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Claus Meyer - One of the best experts on this subject based on the ideXlab platform.
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Long-term remission of therapy-related acute myeloid leukemia with a new t(11;18)(q23;q21.2) translocation and KMT2A-ME2 (MLL-ME2) fusion Gene
Cancer genetics, 2015Co-Authors: Tomáš Szotkowski, Rolf Marschalek, Claus Meyer, Marie Jarosova, Olga Zimmermannova, Jan Zuna, Hubácek J, Karel IndrakAbstract:We describe a unique case of a woman with acute myeloid leukemia with a new, previously undescribed translocation, t(11;18)(q23;q21.2), affecting the KMT2A (MLL) Gene and resulting in an KMT2A(MLL)-ME2 fusion. This disease occurred secondarily following chemotherapy for a different acute myeloid leukemia with the recurrent Genetic abnormality inv(16)(p13.1;q22). The secondary leukemia was treated with intensive chemotherapy without alloGeneic hematopoietic cell transplantation. Complete remission lasting more than 10 years has been achieved with concurrent and sustained remission of the primary leukemia.
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RESEARCH ARTICLE Open Access A novel spliced fusion of MLL with CT45A2 in a pediatric biphenotypic acute leukemia
2013Co-Authors: Nuno Cerveira, Claus Meyer, Joana Santos, Lurdes Torres, Susana Lisboa, Manuela Pinheiro, Susana Bizarro, Cecília Correia, Lucília Norton, Rolf MarschalekAbstract:Background: Abnormalities of 11q23 involving the MLL Gene are found in approximately 10 % of human leukemias. To date, nearly 100 different chromosome bands have been described in rearrangements involving 11q23 and 64 fusion Genes have been cloned and characterized at the molecular level. In this work we present the identification of a novel MLL fusion partner in a pediatric patient with de novo biphenotypic acute leukemia. Methods: CytoGenetics, fluorescence in situ hybridization (FISH), molecular studies (RT-PCR and LDI-PCR), and bioinformatic sequence analysis were used to characterize the CT45A2 Gene as novel MLL fusion partner in pediatric acute leukemia. Results: Fluorescence in situ hybridization of bone marrow G-banded metaphases demonstrated a cryptic insertion of 11q23 in Xq26.3 involving the MLL Gene. Breakpoint fusion analysis revealed that a DNA fragment of 653 kb from 11q23, containing MLL exons 1-9 in addition to 16 other 11q23 Genes, was inserted into the upstream region of the CT45A2 Gene located at Xq26.3. In addition, a deletion at Xq26.3 encompassing the 3 ’ region of the DDX26B Gene (exons 9-16) and the entire CT45A1 Gene was identified. RNA analysis revealed the presence of a novel MLL-CT45A2 fusion transcript in which the first 9 exons of the MLL Gene were fused in-frame to exon 2 of the CT45A2 Gene, resulting in a spliced MLL fusion transcript with an intact open reading frame. The resulting chimeri
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The MLL recombinome of acute leukemias in 2013
Leukemia, 2013Co-Authors: Claus Meyer, Julia Hofmann, Thomas Burmeister, Daniela Gröger, T. S. Park, Mariana Emerenciano, M. Pombo De Oliveira, Aline Renneville, Patrick Villarese, Elizabeth MacintyreAbstract:Chromosomal rearrangements of the human MLL (mixed lineage leukemia) Gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL-rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL Gene and the involved translocation partner Genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL Gene (∼90%): AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, ELL, partial tandem duplications (MLL PTDs) and MLLT4/AF6, respectively. The MLL breakpoint distributions for all clinical relevant subtypes (gender, disease type, age at diagnosis, reciprocal, complex and therapy-induced translocations) are presented. Finally, we present the extending network of reciprocal MLL fusions deriving from complex rearrangements.
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a novel spliced fusion of MLL with ct45a2 in a pediatric biphenotypic acute leukemia
BMC Cancer, 2010Co-Authors: Nuno Cerveira, Claus Meyer, Joana Santos, Lurdes Torres, Susana Lisboa, Manuela Pinheiro, Susana Bizarro, Cecília Correia, Lucília Norton, Rolf MarschalekAbstract:Background Abnormalities of 11q23 involving the MLL Gene are found in approximately 10% of human leukemias. To date, nearly 100 different chromosome bands have been described in rearrangements involving 11q23 and 64 fusion Genes have been cloned and characterized at the molecular level. In this work we present the identification of a novel MLL fusion partner in a pediatric patient with de novo biphenotypic acute leukemia.
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nebulette is the second member of the nebulin family fused to the MLL Gene in infant leukemia
Cancer Genetics and Cytogenetics, 2010Co-Authors: Virginia Maria Coser, Rosania Basegio, Juliane Menezes, Rolf Marschalek, Claus Meyer, Maria S PombodeoliveiraAbstract:Abstract Genetic aberrations involving the mixed lineage leukemia ( MLL ) Gene are frequently diagnosed in infant acute lymphoblastic and acute myeloid leukemia. More than 60 fusion partner Genes have been described at the molecular level, 31 of which have been characterized solely in infant leukemia cases. Here we describe a new MLL fusion partner Gene, NEBL, which was identified in a case of acute myeloid leukemia in an infant. The chromosomal breakpoints of the MLL–NEBL and NEBL–MLL fusion Genes were cloned by long-distance inverse polymerase chain reaction. The chromosomal breakpoints were located at 10p12, approximately 570 kb telomic of the MLLT10 ( AF10 ) Gene. AF10 and NEBL are localized in such close vicinity that they cannot be distinguished cytoGenetically by G banding. Therefore, the combination of cytoGenetic and independent molecular techniques such as long-distance inverse polymerase chain reaction are indispensable for the rapid identification and characterization of rare MLL rearrangements.
Rolf Marschalek - One of the best experts on this subject based on the ideXlab platform.
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systematic classification of mixed lineage leukemia fusion partners predicts additional cancer pathways
Korean Journal of Laboratory Medicine, 2016Co-Authors: Rolf MarschalekAbstract:Chromosomal translocations of the human mixed-lineage leukemia (MLL) Gene have been analyzed for more than 20 yr at the molecular level. So far, we have collected about 80 direct MLL fusions (MLL-X alleles) and about 120 reciprocal MLL fusions (X-MLL alleles). The reason for the higher amount of reciprocal MLL fusions is that the excess is caused by 3-way translocations with known direct fusion partners. This review is aiming to propose a solution for an obvious problem, namely why so many and completely different MLL fusion alleles are always leading to the same leukemia phenotypes (ALL, AML, or MLL). This review is aiming to explain the molecular consequences of MLL translocations, and secondly, the contribution of the different fusion partners. A new hypothesis will be posed that can be used for future research, aiming to find new avenues for the treatment of this particular leukemia entity.
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Long-term remission of therapy-related acute myeloid leukemia with a new t(11;18)(q23;q21.2) translocation and KMT2A-ME2 (MLL-ME2) fusion Gene
Cancer genetics, 2015Co-Authors: Tomáš Szotkowski, Rolf Marschalek, Claus Meyer, Marie Jarosova, Olga Zimmermannova, Jan Zuna, Hubácek J, Karel IndrakAbstract:We describe a unique case of a woman with acute myeloid leukemia with a new, previously undescribed translocation, t(11;18)(q23;q21.2), affecting the KMT2A (MLL) Gene and resulting in an KMT2A(MLL)-ME2 fusion. This disease occurred secondarily following chemotherapy for a different acute myeloid leukemia with the recurrent Genetic abnormality inv(16)(p13.1;q22). The secondary leukemia was treated with intensive chemotherapy without alloGeneic hematopoietic cell transplantation. Complete remission lasting more than 10 years has been achieved with concurrent and sustained remission of the primary leukemia.
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RESEARCH ARTICLE Open Access A novel spliced fusion of MLL with CT45A2 in a pediatric biphenotypic acute leukemia
2013Co-Authors: Nuno Cerveira, Claus Meyer, Joana Santos, Lurdes Torres, Susana Lisboa, Manuela Pinheiro, Susana Bizarro, Cecília Correia, Lucília Norton, Rolf MarschalekAbstract:Background: Abnormalities of 11q23 involving the MLL Gene are found in approximately 10 % of human leukemias. To date, nearly 100 different chromosome bands have been described in rearrangements involving 11q23 and 64 fusion Genes have been cloned and characterized at the molecular level. In this work we present the identification of a novel MLL fusion partner in a pediatric patient with de novo biphenotypic acute leukemia. Methods: CytoGenetics, fluorescence in situ hybridization (FISH), molecular studies (RT-PCR and LDI-PCR), and bioinformatic sequence analysis were used to characterize the CT45A2 Gene as novel MLL fusion partner in pediatric acute leukemia. Results: Fluorescence in situ hybridization of bone marrow G-banded metaphases demonstrated a cryptic insertion of 11q23 in Xq26.3 involving the MLL Gene. Breakpoint fusion analysis revealed that a DNA fragment of 653 kb from 11q23, containing MLL exons 1-9 in addition to 16 other 11q23 Genes, was inserted into the upstream region of the CT45A2 Gene located at Xq26.3. In addition, a deletion at Xq26.3 encompassing the 3 ’ region of the DDX26B Gene (exons 9-16) and the entire CT45A1 Gene was identified. RNA analysis revealed the presence of a novel MLL-CT45A2 fusion transcript in which the first 9 exons of the MLL Gene were fused in-frame to exon 2 of the CT45A2 Gene, resulting in a spliced MLL fusion transcript with an intact open reading frame. The resulting chimeri
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a novel spliced fusion of MLL with ct45a2 in a pediatric biphenotypic acute leukemia
BMC Cancer, 2010Co-Authors: Nuno Cerveira, Claus Meyer, Joana Santos, Lurdes Torres, Susana Lisboa, Manuela Pinheiro, Susana Bizarro, Cecília Correia, Lucília Norton, Rolf MarschalekAbstract:Background Abnormalities of 11q23 involving the MLL Gene are found in approximately 10% of human leukemias. To date, nearly 100 different chromosome bands have been described in rearrangements involving 11q23 and 64 fusion Genes have been cloned and characterized at the molecular level. In this work we present the identification of a novel MLL fusion partner in a pediatric patient with de novo biphenotypic acute leukemia.
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the af4 MLL fusion protein is capable of inducing all in mice without requirement of MLL af4
Blood, 2010Co-Authors: A Bursen, Karen Schwabe, Brigitte Ruster, Reinhard Henschler, Martin Ruthardt, Theo Dingermann, Rolf MarschalekAbstract:The chromosomal translocation t(4;11)(q21;q23) is the most frequent Genetic aberration of the human MLL Gene, resulting in high-risk acute lymphoblastic leukemia (ALL). To elucidate the leukemogenic potential of the fusion proteins MLL.AF4 and AF4.MLL, Lin(-)/Sca1(+) purified cells (LSPCs) were retrovirally transduced with either both fusion Genes or with MLL.AF4 or AF4.MLL alone. Recipients of AF4.MLL- or double-transduced LSPCs developed pro-B ALL, B/T biphenotypic acute leukemia, or mixed lineage leukemia. Transplantation of MLL.AF4- or mock-transduced LSPCs did not result in disease development during an observation period of 13 months. These findings indicate that the expression of the AF4.MLL fusion protein is capable of inducing acute lymphoblastic leukemia even in the absence of the MLL.AF4 fusion protein. In view of recent findings, these results may imply that t(4;11) leukemia is based on 2 oncoproteins, providing an explanation for the very early onset of disease in humans.
Jay L Hess - One of the best experts on this subject based on the ideXlab platform.
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menin MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia
Nature Chemical Biology, 2012Co-Authors: Jolanta Grembecka, Andrew G. Muntean, Aibin Shi, Trupta Purohit, Roderick J Sorenson, H Hollis D Showalter, Marcelo J Murai, Amalia M Belcher, Thomas Hartley, Jay L HessAbstract:Translocations involving the mixed lineage leukemia (MLL) Gene result in human acute leukemias with very poor prognosis. The leukemogenic activity of MLL fusion proteins is critically dependent on their direct interaction with menin, a product of the multiple endocrine neoplasia (MEN1) Gene. Here we present what are to our knowledge the first small-molecule inhibitors of the menin-MLL fusion protein interaction that specifically bind menin with nanomolar affinities. These compounds effectively reverse MLL fusion protein-mediated leukemic transformation by downregulating the expression of target Genes required for MLL fusion protein oncogenic activity. They also selectively block proliferation and induce both apoptosis and differentiation of leukemia cells harboring MLL translocations. Identification of these compounds provides a new tool for better understanding MLL-mediated leukemoGenesis and represents a new approach for studying the role of menin as an oncogenic cofactor of MLL fusion proteins. Our findings also highlight a new therapeutic strategy for aggressive leukemias with MLL rearrangements.
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CBX8, a Polycomb Group Protein, Is Essential for MLL-AF9-Induced LeukemoGenesis
Cancer cell, 2011Co-Authors: Jiaying Tan, Morgan Jones, Haruhiko Koseki, Manabu Nakayama, Andrew G. Muntean, Ivan Maillard, Jay L HessAbstract:Chromosomal translocations involving the mixed lineage leukemia (MLL) Gene lead to the development of acute leukemias. Constitutive HOX Gene activation by MLL fusion proteins is required for MLL-mediated leukemoGenesis; however, the underlying mechanisms remain elusive. Here, we show that chromobox homolog 8 (CBX8), a Polycomb Group protein that interacts with MLL-AF9 and TIP60, is required for MLL-AF9-induced transcriptional activation and leukemoGenesis. Conversely, both CBX8 ablation and specific disruption of the CBX8 interaction by point mutations in MLL-AF9 abrogate HOX Gene upregulation and abolish MLL-AF9 leukemic transformation. Surprisingly, Cbx8-deficient mice are viable and display no apparent hematopoietic defects. Together, our findings demonstrate that CBX8 plays an essential role in MLL-AF9 transcriptional regulation and leukemoGenesis.
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requirement for dot1l in murine postnatal hematopoiesis and leukemoGenesis by MLL translocation
Blood, 2011Co-Authors: Eric M Granowicz, Ivan Maillard, Dafydd G Thomas, Jay L HessAbstract:Disruptor of telomeric silencing 1-like (Dot1l) is a histone 3 lysine 79 methyltransferase. Studies of constitutive Dot1l knockout mice show that Dot1l is essential for embryonic development and prenatal hematopoiesis. DOT1L also interacts with translocation partners of Mixed Lineage Leukemia (MLL) Gene, which is commonly translocated in human leukemia. However, the requirement of Dot1l in postnatal hematopoiesis and leukemoGenesis of MLL translocation proteins has not been conclusively shown. With a conditional Dot1l knockout mouse model, we examined the consequences of Dot1l loss in postnatal hematopoiesis and MLL translocation leukemia. Deletion of Dot1l led to pancytopenia and failure of hematopoietic homeostasis, and Dot1l-deficient cells minimally reconstituted recipient bone marrow in competitive transplantation experiments. In addition, MLL-AF9 cells required Dot1l for oncogenic transformation, whereas cells with other leukemic oncoGenes, such as Hoxa9/Meis1 and E2A-HLF, did not. These findings illustrate a crucial role of Dot1l in normal hematopoiesis and leukemoGenesis of specific oncoGenes.
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MLL a histone methyltransferase disrupted in leukemia
Trends in Molecular Medicine, 2004Co-Authors: Jay L HessAbstract:Rearrangements of the MLL Gene, which is located at chromosome 11q23, are associated with aggressive acute leukemias in both children and adults. MLL regulates Hox Gene expression through direct promoter binding and histone modification. MLL rearrangements occurring in leukemia include MLL fusion Genes, partial tandem duplications of MLL and MLL amplification. MLL fusions and amplification upregulate Hox expression, apparently resulting in a block of hematopoietic differentiation. Future therapies for MLL-associated leukemia might involve blocking Hox Gene upregulation by using fusion proteins or inhibiting the activity of Hox proteins themselves.
Terence H. Rabbitts - One of the best experts on this subject based on the ideXlab platform.
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an MLL af9 fusion Gene made by homologous recombination causes acute leukemia in chimeric mice a method to create fusion oncoGenes
Cell, 1996Co-Authors: Javier Corral, Isabelle Lavenir, Helen Impey, Alan J Warren, Teresa A Larson, Sarah Bell, Gareth King, Andrew N J Mckenzie, Terence H. RabbittsAbstract:Abstract Homologous recombination in embryonal stem cells has been used to produce a fusion oncoGene, thereby mimicking chromosomal translocations that frequently result in formation of tumor-specific fusion oncoGenes in human malignancies. AF9 sequences were fused into the mouse MLL Gene so that expression of the MLL–AF9 fusion Gene occurred from endogenous MLL transcription control elements, as in t(9;11) found in human leukemias. Chimeric mice carrying the fusion Gene developed tumors, which were restricted to acute myeloid leukemias despite the widespread activity of the MLL promoter. Onset of perceptible disease was preceded by expansion of ES cell derivatives in peripheral blood. This novel use of homologous recombination formally proves that chromosomal translocations contribute to malignancy and provides a General strategy to create fusion oncoGenes for studying their role in tumoriGenesis. *Present address: Centro de Hemodonacion, Universidad de Murcia, Ronda de Garay, 30003 Murcia, Spain. † Present address: Wellcome Trust Immunology Unit, Department of Medicine, University of Cambridge School of Medicine, Cambridge CB2 2SP, United Kingdom.
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an MLL af9 fusion Gene made by homologous recombination causes acute leukemia in chimeric mice a method to create fusion oncoGenes
Cell, 1996Co-Authors: Javier Corral, Isabelle Lavenir, Helen Impey, Alan J Warren, Teresa A Larson, Sarah Bell, Gareth King, Andrew N J Mckenzie, A Forster, Terence H. RabbittsAbstract:Homologous recombination in embryonal stem cells has been used to produce a fusion oncoGene, thereby mimicking chromosomal translocations that frequently result in formation of tumor-specific fusion oncoGenes in human malignancies. AF9 sequences were fused into the mouse MLL Gene so that expression of the MLL-AF9 fusion Gene occurred from endogenous MLL transcription control elements, as in t(9;11) found in human leukemias. Chimeric mice carrying the fusion Gene developed tumors, which were restricted to acute myeloid leukemias despite the widespread activity of the MLL promoter. Onset of perceptible disease was preceded by expansion of ES cell derivatives in peripheral blood. This novel use of homologous recombination formally proves that chromosomal translocations contribute to malignancy and provides a General strategy to create fusion oncoGenes for studying their role in tumoriGenesis.
Javier Corral - One of the best experts on this subject based on the ideXlab platform.
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an MLL af9 fusion Gene made by homologous recombination causes acute leukemia in chimeric mice a method to create fusion oncoGenes
Cell, 1996Co-Authors: Javier Corral, Isabelle Lavenir, Helen Impey, Alan J Warren, Teresa A Larson, Sarah Bell, Gareth King, Andrew N J Mckenzie, Terence H. RabbittsAbstract:Abstract Homologous recombination in embryonal stem cells has been used to produce a fusion oncoGene, thereby mimicking chromosomal translocations that frequently result in formation of tumor-specific fusion oncoGenes in human malignancies. AF9 sequences were fused into the mouse MLL Gene so that expression of the MLL–AF9 fusion Gene occurred from endogenous MLL transcription control elements, as in t(9;11) found in human leukemias. Chimeric mice carrying the fusion Gene developed tumors, which were restricted to acute myeloid leukemias despite the widespread activity of the MLL promoter. Onset of perceptible disease was preceded by expansion of ES cell derivatives in peripheral blood. This novel use of homologous recombination formally proves that chromosomal translocations contribute to malignancy and provides a General strategy to create fusion oncoGenes for studying their role in tumoriGenesis. *Present address: Centro de Hemodonacion, Universidad de Murcia, Ronda de Garay, 30003 Murcia, Spain. † Present address: Wellcome Trust Immunology Unit, Department of Medicine, University of Cambridge School of Medicine, Cambridge CB2 2SP, United Kingdom.
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an MLL af9 fusion Gene made by homologous recombination causes acute leukemia in chimeric mice a method to create fusion oncoGenes
Cell, 1996Co-Authors: Javier Corral, Isabelle Lavenir, Helen Impey, Alan J Warren, Teresa A Larson, Sarah Bell, Gareth King, Andrew N J Mckenzie, A Forster, Terence H. RabbittsAbstract:Homologous recombination in embryonal stem cells has been used to produce a fusion oncoGene, thereby mimicking chromosomal translocations that frequently result in formation of tumor-specific fusion oncoGenes in human malignancies. AF9 sequences were fused into the mouse MLL Gene so that expression of the MLL-AF9 fusion Gene occurred from endogenous MLL transcription control elements, as in t(9;11) found in human leukemias. Chimeric mice carrying the fusion Gene developed tumors, which were restricted to acute myeloid leukemias despite the widespread activity of the MLL promoter. Onset of perceptible disease was preceded by expansion of ES cell derivatives in peripheral blood. This novel use of homologous recombination formally proves that chromosomal translocations contribute to malignancy and provides a General strategy to create fusion oncoGenes for studying their role in tumoriGenesis.
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acute leukemias of different lineages have similar MLL Gene fusions encoding related chimeric proteins resulting from chromosomal translocation
Proceedings of the National Academy of Sciences of the United States of America, 1993Co-Authors: Javier Corral, A Forster, S Thompson, F Lampert, Y Kaneko, R Slater, W Kroes, C E Van Der Schoot, W D Ludwig, A KarpasAbstract:The MLL Gene, on human chromosome 11q23, undergoes chromosomal translocation in acute leukemias, resulting in Gene fusion with AF4 (chromosome 4) and ENL (chromosome 19). We report here translocation of MLL with nine different chromosomes and two paracentric chromosome 11 deletions in early B cell, B- or T-cell lineage, or nonlymphocytic acute leukemias. The mRNA translocation junction from 22 t(4;11) patients, including six adult leukemias, and nine t(11;19) tumors reveals a remarkable conservation of breakpoints within MLL, AF4, or ENL Genes, irrespective of tumor phenotype. Typically, the breakpoints are upstream of the zinc-finger region of MLL, and deletion of this region can accompany translocation, supporting the der(11) chromosome as the important component in leukemoGenesis. Partial sequence of a fusion between MLL and the AFX1 Gene from chromosome X shows the latter to be rich in Ser/Pro codons, like the ENL mRNA. These data suggest that the heteroGeneous 11q23 abnormalities might cause attachment of Ser/Pro-rich segments to the NH2 terminus of MLL, lacking the zinc-finger region, and that translocations occur in early hematopoietic cells, before commitment to distinct lineages.