Recently, it was shown that t(10;16)(q22;p13) fuses the MORF and CREBBP genes in a case of childhood acute myeloid leukemia (AML) M5a, with a complex karyotype containing other rearrangements. Here, we report a new case with the MORF-CREBBP fusion in an 84-year-old patient diagnosed with AML M5b, in which the t(10;16)(q22;p13) was the only cytogenetic aberration. This supports that this is a recurrent pathogenic translocation in AML

Alvarez, C. (Carmen)

Calasanz-Abinzano, M.J. (Maria Jose)

Floristan, F. (Filomena)

Lahortiga, I. (Idoya)

Larrayoz, M.J. (María J.)

Novo-Villaverde, F. J. (Francisco Javier)

Odero, M.D. (Maria Dolores)

Vizmanos-Pérez, J.L. (José Luis)

Dadun, University of Navarra

t(10;16)(q22;p13) and MORF-CREBBP Fusion Is aRecurrent Event in Acute Myeloid LeukemiaJose´ L. Vizmanos,1* Marı´a J. Larra´yoz, 1 Idoya Lahortiga, 1 Filomena Florista´n, 2 Carmen A´lvarez, 2Marı´a D. Odero, 1 Francisco J. Novo, 1 and Marı´a J. Calasanz11Department of Genetics, School of Science, University of Navarra, Pamplona, Spain2Hematology Service, Hospital de Cruces, Servicio Vasco de Salud-Osakidetza, Baracaldo, SpainRecently, it was shown that t(10;16)(q22;p13) fuses the MORF and CREBBP genes in a case of childhood acute myeloid leukemia(AML) M5a, with a complex karyotype containing other rearrangements. Here, we report a new case with the MORF-CREBBPfusion in an 84-year-old patient diagnosed with AML M5b, in which the t(10;16)(q22;p13) was the only cytogenetic aberration.This supports that this is a recurrent pathogenic translocation in AML. © 2003 Wiley-Liss, Inc.Some acquired chromosomal abnormalities re-sulting in fusion genes characterize acute myeloidleukemias (AMLs) and their detection is importantfor the clinical management and to uncover themolecular basis of the disease. Recently, it wasshown that the t(10;16)(q22;p13) fuses MORF andCREBBP genes in a case of childhood AML M5a(Panagopoulos et al., 2001). CREBBP is a largenuclear protein and a transcriptional coactivator,implicated in hematopoiesis, which physically in-teracts with various sequence-speciﬁc DNA-bind-ing factors through conserved domains (McManusand Hendzel, 2001; Blobel, 2002; Cantor and Or-kin, 2002). Mutations and constitutional transloca-tions affecting the CREBBP gene, located at 16p13,are responsible for RubinsteinTaybi syndrome(RTS), a complex developmental disorder thatleads to an increased incidence of neoplasia (Petrijet al., 1995, 2000). CREBBP is also rearranged withMOZ in leukemias with the t(8;16)(p11;p13) (Bor-row et al., 1996; Chaffanet et al., 1999; Panagopou-los et al., 2000a) and with MLL in hematologicmalignancies with t(11;16)(q23;p13) (Rowley et al.,1997; Satake et al., 1997; Sobulo et al., 1997; Takiet al., 1997; Sugita et al., 2000). MORF (monocyticleukemia zinc ﬁnger protein-related factor) is aubiquitously expressed gene, located at 10q22,which displays a high degree of similarity withMOZ and which also contains zinc ﬁngers, a histoneacetyltransferase (HAT) domain, an acidic region,and a COOH-terminal Ser/Met-rich domain(Champagne et al., 1999).We report here a t(10;16)(q22;p13), with aMORF-CREBBP fusion, as the only cytogeneticabnormality in an AML M5b. This is the secondcase of such a translocation reported in the litera-ture, suggesting that this translocation is a recur-rent event in AML.An 84-year-old patient was admitted to the hos-pital because of pain in the left upper limb irradi-ating to the ﬂank and a ﬂulike syndrome. Theperipheral blood values were hemoglobin 13.6g/100 ml, platelets 10.9  109/L, and WBC count24.5  109/L with 33% blasts. The bone marrowaspirate was almost completely inﬁltrated withatypical cells (89% monocytes). Bone marrow cyto-genetics showed a t(10;16)(q22;p13) in 100% of themetaphases (38/38) as the only aberration (Fig. 1A).A diagnosis of AML M5b was made. The patientreceived no curative intended treatment, and diedone month later.One patient with AML (M4) with a similar trans-location t(10;16)(q21;p13), showing also an 11q23rearrangement, was previously reported (Pebusqueet al., 1988), although molecular studies were notperformed. Recently, a 4-year-old girl with AMLM5a was reported (Panagopoulos et al., 2001) witha complex karyotype including a t(10;16)(q22;p13).Fluorescence in situ hybridization (FISH) and mo-lecular analyses showed that the t(10;16)(q22;p13)resulted in a fusion between MORF and CREBBP.This ﬁnding prompted us to investigate whetherthe same fusion gene could be present also in ourpatient.*Correspondence to: Dr. Jose´ L. Vizmanos, Department of Ge-netics, University of Navarra, C/Irunlarrea s/n, 31080 Pamplona,Spain. E-mail: jlvizmanos@unav.esReceived 18 September 2002; Accepted 29 October 2002DOI 10.1002/gcc.10174GENES, CHROMOSOMES & CANCER 36:402–405 (2003)BRIEF COMMUNICATION© 2003 Wiley-Liss, Inc.Reverse transcriptase–polymerase chain reaction(RT-PCR) analysis was performed as reported byPanagopoulos et al. (2001). One-step RT-PCR withprimers MORF2843F and CBP425R was done asdescribed and yielded the expected 0.4-kb frag-ment, showing the presence of the MORF-CREBBP fusion gene (Fig. 2A). Nested RT-PCRwith primers CBP96F/MORF3383R and CBP174F/MORF3277R was necessary (Panagopoulos et al.,2001) to amplify the expected 0.3-kb fragment cor-responding to the reciprocal CREBBP-MORF tran-script (Fig. 2A). Sequence analysis of the MORF-CREBBP ampliﬁcation product showed that thetranslocation fused MORF exon 15 with CREBBPexon 3 (Fig. 2B). Thus, the breakpoints in our caseled to the fusion of the same exons as described inthe previously reported patient. FISH analysis ofbone marrow cells with bacterial artiﬁcial chromo-somes (BACs) RPCI-11 461A8 and RPCI-11 95J11(Fig. 1B) was consistent with the disruption of theCREBBP gene in this region because the splitaffected 95J11, which covers the initial part of thegene.The present case displays some features in com-mon with the one published by Panagopoulos et al.(2001). Both were diagnosed as AML M5 and thebreakpoints led to fusion of the same exons ofMORF and CREBBP. However, the case publishedpreviously was a 4-year-old girl who was alive at thetime of publication. We report an 84-year-old malewho died one month later. Furthermore, the t(10;16)(q22;p13) was not the only cytogenetic aberra-tion in the previous case. Hence, it was unclearwhether the MORF-CREBBP fusion was responsi-ble for the development of leukemia. In our pa-tient, the t(10;16) was the sole cytogenetic event inleukemic cells, suggesting that the fusion genecould contribute directly to the development of theAML.MORF is very similar to MOZ, a gene fused toCREBBP in t(8;16)(p11;p13) (Borrow et al., 1996;Chaffanet et al., 1999; Panagopoulos et al., 2000a),TIF2 in inv(8)(p11q13) (Carapeti et al., 1998, 1999;Liang et al., 1998; Panagopoulos et al., 2000b; Billioet al., 2002), and to EP300 in t(8;22)(p11;q13)(Chaffanet et al., 2000; Kitabayashi et al., 2001).Fusion genes involving MOZ are mainly seen inyoung patients with AML M4/M5, in which theleukemic blasts frequently display erythrophagocy-tosis. Thus, it is frequently associated with certainmorphological and clinical features irrespective ofthe partner gene. However, despite the similaritiesbetween MOZ and MORF, the morphological anal-ysis of bone marrow aspirate from our patient didnot reveal any signs of erythrophagocytosis. Unlikethe case with inv(8)(p11q13) and MOZ-TIF2 fusionrecently published (Billio et al., 2002), the casereported here was negative for the FLT3-ITD (Na-kao et al., 1996) and D835 mutation (Yamamoto etal., 2001) (data not shown).Figure 1. G-Band and FISH analyses. A: Partial karyotype showing the t(10;16)(q22;p13). Arrowsindicate breakpoints. B: FISH analysis by use of BACs RPCI-11 461A8 (green) and RPCI-11 95J11 (red)showing that the signal of 95J11, which covers the initial part of the CREBBP gene, is split between der(10)and der(16). [Color ﬁgure can be viewed in the online issue, which is available at www.interscience.wiley.com.]403A NEW CASE OF t(10;16)(q22;p13) IN AMLIn both patients with the t(10;16)(q22;p13) de-scribed to date, both MORF-CREBBP andCREBBP-MORF transcripts were detected. It isnot yet clear which of them is mainly responsiblefor the leukemogenic effect, but it has been sug-gested that this results from the substitution of theCOOH-terminal part of MORF or MOZ by theCOOH-terminal part of CREBBP, P300 or TIF2.As in the previously reported patient, a one-stepRT-PCR was sufﬁcient to detect the MORF-CREBBP transcript, whereas a nested RT-PCRwas necessary to detect CREBBP-MORF. Thiscould indicate that the transcription level of theformer transcript is higher.In summary, we report an 84-year-old patientwith AML M5b showing a t(10;16)(q22;p13) as thesole cytogenetic aberration, with the presence ofMORF-CREBBP and CREBBP-MORF fusion tran-scripts. This case, the second one reported thus far,proves that this is a recurrent pathogenic event inAML.ACKNOWLEDGMENTSWe thank Nekane Sanjose´ and Carmen Ferreirafor technical assistance.REFERENCESBillio A, Steer EJ, Pianezze G, Svaldi M, Casin M, Amato B, CoserP, Cross NCP. 2002. 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t(10;16)(q22;p13) and MORF-CREBBP fusion is a recurrent event in acute myeloid leukemia

Universidad de Navarra

t(10;16)(q22;p13) and MORF-CREBBP fusion is a recurrent event in acute myeloid leukemia

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Dadun, University of Navarra

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