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Blood ; 18 : — At the time of preparation of the WHO classification, one argument for considering NPM1 -mutated AML as a provisional rather than a distinct entity was that it showed overlapping features with AML with myelodysplasia MD —related changes, whose significance was unclear. Only patients with NPM1 -mutated AML with information on cytomorphologic features, cytogenetics, and prognosis were included in this study.

The patients from the LAM99P and AML12 registration phase only protocols received the same therapy, that consisted in a 3-drug induction cycle with daunorubicin, etoposide, and arabinosylcytosine. After consolidation, younger patients with a sibling donor were assigned to undergo allogeneic stem cell transplantation. Those without donor as well as older patients received unpurged autologous stem cell transplantation.

Approval for the above studies was obtained from the institutional board of each participating center with consent obtained in accordance with the Declaration of Helsinki. The bone marrow biopsy is a well-accepted procedure for detecting dysmegakaryopoiesis because clusters and dysplastic changes of megakaryocytes, such as absence of lobulation or multinuclearity, are usually well appreciated in tissue sections.

Smears were analyzed in the MLL by K. Karyotypes were analyzed after G-banding and described according to the International System for Human Cytogenetic nomenclature. After quality control, raw data were normalized with the use of the robust multiarray average normalization algorithm as implemented in the R-package affy Version 1. To visualize the similarity of gene expression patterns, principal component analyses were applied.

Transformed gene expression data were analyzed with the use of Partek Genomics Suite Version 6. Microarray data can be downloaded at Gene Expression Omnibus, under accession no. Mean differences were analyzed with the t test, and the chi-square test was applied in case of contingency tables. For prognostic analysis, characteristics of patients were summarized by cross-tabulations categorical variables , quantiles median for ordinal factors or by standard positional and variation parameters mean and SD for continuous variables.

Survival was defined as the time from diagnosis to death or date of the last follow-up. Event-free survival EFS was defined as the time from diagnosis to date of failure no CR, relapse, death or date of the last follow-up.

Cox proportional hazard regression models were performed to examine and check for treatment results and the risk factors affecting time to event.

All tests were 2-sided, accepting P values less than or equal to. Dysplasia of 3 lineages was observed in 17 of cases. Bone marrow; Pappenheim staining. E-F Expression of CD34 by multiparameter flow cytometry. MLD was detected in smears from 20 of cases Correlation between these 2 parameters was poor.

In addition to smears, morphologic examination of bone marrow biopsy helped to identify dysplastic megakaryocytes Figure 2 , which is in keeping with the data from the literature. Top left Infiltration by myeloid blasts double arrows admixed with dysplastic, monolobated megakaryocytes single arrows; paraffin sections; hematoxylin-eosin. Bottom left Myeloid blasts double arrows and a dysplastic monolobated megakaryocyte single arrow show aberrant cytoplasmic expression of NPM.

As given in the principal component analysis, the top genes were not able to separate the corresponding groups Figure 3 A , but different expression patterns were mainly caused by the respective known FLT3 -ITD status of these cases Figure 3 B.

In contrast, when the respective cases were analyzed according to their NPM1 mutation status, 40 cases were NPM1 mutated, 8 cases were NPM1 wild-type, respectively; the resulting signature of the top differentially expressed probe sets clearly separated these 2 AML subgroups Figure 3 C , indicating they are biologically distinct. Principal component analysis. Ellipsoids are drawn with 2-fold standard deviations.

B The same signature is now annotated according to known FLT3 mutation status of the cases. Detailed information on the probe sets is available online. Thus, a strong underlying gene expression pattern separating biologic subgroups was observable according to mutation status of NPM1 , but not according to MLD. The corresponding gene lists are provided in the supplemental Table 1 available on the Blood Web site; see the Supplemental Materials link at the top of the online article.

Males were 41 of 74 The median WBC count was Negativity for CD34 was found in 42 of 55 CD34 expression in representative cases is shown at flow cytometry Figure 1 and in bone marrow tissue sections Figure 2.

Cytogenetics was available in all cases. Abnormal karyotype was present in 43 of cases The same was true when this analysis was restricted to cases with normal karyotype Figure 6 C-D. MLD was identified in 20 of 55 Neither OS median not reached vs This study provides evidence that NPM1 -mutated AML with and without MLD changes have an overlapping gene expression profile and show similar immunophenotypic and prognostic features.

Thus, for classification purposes, the detection of an NPM1 mutation should take diagnostic precedence over the presence of MD-related changes, as is now accepted for cytogenetic alterations listed in the group of AML with recurrent genetic abnormalities.

In particular, they provide evidence that MLD has less effect than the genetic lesion NPM1 mutation in defining the leukemia entity. Indeed, there are several clinical and immunophenotypic differences that call for a separation of the 2 entities. On the basis of our results, the term AML with MD-related changes should be restricted to cases with MD-related changes without accompanying recurrent genetic abnormalities, including NPM1 mutation.

The publication costs of this article were defrayed in part by page charge payment. The authors from the Munich Leukemia Laboratory MLL thank all physicians and especially participants of the AMLCG group for sending bone marrow or blood samples to our laboratory for reference diagnosis and for submitting clinical data. Staib, F. Gropp ; Katholisches Krankenhaus, Hagen H. Lindemann ; Evangelisches Krankenhaus, Hamm L. Wahnschaffe ; Helios Klinikum, Berlin W.

Weh ; Knappschaftskrankenhaus, Bottrop G. Eissele ; Klinikum Krefeld Th. Wolf ; Bundeswehrzentralkrankenhaus, Koblenz G. Herzog ; Klinikum Landshut B. Schwonzen ; Klinikum Passau Th. The centers and investigators are listed in order of the number of cases provided: Istituto di Ematologia, Universita La Sapienza, Roma G.

Meloni ; Divisione di Ematologia, Ospedale V. Cervello, Palermo F. Sborgia ; Cattedra di Ematologia, Bari, V. Liso ; Az. Moscati, Avellino N. Nobile ; Ospedale Ferrarotto-S. Bambino, Catania F. Tabilio ; Cattedra di Ematologia, Ospedale S. Chiara, Pisa M. Rotoli ; Divisione di Ematologia, Ospedale S. Carlo, Potenza F. Giovanni Rotondo L.

Melillo ; Istituto di Ematologia, Ospedale A. Businco, Cagliari E. Angelucci ; Divisione di Ematologia, Ospedale S. Giovanni Bosco, Napoli E. Raffaele del Monte Tabor, Milano L. Moranti ; Divisione di Ematologia, Ospedale S. Eugenio, Roma A. Nalli ; Divisione di Ematologia, Ospedale S. Francesco, Nuoro A. Antonio e Biagio, Alessandria A. Levis ; Azienda Ospedaliera A. Di Summa, Brindisi G. Quarta ; Divisione di Ematologia, Ospedale S.

Croce, Cuneo A. Contribution: B. Conflict-of-interest disclosure: B. The remaining authors declare no competing financial interests. Sign In or Create an Account. Sign In. Content Menu. Close Abstract. Article Navigation. This Site. Google Scholar. Katja Macijewski , Katja Macijewski.

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