Professor of Pediatrics, University of Pennsylvania School of Medicine
AddressColket Translational Research Bldg, Room 4006 The Children's Hospital of Philadelphia 3501 Civic Center Blvd
Pediatric leukemias, infant leukemias, treatment-related secondary leukemias
Infant and chemotherapy-related leukemias with MLL (Mixed Lineage Leukemia; Myeloid Lymphoid Leukemia) gene translocations.
Key words: leukemia, infant, topoisomerase II, epipodophyllotoxin, MLL gene, translocation.
Description of Research
I am a physician scientist with clinical and translational research interests focused on unraveling the causes and consequences of MLL 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 treatment 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 have 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. Recently we reported that despite their long appreciated refractoriness to conventional treatments, upon ex vivo treatment with a small molecule inhibitor, primary acute lymphoblastic leukemia cells from infants were sensitive to activation of three pathways to cell death (apoptosis, autophagy, necroptosis). Therefore a major focus of our preclinical work is to decipher the actionable therapeutic targets leading to this triple mode of killing in order to translate this discovery into clinical trials.
Thus my research program represents a cross-cultivation of strategies that is possible from the merger of disparate yet complementary scientific disciplines spanning basic research, preclinical analyses and clinical applications that are relevant to MLL leukemia diagnosis, prognosis, monitoring, treatment and prevention.
- Professor of Pediatrics at University of Pennsylvania School of Medicine (2006– present)
- Assistant Professor of Pediatrics at University of Pennsylvania School of Medicine (1991 – 2000)
- Associate Professor of Pediatrics at University of Pennsylvania School of Medicine (2000 – 2006)
- MD, Boston University School of Medicine (1981)
- NA, University of Pittsburgh School of Medicine (1978)
- BS, Biology/Chemistry (summa cum laude), Boston College (1977)
Description of Research
The research activities of my laboratory are directed at solving the problems of leukemias in infants and leukemias caused by chemotherapeutic DNA topoisomerase II inhibitors. My research group has shown that these leukemias have similar chromosomal translocations of the MLL gene at chromosme band 11q23. While most children with leukemia can be cured; the treatment options for patients with MLL-rearranged leukemias, which include intensive chemotherapy and hematopoietic stem cell transplantation, are associated with excessive toxicity and a poor prognosis. The therapies have lagged far behind the scientific advances of the new genomics era. New risk factors and insights on the DNA damage leading to the translocations have emerged from the work of my laboratory, the mission of which is to build bridges between basic science and the bedside that will accelerate targeted prevention and more efficacious, less toxic, targeted new treatments for these high-risk patients.
The research of my laboratory has pioneered new panhandle PCR methodology for the detection of MLL translocations. The MLL gene can be fused with one of many different partner genes to form translocations. My laboratory has discovered a large proportion of the known partner genes of MLL. In studies of AML in infant twins we have shown that the translocations and, therefore the DNA damage leading to the translocations, occur in the prenatal period. In the chemotherapy-related cases we have shown that the translocations can be present early during the primary cancer treatment. Work in my laboratory using an in vitro assay has suggested that DNA topoisomerase II, an essential protein in all cells, may be involved in the chromosomal breakage that leads to translocations. These studies are important because the chemotherapy drugs associated with this form of leukemia are DNA topoisomerase II inhibitors and, in leukemia in infants, classical epidemiology has suggested associations of maternal prenatal consumption of certain dietary DNA topoisomerase II inhibitors with an increased risk. Currently we are developing an experimental model that exploits human bone marrow progenitor cells and novel DNA array technology in order to mimic the damage to the MLL gene and localize the DNA topoisomerase cleavage complexes that are formed in vivo. In other work, we have determined that genetic variations in the detoxifying pathways NQO1 and CYP3A4, respectively, confer susceptibility to infant and treatment-related leukemias with MLL translocations. In the infant leukemias, 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 leukemias, the identification of high-risk individuals could lead to alterations in chemotherapy dose or schedule and preventative strategies for the future. In addition to experiments that are focused on prevention, other efforts in my laboratory are directed at developing better treatments. We are using gene expression profiling and we are planning profiling experiments via large-scale proteomics to understand the influence of the partner genes of MLL on disease biology and identify new drug targets. We have also shown that leukemias in infants have increased Bcl-2 expression, and other current research involves testing an anti-sense compound directed at this central anti-apoptotic protein, which confers chemotherapy resistance. Therefore, the research of my laboratory is relevant to new gene discovery and to diagnosis, prognosis and monitoring in patients with leukemia, and may lead to strategies for treatment and prevention.
- 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. Vol 121(14) . 2013 Apr:2689-703.
- 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. Vol 119(8) . 2012 Feb:1872-81.
- 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. Vol 152(3) . 2011 Feb:307-21.
- 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. Vol 141(6) . 2008 Jun:827-39.
- 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. Vol 111(7) . 2008 Apr:3802-12.
- 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. Vol 5(10) . 2006 Oct:2743-53.
- 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. Vol 105(5) . 2005 Mar:2124-31.
- 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. Vol 14(3) . 2005 Mar:651-5.
- 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. Vol 352(15) . 2005 Apr:1529-38.
- 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. Vol 99(7) . 2002 Apr:4568-73.