Published online 11 February 2008
Haematologica, Vol 93, Issue 3, 439-442 doi:10.3324/haematol.12153
Copyright © 2008 by Ferrata Storti Foundation
Brunangelo Falini1, ,
Cristina Mecucci1 ,
Giuseppe Saglio2 ,
Francesco Lo Coco3 ,
Daniela Diverio4 ,
Patrick Brown5 ,
Fabrizio Pane6 ,
Marco Mancini4 ,
Maria Paola Martelli1 ,
Stefano Pileri7 ,
Torsten Haferlach8 ,
Claudia Haferlach8 ,
Susanne Schnittger8
Acute myeloid leukemia carrying NPM1 mutations and cytoplasmic nucleophosmin (NPMc+ acute myeloid leukemia) represents one-third of adult AML (50–60% of all acute myeloid leukemia with normal karyotype) and shows distinct biological, pathological and clinical features. We confirm in 2562 patients with acute myeloid leukemia our previous observation that NPM1 mutations and cytoplasmic nucleophosmin are mutually exclusive of recurrent genetic abnormalities. Taken together, these findings make NPMc+ acute myeloid leukemia a good candidate for inclusion in the upcoming World Health Organization classification.
One of the most controversial issues in the WHO classification of myeloid malignancies is acute myeloid leukemias not otherwise characterized.1 This category accounts for 60–70% of AML, including cases with normal cytogenetics (AML-NC) which are characterized by a great molecular, pathological and clinical heterogeneity. AML not otherwise characterized is currently defined according to FAB criteria which are, however, insufficient to characterize AML-NC, since they do not identify distinct disease entities within this heterogeneous group. Recognition of underlying molecular alterations is crucial for the improvement of AML-NC classification.
Leukemic samples
The aim of the study for AML patients enrolled in the GIMEMA LAM99P and the GIMEMA/EORTC AML12 trials was to compare the subcellular expression of NPM with the results of molecular studies for recurrent genetic alterations. The rationale for this approach derives from our previous observations that immunohistochemistry is fully predictive of NPM1 mutation status.12 Bone marrow biopsies for immunohistochemical studies were available from 1073 unselected, consecutively observed AML cases, 591 of whom had been previously reported.2 Ninety-six acute promyelocytic leukemia cases (not included in the GIMEMA LAM 99P and GIMEMA/EORCT-AML12) were also available for comparative immunohistochemical and molecular analysis. In addition, 1403 unselected AML cases were investigated at the Munich Leukemia Laboratory (MLL). Cytogenetics failed in 10 cases and these were excluded from the present study. Therefore, the Munich cohort consisted of 1393 consecutively observed, unselected newly diagnosed AML for which complete cytogenetic/molecular studies were available. In these cases, we compared the results of NPM1 mutational analysis13 and cytogenetic/molecular studies. Written informed consents for the study was obtained from each participating center.
Of the 1073 bone marrow biopsies from patients of the GIMEMA LAM99P and GIMEMA/EORTC AML12 trials, 368 (34.2%) were characterized by aberrant cytoplasmic expression of nucleophosmin (NPMc+) associated with nucleus-restricted positivity for nucleolin (C23) (Figure 1). As previously reported,12 this staining pattern is fully predictive of a mutated NPM1 gene. All other biopsies showed a nucleus-restricted positivity for nucleophosmin (NPMc-) which is fully predictive of NPM1 gene in a germline configuration.12 Comparison of immunohistochemistry with the results of molecular studies for the recurrent genetic abnormalities is shown in Table 1. Remarkably, all 300 AMLs carrying various types of recurrent genetic abnormalities showed a nucleus-restricted expression of NPM. Representative examples of these staining patterns in AML carrying the most frequent recurrent genetic abnormalities, i.e. t(15;17), inv(16) and t(8;21), are shown in Figure 2. Completely overlapping results were obtained in cases from the Munich Leukemia Laboratory, by comparing the mutation status of the NPM1 gene with the results on cytogenetic/molecular studies for recurrent genetic abnormalities. In total, we investigated 1393 AML cases, 835 of which had a normal and 558 an abnormal karyotype. NPM1 mutations were detected in 420 out of 1393 patients (30.1%) while the other cases harboured a NPM1 gene in a germline configuration. In 246 of 1393 patients, reciprocal translocations and the respective fusion genes were detected; RT-PCR and/or FISH were performed for all respective fusion genes. The results are shown in Table 2. Notably, none of the 246 AMLs carrying different types of genetic abnormalities harbored NPM1 mutations. These results were obtained independently from a total of 2562 AMLs from two large series using different approaches, support our original finding that, cytoplasmic mutated NPM is mutually exclusive of recurrent genetic abnormalities.2 Our findings raise several issues surrounding the significance of the sporadic cases of NPM1 mutations coinciding with recurrent genetic abnormalities, as reported in some studies.8–10 First, none of these studies documented whether NPM1 mutations and concurrent genetic abnormalities occur in the same or different leukemic cell populations. Another major concern is specificity control in large multi-center trials. This is addressed in Falini B. et al.2 (Supplementary Materials). In particular, 4 patients in the GIMEMA EORTC AML12 trial were diagnosed as having cytoplasmic mutated NPM together with inv(16), t(8;21) or MLL rearrangement. In-depth re-investigation of these cases revealed errors in sample registration or PCR contamination. Because of the presence of NPM1 mutation in association with a t(16;16)/MYH11-CBFB transcript, 1 patient from the CCG-2961 AML pediatric trial was also re-investigated and found not to have a NPM1 mutation (Patrick Brown, unpublished results). Therefore, in our experience, re-analysis according to strict criteria showed that NPM1 mutations are mutually exclusive of recurrent genetic abnormalities. Whether the occurrence of two or more specific genetic markers in exceptional cases is just coincidental or represents a true association is still not understood. Rare examples include t(15;17) plus t(8;21),15 t(15;17) plus t(9;22),16 and t(9;22) or BCR-ABL plus inv(16).17,18 Interestingly, 1 case reported by Thiede et al.9 carried both a t(8;21) and an inv(16) in addition to NPM1 mutations with a NPM1 mut/wt ratio of only 0.37 (Christian Thiede, personal communication on February 6, 2006). More recently, coexistence of JAK2V617F and BCR-ABL has also been reported in chronic myeloproliferative disorders19,20 and association of JAK2V617F with t(8;21) in AML therapy-related21 or secondary to a myeloproliferative syndrome.22 In conclusion, our data unequivocally confirm in a large series of patients with acute myeloid leukemia that NPM1 mutations are mutually exclusive of other recurrent genetic abnormalities and that NPM1 mutations identify a distinct acute myeloid leukemia genetic entity which should be considered for inclusion in the upcoming WHO Classification.
we would like to thank Roberta Pacini and Manola Carini for performing the immunohistochemical stainings and Mrs. Claudia Tibidò for her secretarial assistance
Authorship and Disclosures
Haematologica, Vol 93, Issue 3, 439-442 doi:10.3324/haematol.12153
Copyright © 2008 by Ferrata Storti Foundation
Acute Myeloid Leukemia |
NPM1 mutations and cytoplasmic nucleophosmin are mutually exclusive of recurrent genetic abnormalities: a comparative analysis of 2562 patients with acute myeloid leukemia
1 Institute of Hematology, University of Perugia, Perugia, Italy
2 Department of Clinical and Biological Sciences, University of Turin, San Luigi Hospital, Orbassano, Turin, Italy
3 Department of Biopathology and Diagnostic Imaging, Policlinico Tor Vergata, Rome, Italy
4 Department of Cellular Biotechnologies and Hematology, Policlinico "La Sapienza", Rome, Italy
5 Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, USA
6 Department of Biochemistry and Medical Biotechnologies, University "Federico II", Neples, Italy
7 Laboratory of Hematopathology, University of Bologna, Policlinico S. Orsola, Bologna, Italy and
8 Munich Leukemia Laboratory GmbH, Munich, Germany
Correspondence: Brunangelo Falini, MD, Institute of Hematology, University of Perugia, Perugia, Italy. E-mail: faliniem{at}unipg.it
ABSTRACT
 TOP ABSTRACT IntroductionDesign and MethodsResults and DiscussionReferences |
|---|
Acute myeloid leukemia carrying NPM1 mutations and cytoplasmic nucleophosmin (NPMc+ acute myeloid leukemia) represents one-third of adult AML (50–60% of all acute myeloid leukemia with normal karyotype) and shows distinct biological, pathological and clinical features. We confirm in 2562 patients with acute myeloid leukemia our previous observation that NPM1 mutations and cytoplasmic nucleophosmin are mutually exclusive of recurrent genetic abnormalities. Taken together, these findings make NPMc+ acute myeloid leukemia a good candidate for inclusion in the upcoming World Health Organization classification.
Key words: acute myeloid leukemia, nucleophosmin, NPM, mutations, antibodies, immunohistochemistry.
Introduction
|
TOPABSTRACTIntroductionDesign and MethodsResults and DiscussionReferences |
|---|
One of the most controversial issues in the WHO classification of myeloid malignancies is acute myeloid leukemias not otherwise characterized.1 This category accounts for 60–70% of AML, including cases with normal cytogenetics (AML-NC) which are characterized by a great molecular, pathological and clinical heterogeneity. AML not otherwise characterized is currently defined according to FAB criteria which are, however, insufficient to characterize AML-NC, since they do not identify distinct disease entities within this heterogeneous group. Recognition of underlying molecular alterations is crucial for the improvement of AML-NC classification.
We previously identified nucleophosmin (NPM1) mutations, causing aberrant cytoplasmic expression of NPM,2–4 as the most frequent genetic alteration associated with AML-NC (50–60% of cases). NPM1 mutations and cytoplasmic NPM appear to be mutually exclusive of recurrent genetic abnormalities2 and identify a leukemia subgroup called NPMc+ (cytoplasmic-positive) AML that show distinct biological, pathological and clinical features,5,6 as well as a unique gene expression profile.7 For these reasons, NPMc+ AML (as well as AML with CEBPA mutations that also appear to be mutually exclusive with recurrent genetic abnormalities) is a good candidate for inclusion as a new entity in the forthcoming WHO classification. However, since a few studies8–11 have reported very rare cases of NPM1 mutations coinciding with either inv(16), t(8;21) or t(9;22), we extended our analysis to 2562 patients with acute myeloid leukemia.
Design and Methods
|
TOPABSTRACTIntroductionDesign and MethodsResults and DiscussionReferences |
|---|
Leukemic samples
The aim of the study for AML patients enrolled in the GIMEMA LAM99P and the GIMEMA/EORTC AML12 trials was to compare the subcellular expression of NPM with the results of molecular studies for recurrent genetic alterations. The rationale for this approach derives from our previous observations that immunohistochemistry is fully predictive of NPM1 mutation status.12 Bone marrow biopsies for immunohistochemical studies were available from 1073 unselected, consecutively observed AML cases, 591 of whom had been previously reported.2 Ninety-six acute promyelocytic leukemia cases (not included in the GIMEMA LAM 99P and GIMEMA/EORCT-AML12) were also available for comparative immunohistochemical and molecular analysis. In addition, 1403 unselected AML cases were investigated at the Munich Leukemia Laboratory (MLL). Cytogenetics failed in 10 cases and these were excluded from the present study. Therefore, the Munich cohort consisted of 1393 consecutively observed, unselected newly diagnosed AML for which complete cytogenetic/molecular studies were available. In these cases, we compared the results of NPM1 mutational analysis13 and cytogenetic/molecular studies. Written informed consents for the study was obtained from each participating center.
Immunohistochemical studies
Immunohistochemistry for NPM was available in 1073 AML cases, 591 of whom had been previously reported.2 NPM subcellular expression was detected in paraffin-sections from B5-fixed/EDTA decalcified bone marrow trephines using a specific anti-NPM monoclonal antibody (clone 376) and the highly sensitive alkaline phosphatase anti-alkaline phosphatase (APAAP) technique, as previously described.2 Monoclonal antibody against nucleolin/C23 was purchased from Santa Cruz Biotechnology.
Cytogenetics and molecular studies for recurrent genetic abnormalities
Cytogenetic investigation was performed after short-term culture. Karyotypes were analyzed after G-banding and described according to the International System for Human Cytogenetic Nomenclature.14 Fluorescence in situ hybridization was carried out according to standard techniques. Reverse-transcriptase-polymerase-chain-reaction (RT-PCR) for AML1-ETO, CBFB-MYH11, DEK-CAN and BCR-ABL, performed as previously reported,2 was available in 1019/1073, 1020/1073, 936/1073 and 1015/1073 AML cases respectively. Southern blotting and FISH for rearrangements of the mixed-lineage leukemia gene (MLL)2 was carried out in 728/1073 patients.
Mutational analysis of the NPM1 gene
Mononucleated cells were isolated by standard Ficoll-Hypaque density gradient centrifugation. Nucleic acid isolation, cDNA synthesis and screening for NPM1 gene mutations were performed using a melting curve based LightCycler assay, as previously described.13 AML samples with an aberrant melting curve underwent nucleotide sequence analysis.
Results and Discussion
|
TOPABSTRACTIntroductionDesign and MethodsResults and DiscussionReferences |
|---|
Of the 1073 bone marrow biopsies from patients of the GIMEMA LAM99P and GIMEMA/EORTC AML12 trials, 368 (34.2%) were characterized by aberrant cytoplasmic expression of nucleophosmin (NPMc+) associated with nucleus-restricted positivity for nucleolin (C23) (Figure 1). As previously reported,12 this staining pattern is fully predictive of a mutated NPM1 gene. All other biopsies showed a nucleus-restricted positivity for nucleophosmin (NPMc-) which is fully predictive of NPM1 gene in a germline configuration.12 Comparison of immunohistochemistry with the results of molecular studies for the recurrent genetic abnormalities is shown in Table 1. Remarkably, all 300 AMLs carrying various types of recurrent genetic abnormalities showed a nucleus-restricted expression of NPM. Representative examples of these staining patterns in AML carrying the most frequent recurrent genetic abnormalities, i.e. t(15;17), inv(16) and t(8;21), are shown in Figure 2. Completely overlapping results were obtained in cases from the Munich Leukemia Laboratory, by comparing the mutation status of the NPM1 gene with the results on cytogenetic/molecular studies for recurrent genetic abnormalities. In total, we investigated 1393 AML cases, 835 of which had a normal and 558 an abnormal karyotype. NPM1 mutations were detected in 420 out of 1393 patients (30.1%) while the other cases harboured a NPM1 gene in a germline configuration. In 246 of 1393 patients, reciprocal translocations and the respective fusion genes were detected; RT-PCR and/or FISH were performed for all respective fusion genes. The results are shown in Table 2. Notably, none of the 246 AMLs carrying different types of genetic abnormalities harbored NPM1 mutations. These results were obtained independently from a total of 2562 AMLs from two large series using different approaches, support our original finding that, cytoplasmic mutated NPM is mutually exclusive of recurrent genetic abnormalities.2 Our findings raise several issues surrounding the significance of the sporadic cases of NPM1 mutations coinciding with recurrent genetic abnormalities, as reported in some studies.8–10 First, none of these studies documented whether NPM1 mutations and concurrent genetic abnormalities occur in the same or different leukemic cell populations. Another major concern is specificity control in large multi-center trials. This is addressed in Falini B. et al.2 (Supplementary Materials). In particular, 4 patients in the GIMEMA EORTC AML12 trial were diagnosed as having cytoplasmic mutated NPM together with inv(16), t(8;21) or MLL rearrangement. In-depth re-investigation of these cases revealed errors in sample registration or PCR contamination. Because of the presence of NPM1 mutation in association with a t(16;16)/MYH11-CBFB transcript, 1 patient from the CCG-2961 AML pediatric trial was also re-investigated and found not to have a NPM1 mutation (Patrick Brown, unpublished results). Therefore, in our experience, re-analysis according to strict criteria showed that NPM1 mutations are mutually exclusive of recurrent genetic abnormalities. Whether the occurrence of two or more specific genetic markers in exceptional cases is just coincidental or represents a true association is still not understood. Rare examples include t(15;17) plus t(8;21),15 t(15;17) plus t(9;22),16 and t(9;22) or BCR-ABL plus inv(16).17,18 Interestingly, 1 case reported by Thiede et al.9 carried both a t(8;21) and an inv(16) in addition to NPM1 mutations with a NPM1 mut/wt ratio of only 0.37 (Christian Thiede, personal communication on February 6, 2006). More recently, coexistence of JAK2V617F and BCR-ABL has also been reported in chronic myeloproliferative disorders19,20 and association of JAK2V617F with t(8;21) in AML therapy-related21 or secondary to a myeloproliferative syndrome.22 In conclusion, our data unequivocally confirm in a large series of patients with acute myeloid leukemia that NPM1 mutations are mutually exclusive of other recurrent genetic abnormalities and that NPM1 mutations identify a distinct acute myeloid leukemia genetic entity which should be considered for inclusion in the upcoming WHO Classification.
 View larger version (58K): [in a new window] [Download PPT slide] |
Figure 1. Expression pattern of nucleophosmin in a case of typical NPMc+ AML. Left panel: LAM FAB-M5a showing diffuse infiltration by monoblasts (bone marrow trephine; hematoxylineosin; x800). Middle panel: leukemic cells show aberrant cytoplasmic expression of nucleophosmin (NPM). Bone marrow trephine immunostained with anti-NPM monoclonal antibody (APAAP technique; hematoxylin counterstain; x800). Right panel: leukemic cells show nucleus-restricted positivity for nucleolin/C23 (bone marrow trephine; APAAP technique; hematoxylin counterstain; x800).
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View this table: [in a new window] [Download PPT slide] |
Table 1. Correlation between recurrent genetic abnormalities and NPM subcellular expression in the GIMEMA/EORTC AML12 trial.
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 View larger version (99K): [in a new window] [Download PPT slide] |
Figure 2. Expression pattern of nucleophosmin (NPM) in AML with recurrent genetic abnormalities. Left panels: typical morphological appearance of acute promyelocytic leukemia with t(15;17) (top), LAM FAB-M4eo with inv(16) (middle) and LAM FAB-M2 with t(8;21) (bottom). All cases are bone marrow trephines (hematoxylin-eosin; x800). Right panels: leukemic cells in all AML cases with recurrent genetic abnormalities show a nucleus-restricted positivity for nucleophosmin which is indicative of wild-type NPM1 gene. The arrows points to mitotic figures showing the expected cytoplasmic positivity. Bone marrow trephines immunostained with anti-NPM monoclonal antibody (APAAP technique; hematoxylin counterstain; x800).
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View this table: [in a new window] [Download PPT slide] |
Table 2. Correlation between recurrent genetic abnormalities and NPM1 mutations in acute myeloid leukemia cases from the Munich Leukemia Laboratory.
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Acknowledgments
we would like to thank Roberta Pacini and Manola Carini for performing the immunohistochemical stainings and Mrs. Claudia Tibidò for her secretarial assistance
Footnotes
Authorship and Disclosures
BF is responsible for the study concept and wrote the manuscript; GS, FLC, DD, FP, CM, MM were involved ni the molecular and cytogenetic studies of patients from GIMEMA/EORTC AML12; MPM and SP were involved in the immunohistochemical study of NPM expression in AML specimens. TH, CH and SS carried out the molecular analysis of cases from the Munich Leukemia Laboratory. BF and CM applied for a patent on the clinical use of NPM1 mutants.
Funding: This work was supported by the Associazione Italiana per la Ricerca sul Cancro (A.I.R.C.).
Received for publication August 24, 2007. Accepted for publication December 17, 2007.
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