Common gene fusions caused by chromosomal abnormalities and associated with acute myeloid leukemia.
Acute myeloid leukemia (AML) is characterized by the malignant transformation of myeloid cells from myeloblasts to a pathological cell clone. These pathological cell clones lose their ability to differentiate and mature, are no longer subject to regulatory mechanisms and suppress other components of normal hemopoiesis. AML does not fall under a single nosological entity. The heterogeneity of AML is reflected by differences in morphology and immunophenotype, as well as cytogenetic and molecular genetic abnormalities. It includes a number of subtypes, which can be further classified according to the FAB and World Health Organization (WHO) criteria.
Acute myeloid leukemia represents 15% to 20% of all childhood leukemias, approximately 33% of adolescent leukemias, and approximately 50% of adult leukemias. After a peak during the first 2 years of life, the subsequent annual incidence of AML slowly increases after 9 years of age (incidence rate 5/1 million in 5 to 9-year-olds, 9/1 million in 15 to 19-year-olds). In general, the biological features, other than age, of pediatric and adult AML appear to be similar, but the differences have not been reviewed systematically .
The rate of
Acute myeloid leukemia is a curable disease; the chance of cure for a specific patient depends on a number of prognostic factors. The current five-year survival rates of adult patients under age 60 range from 30% - 40%; for pediatric patients, five-year survival rates are up to 65% [3, 4].
The cure rates in pediatric AML have been achieved not only by the more effective use of anti-leukemic agents but also by improvements in supportive care and better risk-group stratification. Recurrent cytogenetic and genetic aberrations and early responses to treatment are important prognostic factors in AML and therefore are used for risk group stratification.
The prognostic value of cytogenetics is well established in all age groups. The biologic data differ considerably between infants and older age groups but only slightly between children, adolescents, and young adults. The distribution of cytogenetic aberrations in infants is different from that in older patients. Infants have almost no favorable aberrations but have frequent 11q23 aberrations and complex karyotypes, which is similar to older AML patients (>60 years). Schochet et al.  analyzed the effect of age and cytogenetics on clinical outcome in adult patients (>16 years). They found that both age and cytogenetics were independent prognostic parameters in AML; however, up to the age of 49 years, age had no major impact on prognosis, whereas the karyotype did. Therapy today consists of a limited number of intensive courses of chemotherapy based on cytarabine and an anthracycline. An important problem in the treatment of AML remains the high frequency of treatment-related deaths and long-term side effects [6,7].
This problem hampers further therapy-intensification, and most investigators therefore feel that we have reached a plateau in the number of patients that can be cured with current chemotherapy regimens. Our efforts should therefore focus on clarifying the biology of pediatric AML. This knowledge can be used for novel classification and risk-group stratification. In addition, it creates the potential for targeted, i.e., more leukemia-specific, therapy. It is anticipated that such therapies will increase the cure-rate and decrease the toxicity of treatment of patients with AML .
Leukemias bearing translocations involving chromosome 11q23 are of particular interest due to unique clinical and biological characteristics. The development of acute leukemias is associated with
Several translocation partners of
The MLL protein is involved in chromatin regulation. It is specifically hydrolyzed by the endopeptidase Taspase1 and methylates histone core particles at histone H3 lysine 4 residues [17-19]. Therefore, MLL is part of an epigenetic system that co-regulates mitotic gene-expression signatures during embryonic development and tissue differentiation in mammalian organisms. The MLL complex binds to different promoters in various tissues. Recently, a genome-wide array study revealed that MLL was bound to more than 2000 different promoter regions . This protein belongs to the group of Trithorax (trx-G) proteins, which are responsible for maintaining gene expression during growth. It is assumed that the MLL protein controls the expression of
2. Etiology and pathogenesis of causative
MLL gene abnormalities in AML
The cause of 11q23/
|Chromosomal aberation||FAB subtype AML||Frequency||Fusion gene|
|t(8;21) (q22;q22)||AML- M2||18% (30%)|
|t(15;17) (q21-q11-22)||AML- M3||10% (98%)|
|t(11;17) (q23;q21)||AML- M3||rare|
|Inv(16) or t(16;16)||AML- M4Eo||8% (~100%)|
|t(9;11) (p22;q23)||AML- M4||11% (30%)|
|AML- M5||~ 35% AML||MLL-AF6/AF6q21|
|t(6;9) (p23;q34)||AML- M1,M2,M4,M5||1%|
|t(16;21) (p11;q22)||AML||< 1%|
|t(16;21) (q24;q22)||t-AML, MDS||< 1%|
|t(7;11) (p15;p15)||AML- M2, M4||< 1%|
|t(1;11) (q23;p15)||AML- M2||< 1%|
|t(8;16) (p11;p13)||AML- M4, M5||< 1%|
|Inv(8) (p11;q13)||AML- M0, M1, M5||< 1%|
|t(8;22) (p11;p13)||AML- M5||< 1%|
|t(12;22) (p13;q23)||AML- M4, CML||< 1%|
|t(1;19) (q23;p13)||AML- M7||< 1%|
The WHO suggested characterizing 11q23
3. Distribution of
MLL gene alterations
4. Conversion mechanism from an
MLL proto-oncogene to an oncogene
Extensive cytogenetic and molecular studies have revealed that 11q23/MLL is a highly promiscuous locus. Based on the results of research from the past 19 years, 71 different
complex chromosomal alterations, such as deletions, inversions in the area of 11q, MLL gene insertions into other chromosomes or the insertion of chromatin material into the MLL gene
partial tandem duplications
amplifications and gains
B. Partial tandem duplication (PTD) and MLL gene amplification
Approximately 7.5% of AML patients with a normal karyotype are hiding a PTD of the
Previous studies have associated an
Some AML patients have an increased number of
The amplification of genes, a common occurrence in a wide range of tumors, is rarely observed in acute leukemia. Gene amplification is identified in approximately 1% of patients with AML by conducting a cytogenetic analysis in the form of dmin (the area of the
It was found that patients with the
5. Detection methods for
MLL gene conversions
In diagnostic procedures, methods such as cytogenetic analysis, fluorescent in situ hybridization (FISH), and reverse transcriptase-polymerase chain reaction (RT-PCR) are routinely used for the identification of various regroupings within the
5.1. Long-distance inverse PCR (LDI-PCR )
Analyses of novel identified
6. Outcomes of these methods
Translocations of the Mixed Lineage Leukemia (MLL) gene at 11q23 are found in both acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML). The
Rearrangements of the
As with other types of leukemia, the cause of MLL-rearranged AML is unknown. The pathogenesis of AML requires both type-I and type-II mutations.
The monitoring of MRD by RT-PCR detection of leukemia-specific targets (e.g., gene fusions, gene mutations, overexpressed genes) or by multi-parameter flow cytometry identifying leukemia-associated aberrant phenotypes remains an active field of investigation. Despite technical developments, there is still a paucity of large prospective trials demonstrating its clinical utility, except for APL (acute promyelocytic leukemia). Potentially useful applications of MRD monitoring include early assessment of response to therapy to improve risk stratification and guide post-remission therapy and post-treatment monitoring to detect impending relapse and to guide preemptive therapy. Real-time quantitative (RQ)–PCR assays have been developed for other fusion gene targets such as MLLT3-MLL and DEK-NUP214, but the data are very scarce due to the low frequencies of these leukemias. In AML, there is a need for new agents that target specific biological markers with crucial roles in the development of leukemia and that are related to outcome. Benefits from specific treatments have been shown for specific AML FAB 3 - APL with ATRA and for CML and Ph+ ALL, imatinib mesylate.
There are several recently developed agents that may target the
Acute myeloid leukemia is a heterogeneous group of leukemias that result from the clonal transformation of hematopoietic precursors through the acquisition of many chromosomal rearrangements and multiple gene mutations. The cytogenetic aberrations are commonly used as diagnostic and prognostic markers for specific subgroups; in addition, they also have important impacts on achieving complete remission, risk of relapse and overall survival of patients.
Among these aberrations is a subgroup of
However, although subgroup-directed and rationally targeted therapy offers possibilities for the improved care of patients with AML, it will also have implications for the design of clinical trials. In the long term, this may require large randomized trials with international subgroup-specific protocols.
The relationship of outcome with specific translocation partners requires that partners be searched for in the diagnostic work-up of AML and followed-up during treatment. However, to achieve further improvements in survival, unraveling the biology of AML is warranted.
Creutzig U Büchner T Sauerland M. C Zimmermann M Reinhardt D Döhner H Schlenk R. F 2008 Significance of age in acute myeloid leukemia patients younger than 30 years: a common analysis of the pediatric trials AML-BFM 93/98 and the adult trials AMLCG 92/99 and AMLSG HD93/98A 112 3 562 71
Leone G Mele L Pulsoni A Equitani F Pagano L 1999The incidence of secondary leukemias. Haematologica. 84 10 937 45
Kolitz J. E George S. L Marcucci G et al 2010P-glycoprotein inhibition using valspodar (PSC-833) does not improve outcomes for patients under age 60 years with newly diagnosed acute myeloid leukemia: Cancer and Leukemia Group B study 19808. Blood. 116 1413 1421
Kaspers GJLZwaan, CHM ( 2007 Pediatric acute myeloid leukemia: towards high-quality cure of all patients. 1519 EOF 32 EOF
Schoch C Schnittger S Klaus M et al 2003 AML with 11q23/MLL abnormalities as defined by the WHO classification: incidence, partner chromosomes, FAB subtype, age distribution, and prognostic impact in an unselected series of 1897 cytogenetically analyzed AML cases. 102 2395 2402
Van Der Does-Van Den Berg A, Korbijn C, Hählen K, Kamps WA, et al. ( Slats A. M Egeler R. M 2005Causes of death- other than progressive leukemia- in childhood acute lymphoblastic (ALL) and myeloid leukemia (AML): the Dutch Childhood Oncology Group experience. Leukemia. 19 537 44
Rubnitz J. E Lensing S Zhou Y Sandlund J. T Razzouk B. I Ribeiro R. C et al 2004 Death during induction therapy and first remission of acute leukemia in childhood: the St. Jude experience. 101 1677 84
Marshalek R 2010Mechanisms of leukemogenesis by MLL fusion proteins. British Journal of Haematology, 152 141 154
den Boer ML, Minden MD., Sallan SE., Lander ES, Golub TR and Korsmeyer, SJ et al ( Armstrong S. A Staunton J. E Silverman L. B Pieters R 2002MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet. 30 41 47
Yoeh E. J Ross M. E Shurleff S. A Williams W. K Patel D Mafouz R Behm F. G Raimondi S. C Relling M. V Patel A et al 2002Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell. 1 133 143
Mrózek K Heinonen K Lawrence D Carroll A. J Koduru P. R Rao K. W Strout M. P Hutchison R. E Moore J. O Mayer R. J et al 1997Adult patients with de novo acute myeloid leukemia and t(9; 11)( 22q23) have a superior outcome to patients with other translocations involving band 11q23: a cancer and leukemia group B study. Blood 90: 4532-4538.
Balgobind B. V Zwaan C. M Pieters R Van Der Heuvel-eibrink M. M 2011 The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia.Leukemia. 25 1239 1248
Cimino G Rapanotti M. C Sprovieri T Elia L 1998All1 gene alternations in Acute leukemia: biological and clinical aspects. Haematologica. 83 350 357
Lin C Smith E. R Takahashi H Lai K. C Martin-brown S et al 2010 AFF4, a komponent of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transkription elongation to leukemia.Mol Cell. 37 429 437
Arai F and Hirao A Suda T 2005Regulation of hematopoietic stem cells by the niche. Trends Cardiovasc. Med. 15 75 79
De Toni F Racaud-sultan C Chicanne G Mas V. M Careven C Mesange F et al 2006 A crosstalk between the Wnt and the adhesion-dependent signaling pathways governs the chemosensitivity of acute myeloid leukemia. 25 3113 3122
Hsieh JJDCheby EF and Korsmeyer SJ ( 2003Taspasel: a threonine aspartase required for cleavage of MLL and proper HOX gene expression. Cell. 115 293 303
Nakamura T Mori T Tada S Krajewski W Rozovskaia T et al 2002 ALL-1 is a histone methyltransferase that assembler a supercomplex of proteins involved in transcriptional regulation.Mol Cell 10 1119 1128
Yokohama A Wang Z Wysocka J Sanyal M Aufiero D. J et al 2004Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulace Hox gene expression. Mole Cell Biol. 24 5639 5649
Guenter M. G Jenner R. G Chevalier B Nakamura T Croce C. M et al 2005Global and Hox-specific roles for the MLL1 methyltransferase. Proc Natl Acad Sci USA. 102 8603 8608
Lo Coco F, Peschle, C, Testa, U. ( Giampaolo A Felli N Diverio D Morsilli O Samoggia P Breccia M 2002Expression pattern of HOXB6 homeobox gene in myelomonocytic differentiation and acute myeloid leukemia. Leukemia. 16 1293 1301
Burjanivova T Madzo J Muzikova K Meyer C Schneider B Votava F Marschalek R Stary J Trka J Zuna J 2006Prenatal origin of childhood AML occurs less frequently than in childhood ALL. BMC Cancer. 21(6): 100
Jones L. K Neat M. J Van Delft F. W Mitchell M. P Adamaki M Stoneham S. J Patel N Saha V 2003Cryptic rearrangement involving MLL and AF10 occurring in utero.Leukemia. 17 8 1667 9
Cancer Epidemiol Biomarkers Prev. ( Spector L. G Davies S. M Robison L. L Hilden J. M Roesler M Ross J. A 2007 Birth characteristics, maternal reproductive history, and the risk of infant leukemia: a report from the Children’s Oncology Group. 16 1 128 34
Alcalay M Meani N Gelmetti V Fantozzi A Fagioli M Orleth A Riganelli D Sebastiani C Cappelli E Sciurpi Casciari C et al 2003Acute myeloid leukemia fusion proteins deregulate genes involved in stem cell maintenance and DNA repair. JCI. 112 1751 1761
Mikulasova Z Ilencikova D Slamka T Durovcikova D 2010Acute Myeloblastic Leukaemia with Alterations of MLL Proto-Oncogene Protein (11q23/MLL+AML). Klin Onkol. 23 6 401 407
Cox MCHPanetta P, Lo-Coco F, Del Poeta G, Venditti A, Maurillo L, Del Principe MI, Mauriello A, Anemona L, Bruno A, Mazzone C, Palombo P, Amadori S. ( 2004Chromosomal Aberration of the 11q23 Locus in Acute Leukemia and Frequency of MLL Gene Translocation. Am J Clin Pathol. 122 298 306
Ayton P. M Cleary M. L 2001 Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins. 20 5695 5707
Kawagoe H Humphries R. K Blair A and Sutherland H. J Hogge D. E 1999 Expression of HOX genes, HoX cofactors, and MLL in phenotypically and functionally defined subpopulations of leukemic and normal human hematopoietic cells.Leukemia. 13 687 698
Imamura T Morimoto A Takanashi M Hibi S Sugimoto T and Ishii E Imashuku S 2002 Frequent co-expression of HoXA9 and Meis1 genes in infant acute lymphoblastic leukaemia with MLL rearrangement 119 119 121
and Ayton P. M Cleary M. L 2003Transformation of myeloid progenitors by MLL oncoproteins is dependent on Hoxa7 and Hoxa9? Genes and Development. 17 2298 2307
Milne T. A Dou Y Martin M. E Brock H. W and Roeder R. G Hess J. L 2005 MLL associates specifically with a subset of transcriptionally active target genesProceedings of the National Academy of Science of the USA. 102 14765 14770
Caslini C El- Yang Z Osta M Milne T. A and Slany R. K Hess J. L 2007Interaction of Mll amino terminal sequences with menin is required information. Cancer Research. 67 7275 7283
and Yokoyama A Cleary M. L 2008 Menin critically links MLL proteins with LEDGF on cancer-associated target genes 14 36 46
Jin S Zhao H Yi Y Nakata Y and Kalota A Gewirtz A. M 2010c-Myb binds Mll through menin in human leukemia cells and is an important driver of MLL-asociated leukemogenesis. The Journal of Clinical Investigation. 120 593 606
Te Kronnie G and Marschalek R ( Trentin L Giordan M Dingermann T Basso G 2009Two independent gene signatures in pediatric t(4;11)-positive human leukemic cells. Blood. 106 1559 3566
Stam R. W Schneider P Hagelstein J. A Van Der Linden M. H Stumpel D. J De Menezes R. X De Lorenzo P and Valsecchi M. G Pieters R 2010Gene expression profiling-based dissection of MLL translocated and MLL germline acute lymphoblastic leukemia in infants. Blood. 115 2835 2844
Stumpel D. J Schneider P Van Roon E. H Boer J. M De Lorenzo P Valsecchi M. G De Menezes R. X and Pieters R Stam R. W 2009 Specific promoter methylation identifies different subgroups of MLL-rearranged infant acute lymphoblastic leukemia, influences clinical outcome, and provides therapeutic options 114 5490 5498
Garrido Castro P, Büchler L, Scholz A, Brümmendorf TH, Martinez Soria N, Vormoor J, Greil J and Heidenreich O ( Gessner A Thomas M 2010Leukemic fusion genes MLL/AF4 and AML1/MTG8 support leukemic self-renewal by controlling expression of the telomerase sbunit TERT. Leukemi. 24 1751 1759
van den Heuvel-Eibrink M, Zwaan CM, Kung AL and Armstrong SA ( Faber J Krivtsov A. V Stubbs M. C Wright R Davis T. N 2009HOXA9 is required for survival in human MLL-rearranged acute leukemias. Blood. 113 2375 2385
Haferlach T Schoch C Schnittger S Kern W Löffler H Hiddemann W 2002 Distinct genetic patterns can be identified in acute monoblastic and acute monocytic leukaemia (FAB AML M5a and M5b): a study of 124 patientsBr J Haematol. 118 426 431
Le Bris MJ, Herry A et al. ( Arnaud B Douet-guilbert N Morel F 2005Screening by fluorescent in situ hybridization for MLL status at diagnosis in 239 unselected patients with acute myeloblastic leukemia. Cancer Genet Cytogenet. 161 110 115
Raimondi S. C Chang M. N Ravindranath Y Behm F. G Gresik M. V Steuber C. P Weinstein H. J Carroll A. J 1999 Chromosomal abnormalities in 478 children with acute myeloid leukemia: clinical characteristics and treatment outcome in a cooperative pediatric oncology group study-POG 8821. 11 3707 16
Mayer C Burmeister T Strehl S Schneider B Hubert D Zach O et al 2007Spliced MLL fusions: a novel mechanism to generate functional chimeric MLL-MLLT1 transcripts in t(11;19)(q23; 13leukemia. Leukemia. 21:588-590.
Ben Abdelali R, Macintyre E, De Braekeleer E, De Braekeleer M, Delabesse E, et.al. ( Meyer C Kowarz E Hofmann J Renneville A Zuna J Trka J 2009New insights to the MLL recombinome of acute leukemias. Leukemia. 23 8 1490 1499
Whitman S. P Liu S Vukosavljevic T Rush L. J Yu L Liu C. H Klisovic M. I Maharry K Guimond M Strout M. P Becknell B Dorrance A Klisovic R. B Plass C. H Bloomfield C. D Marcucci G Caligiuri M. A 2005The MLL partial tandem duplication: evidence for recessive gain-of-function in acute myeloid leukemia identifies a novel patient subgroup for molecular-targeted therapy. Blood. 106 345 352
Libura M Asnafi V Tu A Delabesse E Tigaud I Cymbalista F Bennaceur-griscelli A Villarese P Solbu G Hagemeijer A Beldjord K Hermine O Macintyre E 2003FLT3 and MLL intragenic abnormalities in AMLreflect a common category of genotoxic stress. Blood. 102 2198 2204
Caligiuri M. A Strout M Lawrence D Arthur D. C Baer M. R Yu F Knuutila S Mrózek K Oberkircher A. R Marcucci G De La Chapelle A Elonen E Block A. W Rao P. N Herzig G. P Powell B. L Ruutu T Schiffer C. A Bloomfield C. D 1998Rearrangement of ALL1 (MLL) in acute myeloid leukemia with normal cytogenetics. Cancer Res. 58 55 59
Schnittger S Kinkelin U Schoch C Heinecke A Haase D Haferlach T Büchner T Wörmann B Hiddemann W Griesinger F 2000 Screening for MLL tandem duplication in 387 unselected patients with AML identify a prognostically unfavorable subset of AML 14 796 804
Wakui M Kuriyama K Miyazaki Y Hata T Taniwaki M Ohtake S Sakamaki H Miyawaki S Naoe T Ohno R Tomonaga M 2008 Diagnosis of acute myeloid leukemia according to the WHO classification in the Japan Adult Leukemia Study Group AML-97 protocolInt J Hematol. 87 144 151
T ( Andersson A Höglund M Johansson B Lassen C Billström R Garwicz S Nilsson P G Mitelman F Fioretos 2001 Paired multiplex reverse-transcriptase polymerase chain reaction (PMRT-PCR) analysis as a rapid and accurate diagnostic tool for the detection of MLL fusion genes in hematologic malignancies.Leukemia. 15 1293 1300
Mayer C Schneider B Reichel M Angermueller S Strehl S Schnittger S et al 2005Diagnostic tool for the identification of MLL rearrangements including unknown partner genes. Proc Natl Acad Sci USA, 102 449 454
Mann G Attarbaschi A Schrappe M De Lorenzo P Peters C Hann I De Rossi G Felice M Lausen B Leblanc T Szczepanski T Ferster A Janka-schaub G Rubnitz J Silverman L. B Stary J Campbell M Li C. K Suppiah R Biondi A Vora A Valsecchi M. G Pieters R 2010Interfant-99 Study Group. Blood. 116 15 2644 50
Chowdhury T Brady H. J 2008 Insights from clinical studies into the role of the MLL gene in infant and childhood leukemiaMol Dis. 40 2 192 9
Balgobind B. V Zwaan C. M Meyer C Marschalek R Pieters R Beverloo H. B et al 2009 NRIP3: a novel translocation partner of MLL detected in a pediatric acute myeloid leukemia with complex chromosome 11 rearrangementsHaematologica. 94(7):1033.
Coenen E. A Zwaan C. M Meyer C Marschalek R Pieters R Van Der Veken L. T et al 2011KIAA1524: A novel MLL translocation partner in acute myeloid leukemia. Leuk Res. 35 1 133 5
van den Heuvel-Eibrink MM. ( Coenen E. A Zwaan C. M Meyer C Marschalek R Creutzig U Pieters R Bradtke J 2012 Abl-interactor 2 (ABI2): A novel MLL translocation partner in acute myeloid leukemiaLeuk Res. 6 (5):e 113 5Epub 2012 Feb 1.
Balgobind B. V Raimondi S. C Harbott J Zimmermann M Alonzo T. A Auvrignon A Beverloo H. B Chang M Creutzig U Dworzak M. N et al 2009Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study. Blood. 114 12 2489 96
Blum W Mrózek K Ruppert A. S Carroll A. J Rao K. W Pettenati M. J Anastasi J Larson R. A Bloomfield C. D 2004Adult de novo acute myeloid leukemia with t(6;11)(q27;q23): results from Cancer and Leukemia Group B Study 8461 and review of the literature. Cancer. 101 6 1420 7
Gilliand D. G Griffin J. D 2002The roles of FLT3 in hematopoesis and leukemia. Blood. 100 1532 1542
Bloomfield CD European LeukemiaNet ( Döhner H Estey E. H Amadori S Appelbaum F. R Büchner T Burnett A. K Dombret H Fenaux P Grimwade D Larson R. A Lo-coco F Naoe T Niederwieser D Ossenkoppele G. J Sanz M. A Sierra J Tallman M. S Löwenberg B 2010Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 115 3 453 74
Sebolt-leopold J. S 2008Advances in the development of cancer therapeutics directed against the RAS-mitogen-activated protein kinase pathway Clin Cancer Res. 14 12 3651 6
Ayton P. M Chen E. H 2004Cleary MLBinding to nonmethylated CpG DNA is essential for target recognition, transactivation, and myeloid transformation by an MLL oncoprotein. Mol Cell Biol. 24 23 10470 8
Bernt K. M Armstrong S. A 2011 Targeting epigenetic programs in MLL-rearranged leukemias.Hematology Am Soc Hematol Educ Program. 2011 354 60