Kliniken & Institute … Institute Institute of Human… Research Department of Human… Acute Lymphoblastic… Molecular Genetics of…

Molecular Genetics of Acute Lymphoblastic Leukaemia

ALL is the most common malignant disease in childhood. For many years now, our laboratory has specialized in the molecular genetic characterization of patients suffering from ALL. We identify genetic mutations in leukaemia cells and use them in order to subclassify the disease or as prognostic criteria (see MRD diagnostics). Also, in genome-wide approaches, we analyze chromosomal regions or genes predisposing to the development of ALL.


Prof. Schrappe (Kiel)
Prof. Koeffler (Los Angeles, USA)
Prof. Hemminki, Prof. Kumar (DKFZ, Heidelberg)
Prof. Houlston (Sutton, Surrey, UK)

Selected Publications

Sherborne A.L., Hosking F.J., Prasad R.B., Kumar R., Koehler R., Vijayakrishnan J., Papaemmanuil E., Bartram C.R., Stanulla M., Schrappe M., Gast A., Dobbins S.E., Ma Y., Sheridan E., Taylor M., Kinsey S.E., Lightfoot T., Roman E., Irving J.A.E., Allan J.M., Moorman A.V., Harrison C., Tomlinson I.P., Richards S., Zimmermann M., Szalai C., Semsei A.F., Erdelyi D.J., Krajinovic M., Sinnett D., Healy J., Neira A.G., Kawamata N., Ogawa S., Koeffler H.P., Hemminki K., Greaves M, Houlston R.S.: Variation at 9p21.3 (CDKN2A) influences childhood acute lymphoblastic leukemia risk.Nature Genet. (in press)

Prasad R.B., Hosking F.J., Vijayakrishnan J., Papaemmanuil E., Koehler R., Greaves M.F., Sheridon E., Gast A., Kinsey S.E., Lightfoot T., Roman E., Taylor M., Pritchard-Jones K., Stanulla M., Schrappe M., Bartram C.R., Houlston R., Kumar R., Hemminki K.: Verification of the susceptibility loci on 7p12.2, 10q21.2 and 14q11.2 in childhood B-cell acute lymphoblastic leukemia.

Blood 115, 1765-1767, 2010

Remke M., Pfister S., Kox C., Toedt G., Becker N., Benner A., Werft W., Breit S., Liu S., Engel F., Wittmann A., Stanuella M., Schrappe M., Ludwig W.D., Bartram C.R., Radlwimmer B., Muckenthaler M., Lichter P., Kulozik A.: High-resolution genomic profiling of childhood T-ALL reveals frequent copy-number alterations affecting the TGF-β and PI3K-AKT pathways and deletions at 6q15-16.1 as a genomic marker for unfavourable early treatment response.Blood 114,1053-1062. 2009

Kawamata N., Ogawa S., Zimmermann M., Niebuhr B., Stocking C., Sanada M., Hemminki K., Yamatomo G., Nannya Y., Koehler R., Flohr T., Miller C.W., Harbott J., Ludwig W.D., Stanulla M., Schrappe M., Bartram C.R.*, Koeffler H.P.*: Cloning of genes involved in chromosomal translocations by high resolution single nucleotide polymorphism genomic micro array. Proc. Natl. Acad. Sci (USA) 105, 11921-11926, 2008

Kawamata N., Ogawa S., Zimmermann M., Kato M., Sanada M., Hemminki K., Yamatomo G., Nannya Y., Koehler R., Flohr T., Miller C.W., Harbott J., Ludwig W.D., Stanulla M., Schrappe M., Bartram C.R.*, Koeffler H.P.*: Molecular allelokaryotyping of pediatric acute lymphoblastic leukemias by high resolution single nucleotide polymorphism oligonucleotide genomic microarray. Blood 111, 776-784, 2008.

Steinemann D., Cario G., Stanulla M., Karawajew C., Tauscher M., Weigmann A., Göhring G., Ludwig W.D., Harbott J., Radlwimmer B., Bartram C.R.,Lichter P., Schrappe M., Schlegelberger B.: Copy number alterations in childhood acute lymphoblastic leukemia and their association with minimal residual disease. Genes, Chromosomes and Cancer 47, 471-480, 2008

Thirumaran R.K., Gast A., Kumar R., Flohr T., Burwinkel B., Bartram C., Hemminki K.-, Kumar R.: MTHFR genetic polymorphisms and susceptibility to childhood acute lymphoblastic leukemia. Blood 106, 2590-2591, 2005.

Pongers-Willemse M.J., Seriu T., Stolz F., Corral L., Gameiro P., Pisa P., Gonzales M., Bartram C.R., Panzer-Grümayer E.R., Biondi A., San Miguel J.F., van Dongen J.J.M.: Primers and protocols for standardized detection of minimal residual disease in acute lymphoblastic leukemia using immunoglobulin and T cell receptor gene rearrangements and TAL1 deletions as PCR targets. Leukemia 13, 110-118, 1999.

Nakao M., Janssen J.W.G., Flohr T., Bartram C.R.: Rapid and reliable quantification of minimal residual disease in acute lymphoblastic leukemia using rearranged immunoglobulin and T-cell receptor loci by LightCycler technology. Cancer Res. 60, 3281-3289, 2000.

Biondi A., Valsecchi M.G., Seriu T., D’Aniello E., Willemse M.P., Fasching K., Pannunzio A., Gadner H., Schrappe M., Kamps W.A., Bartram C.R., van Dongen J.J.M., Panzer-Grümayer E.R.: Molecular detection of minimal residual disease is a strong predictive factor of relapse in childhood B-lineage acute lymphoblastic leukemia with medium risk features. A case control study of the International BFM-Study Group. Leukemia 14, 1939-1943, 2000.

Willemse M.J., Seriu T., d'Aniello E., Hop W.C.J., Panzer-Grümayer E.R., Biondi A., Schrappe M., Kamps W.A., Masera G., Gadner H., Riehm H., Bartram C.R., van Dongen J.J.M.: Detection of minimal residual disease identifies differences in treatment response between T-ALL and precursor-B-ALL. Blood 99, 4386-4393, 2002.

Cario G., Stanulla M., Fine B.M., Teuffel O., v. Neuhoff N., Schrauder A., Flohr T., Schäfer B.W., Bartram C.R., Welte K., Schlegelberger B., Schrappe M.: Distinct gene expression profiles determine molecular treatment response in childhood acute lymphoblastic leukemia.Blood 105, 821-826, 2005

Takeuchi S., Seriu T., van Dongen J.J.M., Szczepanski T., Tsukasaki K., Takeuchi N., Fermin A.C., Seo H., Bartram C.R., Koeffler H.P.: Allelotype analysis in relapsed childhood acute lymphoblastic leukemia. Oncogene 22, 6970-6976, 2003.

Gleißner B., Gökbuget N., Bartram C.R., Janssen L.A.J., Rieder H., Janssen J.W.G., Fonatsch C., Heyll A., Voliotis D., Beck J.,Lipp T., Munzert G., Maurer J., Hoelzer D., Thiel E.: Leading prognostic relevance of the BCR-ABL translocation in adult acute B-lineage lymphoblastic leukemia: a prospective study of the German Multicenter Trial Group and confirmed polymerase chain reaction analysis.Blood 99, 1536-1543, 2002.

Tsukasaki K., Krebs J., Nagai K., Tomonaga M., Koeffler H.P., Bartram C.R., Jauch A.: Comparative genomic hybridization (CGH) analysis of adult T-cell leukemia/lymphoma (ATL): correlation with clinical course. Blood 97, 3875-3881, 2001.

Kamatsu N., Takeuchi S., Ikezoe T., Tasaka T., Hatta Y., Machida H., Williamson I.K., Bartram C.R., Koeffler H.P., Taguchi H.: Mutations of the E2F4 gene in hematological malignancies having microsatellite instability. Blood 95, 1509-1510, 2000.

Takeuchi S., Cho S.K., Seriu T., Koike M., Bartram C.R., Reiter A., Schrappe M., Takeuchi C., Taguchi H., Koeffler H.P.: Identification of three distinct regions of deletion on the long arm of chromosome 11 in childhood acute lymphoblastic leukemia. Oncogene 18, 7387-7388, 1999.

Kawano S., Miller C.W., Gombart A.F., Bartram C.R., Matsuo Y., Asou H., Sakashita A., Said J., Tatsumi E., Koeffler H.P.: Loss of p73 gene expression in leukemias/lymphomas due to hypermethylation.Blood 94, 1113-1120, 1999.

Ludwig W.D., Rieder H., Bartram C.R., Heinze B., Schwartz S., Gassmann W., Löffler H., Hossfeld D., Heil G., Handt S., Heyll A., Diedrich H., Fischer K., Weiss A., Völkers B., Aydemir Ü., Fonatsch C., Gökbuget N., Thiel E., Hoelzer D.: Immunophenotypic and genotypic features, clinical characteristics, and treatment outcome of adult pro-B acute lymphoblastic leukemia: results of the German Multicenter Trials GMALL 03/87 and 04/89.Blood 92, 1898-1909, 1998.

Takeuchi S., Koike M., Seriu T., Bartram C.R., Schrappe M., Reiter A., Park S., Miyoshi I., Koeffler H.P.: Frequent loss of heterozygosity on the long arm of chromosome 6: identification of two distinct regions of deletion in childhood acute lymphoblastic leukemia. Cancer Res. 58, 2618-2623, 1998.

McLean T.W., Ringold S., Neuberg, D., Stegmaier K., Tantravahi R., Ritz, J., Koeffler H.P., Takeuchi S., Janssen, J.W.G., Seriu T., Bartram C.R., Sallan S.E., Gilliland D.G., Golub T.R.: TEL/AML1 dimerizes and is associated with a favorable outcome in childhood acute lympho-blastic leukemia. Blood 88, 4252-4258, 1996.

Stegmaier K., Takeuchi S., Golub T.R., Bohlander S.U., Bartram C.R., Koeffler H.P., Gilliland D.G.: Mutational analysis of the candidate tumor suppressor genes TEL and KIP1 in childhood acute lymphoblastic leukemia. Cancer Res. 56, 1413-1417, 1996.

Morosetti R., Grignani F., Liberatore C., Pelicci P.G., Schiller G.J., Kizaki M., Bartram C.R., Miller C.W., Koeffler H.P.: Infrequent alterations of the RAR gene in acute myelogenous leukemias, retinoic acid-resistant acute promyelocytic leukemias, myelodysplastic syndromes and cell lines. Blood 87, 4399-4403, 1996.

Takeuchi S., Bartram C.R., Miller C.W., Seriu T., Reiter A., Mori N., Slatter J., Zimmermann M., Schrappe M., Koeffler H.P.: Acute lymphoblastic leukemia of childhood: identification of two distinct regions of deletion on the short arm of chromosome 12 in the region of TEL and KJP1. Blood 87, 3368-3374, 1996.

Takeuchi S., Bartram C.R., Wada M., Reiter A., Hatta Y., Seriu T., Lee E., Miller C.W., Miyoshi I., Koeffler H.P.:
Allelotype analysis of childhood acute lymphoblastic leukemia. Cancer Res. 55, 5377-5382, 1995.

Kawamata M., Morosetti R., Miller C.W., Park D., Spirin K.S., Nakamaki T., Takeuchi S., Hatta Y., Simpson J., Wilczynski S., Lee Y.Y., Bartram C., Koeffler H.P.: Molecular analysis of the cyclin-dependent kinase inhibitor p27/Kip1 gene in human malignancies. Cancer Res. 55, 2266-2269, 1995.

Takeuchi S., Bartram C.R., Seriu T., Miller C.W., Tobler A., Janssen J.W.G., Reiter A., Ludwig W.D., Zimmermann M., Schwaller J., Lee E., Miyoshi J., Koeffler H.P.: Analysis of a family of cyclin-dependent kinase inhibitors: p15/MTS2/INK4B, p16/MTS1/INK4A and p18 genes in acute lymphoblastic leukemia (ALL) of childhood. Blood 86, 755-760, 1995.

Hansen-Hagge T.E., Panzer-Grümayer R.E., Mahotka C., Reuter H.J., Schwarz K., van Dongen J.J.M., Bartram C.R.: Alternative splicing prevents translation of illegitimate chimeric / T cell receptor variable regions during thymic differentiation. Blood 85, 1888-1896, 1995.

Janssen J.W.G., Ludwig W.D., Borkhardt A., Spadinger U., Rieder H., Fonatsch C., Hossfeld D.K., Harbott J., Schulz A.S., Repp R., Sykora K.W., Hoelzer D., Bartram C.R.: Pre-pre-B acute lymphoblastic leukemia: high frequency of alternatively spliced ALL1-AF4 transcripts and absence of minimal residual disease during complete remission. Blood 84, 3835-3842, 1994.

Wada M., Bartram C.R., Nakamura H., Hachiya M., Chen D.L., Borenstein J., Hansen-Hagge T.E., Ludwig W.D., Reiter A., Mizoguchi H., Koeffler H.P.: Analysis of p53 mutations in a large series of lymphoid hematological malignancies of childhood. Blood 82, 3163-3169, 1993.

Hansen-Hagge T.E., Yokota S., Reuter H., Schwarz K., Bartram C.R.: Human common acute lymphoblastic leukemia derived cell lines are competent to recombine their T cell receptor / regions along a hierarchically ordered pathway.Blood 80, 2359-2362, 1992.

Maurer J., Janssen J.W.G., Thiel E., van Denderen J., Ludwig W.D., Aydemir Ü., Heinze B., Fonatsch C., Harbott J., Reiter A., Riehm H., Hoelzer D., Bartram C.R.: Detection of chimeric BCR-ABL genes in acute lymphoblastic leukaemia by polymerase chain reaction.Lancet 337, 1055-1058, 1991.

Yokota S., Hansen-Hagge T.E., Ludwig W.D., Reiter A., Raghavachar A., Kleihauer E., Bartram C.R.: The use of polymerase chain reactions to monitor minimal residual disease in acute lymphoblastic leukemia patients.Blood 77 331-339, 1991.

Yokota S., Hansen-Hagge T.E., Bartram C.R.: T-cell receptor  gene recombination in common acute
lymphoblastic leukemia: preferential usage of V2 and frequent involvement of the J cluster. Blood 77, 141-148, 1991.

Morgan G.J., Hughes T., Janssen J.W.G., Gow J., Guo A.P., Goldman J.M., Wiedemann L.M., Bartram C.:
Polymerase chain reaction for detection of residual leukemia. Lancet I, 928-929, 1989.

Hansen-Hagge T.E., Yokota S., Bartram C.R.: Detection of minimal residual disease in acute lymphoblastic leukemia by in vitro amplification of rearranged T cell receptor  chain sequences. Blood 74, 1762-1767, 1989.

Thiel E., Kranz B.R., Raghavachar A., Bartram C.R., Löffler H., Messerer D., Ganser A, Büchner T., Hoelzer D.:
Prethymic phenotypic and genotype of pre-T (CD7+/ER-)- cell leukemia and its clinical significance within adult acute lymphoblastic leukemia. Blood 73, 1247-1258, 1989.

Ludwig W.D., Bartram C.R., Ritter J., Raghavachar A., Hiddemann W., Heil G., Harbott J., Seibt-Jung H., Teichmann J.V., Riehm H.: Ambiguous phenotypes and genotypes in 16 children with acute leukemia as characterized by multiparameter analysis.Blood 71, 1518-1528, 1988.

Janssen J.W.G., Steenvoorden A.C.M., Lyons J., Anger B., Böhlke J.U., Bos J.L., Seliger H., Bartram C.R.: Ras gene mutations in acute and chronic myelocytic leukemias, chronic myeloproliferative disorders and myelodysplastic syndromes.Proc. Natl. Acad. Sci. (USA) 84, 9228-9232, 1987.

Raghavachar A., Thiel E., C.R. Bartram: Analyses of phenotype and genotype in acute lymphoblastic leukemias at first presentation and in relapse. Blood 70, 1079-1083, 1987.

Bartram C.R., Janssen J.W.G., Becher R., de Klein A., Grosveld G.: Persistence of chronic myelocytic leukemia despite deletion of rearranged bcr/c-abl sequences in blast crisis.J. Exp. Med. 164, 1389-1396, 1986.

De Klein A., Hagemeijer A., Bartram C.R., Houwen R., Hoefsloot L., Carbonell F., Chan L., Barnett M., Greaves M., Kleihauer E., Heisterkamp N., Groffen J., Grosveld G.: Bcr rearrangement and translocation of the c-abl oncogene in Philadelphia positive acute lymphoblastic leukemia. Blood 68, 1369-1375, 1986.

Raghavachar A., Bartram C.R., Ganser A., Heil G., Kleihauer E., Kubanek B.: Acute undifferentiated leukemia (AUL): implications for cellular origin and clonality suggested by analysis of surface markers and immunoglobulin gene rearrangement.Blood 68, 658-662, 1986.

Bartram C.R.: Bcr rearrangement without juxtaposition of c-abl in chronic myelocytic leukemia.J. Exp. Med. 162, 2175, 2179, 1985.

Bartram C.R., Kleihauer E., de Klein A., Grosveld G., Teyssier J.R., Heisterkamp N., Groffen J.: C-abl and bcr are rearranged in a Ph-negative CML patient.EMBO J. 4, 683-686, 1985.

Groffen J., Stephenson J.R., Heisterkamp N., de Klein A., Bartram C.R., Grosveld G.: Philadelphia chromosomal breakpoints are clustered within a limited region - bcr - on chromosome 22. Cell 36, 93-99, 1984.

Bartram C.R., de Klein A., Hagemeijer A., van Agthoven T., Geurts van Kessel A., Bootsma D., Grosveld G., Ferguson-Smith M.A., Davies T., Stone M., Heisterkamp N., Stephenson J.R., Groffen J.: Translocation of c-abl oncogene correlates with the presence of a Philadelphia chromosome in chronic myelocytic leukaemia. Nature 306, 277-280, 1983.

Heisterkamp N., Stephenson J.R., Groffen J., Hansen P.F., de Klein A., Bartram C.R., Grosveld G.: Localization of the c-abl oncogene adjacent to a translocation breakpoint in chronic myelocytic leukaemia. Nature 306, 239-242, 1983.

De Klein A., Geurts van Kessel A., Grosveld G., Bartram C.R., Hagemeijer A., Bootsma D., Spurr N.K., Heisterkamp N., Groffen J., Stephenson J.R.: A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia. Nature 300, 765-767, 1982.