Bas Wouters

Keeshan

Ruud Delwel

Wouters

Wouters, B.J. (Bas)

Delwel, H.R. (Ruud)

Erasmus University Digital Repository

in T acute lymphoblastic leukemias improves understanding of early human Tlymphoid lineage commitment. Blood. 2003;101:2693-2703.10. Roumier C, Eclache V, Imbert M, et al. M0 AML, clinical and biologic features ofthe disease, including AML1 genemutations: a report of 59 cases by theGroupe Francais d’Hematologie Cellulaire (GFHC) and the Groupe Francaisde Cytogenetique Hematologique (GFCH). Blood. 2003;101:1277-1283.ResponseCEBPA promoter hypermethylation in a subset of myeloid/T-lymphoid leukemias with adistinct gene expression profileWith great interest we have read the letter by Terriou andcoworkers, who have performed an extensive survey of CEBPACpG promoter hypermethylation in T-ALL as well as in a selectionof immature acute myeloid leukemia (AML) cases. This studyrelates to our previous work in which we identified hypermethyl-ation of the proximal CEBPA promoter in a small subset of AMLswith low CEBPA mRNA.1 It should be noted that the patient groupwe described was not primarily defined by CEBPA promoterhypermethylation. Instead, those cases were studied because theyexhibited a unique gene expression profile. In addition to this mostdiscriminating feature, the leukemic blasts coexpressed CD34 andT-cell antigens with myeloid markers, frequently carried NOTCH1mutations, and expressed the transforming gene TRIB2.1,2 Using apredictive gene expression signature in an independent cohort ofAML, we identified genetically and immunophenotypically similarcases with silenced CEBPA.In the present study, Terriou et al found CEBPA promoterhypermethylation in 4/54 AML cases. These 4 cases all revealedone or more T-cell characteristics (cCD3, CD7, and/or TCRGrearrangement) and may therefore resemble the leukemias wedescribed. In T-ALL, the investigators found CEBPA promoterhypermethylation more frequently, in 37/99 cases. Importantly,however, only a minority of those T-ALLs with methylated CEBPAcoexpressed myeloid surface markers (CD13 and/or CD33) andCD34. The findings of Terriou et al therefore indicate that CEBPAproximal promoter hypermethylation in combination with animmature myeloid/T-lymphoid immunophenotype is generally rarein acute leukemia, and can be found in a small percentage of AMLas well as in a small fraction of T-ALL. It will be important to applygene expression profiling to these cases to fully assess theirrelationship with the leukemias that we described previously.Together, these observations highlight the challenges in classify-ing particular acute leukemias as AML, ALL, or a unique entity. Webelieve that studies as the one performed by Terriou et al will beinstrumental in obtaining a better understanding of this topic. Geneexpression profiling applied to these AML and T-ALL cohorts willclearly be of added value. Combining data from multiple researchgroups will be a requirement to address important questionsregarding prognosis, and should help to evaluate according towhich protocols these relatively small patient groups are besttreated.Bas Wouters and Ruud DelwelConflict-of-interest disclosure: The authors declare no competing financialinterests.Correspondence: Bas Wouters or Ruud Delwel, Department of Hematology,Erasmus University Medical Center, PO Box 2040, 3000CA, Rotterdam, TheNetherlands; e-mail: b.wouters@erasmusmc.nl or h.delwel@erasmusmc.nl.References1. Wouters BJ, Jorda MA, Keeshan K, et al. Distinct gene expression profiles ofacute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations inNOTCH1. Blood. 2007;110:3706-3714.2. Keeshan K, He Y, Wouters BJ, et al. Tribbles homolog 2 inactivates C/EBPal-pha and causes acute myelogenous leukemia. Cancer Cell. 2006;10:401-411.To the editor:JAK2-V617F–triggered preemptive and salvage adoptive immunotherapy withdonor-lymphocyte infusion in patients with myelofibrosis after allogeneic stem celltransplantationPrimary myelofibrosis is a myeloproliferative disease, and resultsof conventional treatment remain unsatisfactory.1,2 Allogeneic stemcell transplantation after dose-reduced conditioning has become areasonable, curative treatment option.3,4 Single case reports aboutsuccessful donor lymphocyte infusion (DLI) for relapsed patientsprovided evidence of a graft-versus-myelofibrosis effect.5-7 Here,we report on 17 patients with either myelofibrosis (n  16) orsecondary AML post myelofibrosis (n  1) and a median age of52 years (range, 32-63 years) who received DLI from related(n  5) or unrelated (n  12) donor, either for clinical relapse(salvage DLI; n  9) or residual disease monitored by JAK2mutation level in peripheral blood (preemptive DLI; n  8).Details are summarized in Table 1. One patient (no. 9) receivedDLI twice: once for molecular residual disease and once forreappearance of molecular disease. Sixteen patients were JAK2-V617F–positive. The median time from transplantation to first DLIwas 269 days (range, 127-1570 days). The median percentage ofJAK2V617 mutation level in peripheral blood before first DLI was6.2% (range, 0.2%-72.8%) and significantly higher in patients withclinical relapse than with molecular relapse (24.7% vs 0.37%;P  .03). The median cell dose of the first DLI was 106 CD3 cellsper kilogram of body weight (BW; range, 0.5-9  106 cells/kg BW). Two patients received as first DLI CD4-selected T cells(5  106 CD4 cells/kg BW). Second and subsequent half-log–increased DLI were given if no graft-versus-host disease (GVHD)and no significant response were observed. The median intervalbetween the first and the second DLI was 103 days (range,43-661 days). The response to DLI for relapsed patients wasdetermined by the response criteria of the International WorkingGroup,8 and for residual disease by quantitative real time JAK2-V617F polymerase chain reaction (PCR) performed from genomicDNA from peripheral blood as recently described.9 The sensitivity1866 CORRESPONDENCE BLOOD, 19 FEBRUARY 2009  VOLUME 113, NUMBER 8

Response: CEBPA promoter hypermethylation in a subset of myeloid/T-lymphoid leukemias with a distinct gene expression profile

Crossref

Wouters, Bas

Delwel, Ruud

EUR Research Repository

Undetermined

CEBPA promoter hypermethylation in a subset of myeloid/T-lymphoid leukemias with a distinct gene expression profile Response

EUR Research Information PortalCEBPA promoter hypermethylation in a subset of myeloid/T-lymphoid leukemias with adistinct gene expression profile ResponsePublished in:BloodPublication status and date:Published: 01/01/2009DOI (link to publisher):10.1182/blood-2008-12-189191Document VersionPublisher's PDF, also known as Version of recordCitation for the published version (APA):Wouters, B., & Delwel, R. (2009). CEBPA promoter hypermethylation in a subset of myeloid/T-lymphoid leukemias with adistinct gene expression profile Response. Blood, 113(8), 1866-1866. https://doi.org/10.1182/blood-2008-12-189191Link to publication on the EUR Research Information PortalTerms and Conditions of UseExcept as permitted by the applicable copyright law, you may not reproduce or make this material available to any third partywithout the prior written permission from the copyright holder(s). Copyright law allows the following uses of this materialwithout prior permission:            • you may download, save and print a copy of this material for your personal use only;            • you may share the EUR portal link to this material.In case the material is published with an open access license (e.g. a Creative Commons (CC) license), other uses may beallowed. Please check the terms and conditions of the specific license.Take-down policyIf you believe that this material infringes your copyright and/or any other intellectual property rights, you may request itsremoval by contacting us at the following email address: openaccess.library@eur.nl. Please provide us with all the relevantinformation, including the reasons why you believe any of your rights have been infringed. In case of a legitimate complaint,we will make the material inaccessible and/or remove it from the website.in T acute lymphoblastic leukemias improves understanding of early human Tlymphoid lineage commitment. Blood. 2003;101:2693-2703.10. Roumier C, Eclache V, Imbert M, et al. M0 AML, clinical and biologic features ofthe disease, including AML1 genemutations: a report of 59 cases by theGroupe Francais d’Hematologie Cellulaire (GFHC) and the Groupe Francaisde Cytogenetique Hematologique (GFCH). Blood. 2003;101:1277-1283.ResponseCEBPA promoter hypermethylation in a subset of myeloid/T-lymphoid leukemias with adistinct gene expression profileWith great interest we have read the letter by Terriou andcoworkers, who have performed an extensive survey of CEBPACpG promoter hypermethylation in T-ALL as well as in a selectionof immature acute myeloid leukemia (AML) cases. This studyrelates to our previous work in which we identified hypermethyl-ation of the proximal CEBPA promoter in a small subset of AMLswith low CEBPA mRNA.1 It should be noted that the patient groupwe described was not primarily defined by CEBPA promoterhypermethylation. Instead, those cases were studied because theyexhibited a unique gene expression profile. In addition to this mostdiscriminating feature, the leukemic blasts coexpressed CD34 andT-cell antigens with myeloid markers, frequently carried NOTCH1mutations, and expressed the transforming gene TRIB2.1,2 Using apredictive gene expression signature in an independent cohort ofAML, we identified genetically and immunophenotypically similarcases with silenced CEBPA.In the present study, Terriou et al found CEBPA promoterhypermethylation in 4/54 AML cases. These 4 cases all revealedone or more T-cell characteristics (cCD3, CD7, and/or TCRGrearrangement) and may therefore resemble the leukemias wedescribed. In T-ALL, the investigators found CEBPA promoterhypermethylation more frequently, in 37/99 cases. Importantly,however, only a minority of those T-ALLs with methylated CEBPAcoexpressed myeloid surface markers (CD13 and/or CD33) andCD34. The findings of Terriou et al therefore indicate that CEBPAproximal promoter hypermethylation in combination with animmature myeloid/T-lymphoid immunophenotype is generally rarein acute leukemia, and can be found in a small percentage of AMLas well as in a small fraction of T-ALL. It will be important to applygene expression profiling to these cases to fully assess theirrelationship with the leukemias that we described previously.Together, these observations highlight the challenges in classify-ing particular acute leukemias as AML, ALL, or a unique entity. Webelieve that studies as the one performed by Terriou et al will beinstrumental in obtaining a better understanding of this topic. Geneexpression profiling applied to these AML and T-ALL cohorts willclearly be of added value. Combining data from multiple researchgroups will be a requirement to address important questionsregarding prognosis, and should help to evaluate according towhich protocols these relatively small patient groups are besttreated.Bas Wouters and Ruud DelwelConflict-of-interest disclosure: The authors declare no competing financialinterests.Correspondence: Bas Wouters or Ruud Delwel, Department of Hematology,Erasmus University Medical Center, PO Box 2040, 3000CA, Rotterdam, TheNetherlands; e-mail: b.wouters@erasmusmc.nl or h.delwel@erasmusmc.nl.References1. Wouters BJ, Jorda MA, Keeshan K, et al. Distinct gene expression profiles ofacute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations inNOTCH1. Blood. 2007;110:3706-3714.2. Keeshan K, He Y, Wouters BJ, et al. Tribbles homolog 2 inactivates C/EBPal-pha and causes acute myelogenous leukemia. Cancer Cell. 2006;10:401-411.To the editor:JAK2-V617F–triggered preemptive and salvage adoptive immunotherapy withdonor-lymphocyte infusion in patients with myelofibrosis after allogeneic stem celltransplantationPrimary myelofibrosis is a myeloproliferative disease, and resultsof conventional treatment remain unsatisfactory.1,2 Allogeneic stemcell transplantation after dose-reduced conditioning has become areasonable, curative treatment option.3,4 Single case reports aboutsuccessful donor lymphocyte infusion (DLI) for relapsed patientsprovided evidence of a graft-versus-myelofibrosis effect.5-7 Here,we report on 17 patients with either myelofibrosis (n  16) orsecondary AML post myelofibrosis (n  1) and a median age of52 years (range, 32-63 years) who received DLI from related(n  5) or unrelated (n  12) donor, either for clinical relapse(salvage DLI; n  9) or residual disease monitored by JAK2mutation level in peripheral blood (preemptive DLI; n  8).Details are summarized in Table 1. One patient (no. 9) receivedDLI twice: once for molecular residual disease and once forreappearance of molecular disease. Sixteen patients were JAK2-V617F–positive. The median time from transplantation to first DLIwas 269 days (range, 127-1570 days). The median percentage ofJAK2V617 mutation level in peripheral blood before first DLI was6.2% (range, 0.2%-72.8%) and significantly higher in patients withclinical relapse than with molecular relapse (24.7% vs 0.37%;P  .03). The median cell dose of the first DLI was 106 CD3 cellsper kilogram of body weight (BW; range, 0.5-9  106 cells/kg BW). Two patients received as first DLI CD4-selected T cells(5  106 CD4 cells/kg BW). Second and subsequent half-log–increased DLI were given if no graft-versus-host disease (GVHD)and no significant response were observed. The median intervalbetween the first and the second DLI was 103 days (range,43-661 days). The response to DLI for relapsed patients wasdetermined by the response criteria of the International WorkingGroup,8 and for residual disease by quantitative real time JAK2-V617F polymerase chain reaction (PCR) performed from genomicDNA from peripheral blood as recently described.9 The sensitivity1866 CORRESPONDENCE BLOOD, 19 FEBRUARY 2009  VOLUME 113, NUMBER 8

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Response: CEBPA promoter hypermethylation in a subset of myeloid/T-lymphoid leukemias with a distinct gene expression profile

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