll Andrew J, Heerema Nyla A, Devidas Meenakshi, Hilden Joanne M, Dreyer ZoAnn E, Hunger Stephen P, Reaman Gregory H, Felix Carolyn A: Potent obatoclax cytotoxicity and activation of triple death mode killing across infant acute lymphoblastic leukemia. Blood 121(14): 2689-703, Apr 2013.

Kang Huining, Wilson Carla S, Harvey Richard C, Chen I-Ming, Murphy Maurice H, Atlas Susan R, Bedrick Edward J, Devidas Meenakshi, Carroll Andrew J, Robinson Blaine W, Stam Ronald W, Valsecchi Maria G, Pieters Rob, Heerema Nyla A, Hilden Joanne M, Felix Carolyn A, Reaman Gregory H, Camitta Bruce, Winick Naomi, Carroll William L, Dreyer ZoAnn E, Hunger Stephen P, Willman Cheryl L: Gene expression profiles predictive of outcome and age in infant acute lymphoblastic leukemia: a Children's Oncology Group study. Blood 119(8): 1872-81, Feb 2012.

Robinson Blaine W, Germano Giuseppe, Song Yuanquan, Abrams Joshua, Scott Marion, Guariento Ilaria, Tiso Natascia, Argenton Francesco, Basso Giuseppe, Rhodes Jennifer, Kanki John P, Look A Thomas, Balice-Gordon Rita J, Felix Carolyn A: mll ortholog containing functional domains of human MLL is expressed throughout the zebrafish lifespan and in haematopoietic tissues. British Journal of Haematology 152(3): 307-21, Feb 2011.

Robinson Blaine W, Behling Kathryn C, Gupta Manish, Zhang Alena Y, Moore Jonni S, Bantly Andrew D, Willman Cheryl L, Carroll Andrew J, Adamson Peter C, Barrett Jeffrey S, Felix Carolyn A: Abundant anti-apoptotic BCL-2 is a molecular target in leukaemias with t(4;11) translocation. British Journal of Haematology 141(6): 827-39, Jun 2008.

Robinson Blaine W, Cheung Nai-Kong V, Kolaris Christos P, Jhanwar Suresh C, Choi John K, Osheroff Neil, Felix Carolyn A: Prospective tracing of MLL-FRYL clone with low MEIS1 expression from emergence during neuroblastoma treatment to diagnosis of myelodysplastic syndrome. Blood 111(7): 3802-12, Apr 2008.

Yocum Anastasia K, Busch Christine M, Felix Carolyn A, Blair Ian A: Proteomics-based strategy to identify biomarkers and pharmacological targets in leukemias with t(4;11) translocations. Journal of Proteome Research 5(10): 2743-53, Oct 2006.

Libura Jolanta, Slater Diana J, Felix Carolyn A, Richardson Christine: Therapy-related acute myeloid leukemia-like MLL rearrangements are induced by etoposide in primary human CD34+ cells and remain stable after clonal expansion. Blood 105(5): 2124-31, Mar 2005.

Spector Logan G, Xie Yang, Robison Leslie L, Heerema Nyla A, Hilden Joanne M, Lange Beverly, Felix Carolyn A, Davies Stella M, Slavin Joanne, Potter John D, Blair Cindy K, Reaman Gregory H, Ross Julie A: Maternal diet and infant leukemia: the DNA topoisomerase II inhibitor hypothesis: a report from the Children's Oncology Group. Cancer Epidemiology, Biomarkers & Prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 14(3): 651-5, Mar 2005.

Mistry Anita R, Felix Carolyn A, Whitmarsh Ryan J, Mason Annabel, Reiter Andreas, Cassinat Bruno, Parry Anne, Walz Christoph, Wiemels Joseph L, Segal Mark R, Adès Lionel, Blair Ian A, Osheroff Neil, Peniket Andrew J, Lafage-Pochitaloff Marina, Cross Nicholas C P, Chomienne Christine, Solomon Ellen, Fenaux Pierre, Grimwade David: DNA topoisomerase II in therapy-related acute promyelocytic leukemia. The New England Journal of Medicine 352(15): 1529-38, Apr 2005.

Raffini Leslie J, Slater Diana J, Rappaport Eric F, Lo Nigro Luca, Cheung Nai-Kong V, Biegel Jaclyn A, Nowell Peter C, Lange Beverly J, Felix Carolyn A: Panhandle and reverse-panhandle PCR enable cloning of der(11) and der(other) genomic breakpoint junctions of MLL translocations and identify complex translocation of MLL, AF-4, and CDK6. Proceedings of the National Academy of Sciences of the United States of America 99(7): 4568-73, Apr 2002.

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Last updated: 07/16/2024
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