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REVIEW CEBPA Point Mutations in Hematological Malignancies

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REVIEW CEBPA Point Mutations in Hematological Malignancies Leukemia (2005) 19, 329–334 & 2005 Nature Publishing Group All rights reserved 0887-6924/05 $30.00 www.nature.com/leu REVIEW CEBPA point mutations in hematological malignancies H Leroy1, C Roumier1, P Huyghe2, V Biggio1, P Fenaux3 and C Preudhomme1 1Laboratoire d’He´matologie A, CHRU Lille, U524 INSERM Lille, France; 2Service des Maladies du sang, CHRU Lille, France; and 3Service d’He´matologie Clinique, Hoˆpital Avicenne-Paris 13 University, France The CCAAT/enhancer-binding protein-alpha (CEBPA) is a wild-type (wt) CEBPA. The 42-kDa CEBPA protein has four transcription factor strongly implicated in myelopoiesis principal domains: the C-terminal part containing a leucine through control of proliferation and differentiation of myeloid progenitors. Recently, several works have reported the pre- zipper domain mediating homo- or heterodimerization; the sence of CEBPA-acquired mutations in hematological malig- DNA-binding domain (DBD), a basic positively charged domain nancies. In this work, we analyzed characteristics of mutations able to interact with specific DNA sequences; and two and their correlation with disease characteristics described regulatory and transactivating domains TAD1 and TAD2 in previous studies. In the 1175 patients reported, 146 CEBPA (Figure 1). mutations were identified in 96 patients. Mutations were found The 42-kDa normal protein acts as a transcription factor with in the whole gene sequence, but cluster regions were clearly identified. Furthermore, two categories of mutations were a crucial role during differentiation of various cell types reported: out-of-frame ins/del often in the N-terminal region, including hepatocytes, adipocytes, enterocytes, keratinocytes, and in-frame ins/del often in the C-terminal region. CEBPA lung, mammary gland cells and hematopoietic cells. In mutations were reported exclusively in acute myeloid hematopoiesis, CEBPA plays a pivotal role in early stages of leukemia (AML) (according to WHO classification criteria) myeloid differentiation and is particularly expressed in myelo- and mutated patients preferentially belonged to M1, M2 and monocytic cells.4–8 CEBPA has multiple actions such as down- M4 FAB subtypes. All but one case belonged to the ‘inter- mediate’ prognostic subgroup of MRC classification. In the regulation of C-MYC expression allowing differentiation, direct absence of poor prognostic factors, patients with CEBPA upregulation of the expression of granulocytic lineage-specific mutation had favorable outcome, very similar to that of the genes and synergistic action with other key genes in myeloid t(8;21), inv(16), t(15;17) subgroup. Systematic analysis of development including CBF complex genes and PU.1.5,9–11 In CEBPA mutations, in addition to that of alterations in master addition to specific DNA binding, CEBPA could act by protein– genes of hematopoiesis, may be useful to assess the prognosis protein interaction. The principal partners of those interactions of AML particularly in patients belonging to the ‘intermediate’ prognostic subgroup. are p21, CDK2, CDK4 and E2F. Repression of E2F-dependent Leukemia (2005) 19, 329–334. doi:10.1038/sj.leu.2403614 transcription genes by CEBPA had previously been shown to be Published online 13 January 2005 a critical event in suppressing cellular proliferation and inducing Keywords: CEBPA; mutations; AML; prognosis; transcription factor; granulocytic or adipocyte differentiation. CEBPA also inhibits CCAAT/enhancer-binding protein cell proliferation by activating transcription of p21/WAF1,by stabilizing p21 and inhibiting CDK2 and CDK4.12–14 CEBPA expression begins with the commitment of myeloid lineage precursors and is upregulated during granulo- Introduction 7 cytic differentiation. CEBPA-defective mice have no mature granulocytes, whereas cells of the other lineages are not Among the many oncogenes affecting proliferation and cell 15 affected. In addition, CEBPA expression could block mono- death, anomalies of the genes implicated in the closely 16 cytic differentiation. regulated pathways of hematopoietic differentiation are key The strong implication of CEBPA in granulocytic differentia- oncogenic events.1 In acute myeloid leukemia (AML), cell tion points to this gene as a key target in leukemogenesis, as differentiation arrest can occur at different levels by alteration 3 shown now in many studies. Pabst et al found that events of specific genes like those of the CBF complex.2 The CEBPA leading to the loss of CEBPA function observed in AML gene (located on chromosome 19q13.1 band) belongs to the contribute to leukemogenesis by blocking granulocytic differ- CCAAT/enhancer-binding protein family, which is involved entiation. Moreover, myeloid blasts observed in those cases in the balance between cell proliferation and terminal were committed myeloid cells generally classified in the M1 or differentiation. CEBPA gene mRNA can be translated from 17 M2 FAB AML subtypes. Recently, three mechanisms of CEBPA the first AUG encoding the 42-kDa normal isoform and also inactivation have been reported. One is downregulation of from the second AUG (nt 508–510) encoding the 30-kDa CEBPA expression by the AML1-ETO fusion transcript in t(8,21) normal isoform, which has lost the 119 first AA including leukemia cells. In this model, conditional expression of CEBPA the TAD1 functional domain. The functions of CEBPA 30-kDa 3 in those cells is sufficient to trigger granulocytic differentia- protein are not well known. Nevertheless, Pabst et al 18 tion. The second mechanism is inhibition of the translation of demonstrated that this shorter CEBPA protein had lost normal CEBPA mRNA by interaction with hnRNPE2, induced by CEBPA functions and had dominant negative effect on 42-kDa 19 BCR-ABL fusion protein. This mechanism could contribute to the transition from chronic phase to myeloid blast crisis in ´ Correspondence: Dr C Preudhomme, Laboratoire d’Hematologie A – CML, by blocking myeloid differentiation. Finally, inactivating hoˆpital Calmette, CHRU, Place de Verdun, 59000 Lille, France; Fax: þ 33 3 20 44 55 10; E-mail: [email protected] CEBPA mutations have been reported in hematological 3,20–26 Received 19 July 2004; accepted 4 November 2004; Published online malignancies, especially in AML. In this review, we 13 January 2005 focused on CEBPA mutations and how, through inactivation of CEBPA mutations in hematological malignancies H Leroy et al 330 120 2nd ATG AA : 99 104 183 189 286 306 317 345 nt : 445 462 697 714 1006 1068 1099 1183 Clustering regions R1 R2 R3 R4 R5 nt 1 445 462 732 855 1059 1062 1137 1152 1196 % 60 50 40 Single alteration 30 20 10 0 R1 R2 R3 R4 R5 % 60 50 Multiple 40 alterations 30 20 10 0 R1 R2 R3 R4 R5 Legend: : Transactivating Domain 1 (Poly-Gly) : Out of frame ins / del mutations : Transactivating Domain 2 (Poly-Pro) : In frame ins / del mutations : DNA Binding Domain (DBD) : Other type mutations : Leucine Zipper Domain Figure 1 Schematic representation of CEBPA functional domain; incidence of the different types of mutation and localization of mutation hot spot regions. transcriptional properties of the CEBPA protein, they could lead Correlation of CEBPA mutations with hematological to leukemogenesis. parameters and prognosis CEBPA mutations and morphological classification Overview of CEBPA gene mutations reported All but two of the 87 reported patients with CEBPA mutation had In the last 3 years, 1175 patients were screened for CEBPA AML, including 30 M1 AML, 35 M2 AML, 14 M4 AML, three M5 mutations in seven studies.3,21–25,27.Those patients included 962 AML, two unclassified AML and one therapy-related AML AML (Table 1), 156 myelodysplastic syndromes, 23 acute (incidence in AML: 85 on 962 patients (8.8 %) ; see Table 1). lymphoblastic leukemia and 34 non-Hodgkin’s lymphoma. The two remaining patients had RAEB-t (a disorder now Among those 1175 patients, 96 (8.2%) had CEBPA mutations included in AML in the new WHO classification of myeloid including nine with silent mutations and 87 with acquired disorders). nonsilent mutations (described in online additional data, FAB classification of AML and MDS was available in 712 supplementary data). CEBPA mutations were only observed in patients studied for CEBPA mutations. Incidences of mutations myeloid malignancies. were 14.5 % of M1, 6.4% of M2, 4% of M4, 2% of M5, one of Leukemia CEBPA mutations in hematological malignancies H Leroy et al 331 the seven therapy-related AML and one of the 12 RAEB-t. No In these four studies, the complete remission rate was not mutations were found in M0, M3, M6 and M7-AML. significantly different in patients with or without CEBPA mutations, but all studies except that of Snaddon et al21 showed better relapse-free survival (RFS) or overall survival (OS) in Cytogenetic findings mutated cases. Discrepancies between Snaddon et al21 and other studies could have been due to some characteristics of Cytogenetic data was available in 83 of the 87 mutated patients their mutated cases, including higher peripheral blood blast (see online additional data). Only one had a complex karyotype count (median of 93 109/l vs o24 109/l in the mutated cases of with more than three abnormalities; 58 cases (70%) had a other studies), the localization of mutations (five of eight normal karyotype and eight (10%) had only one abnormality. In mutated patients had a single alteration of the C-terminal part the remaining 15 mutated cases, the karyotype was classified in of CEBPA protein vs zero of 27 in the other studies), and, the ‘intermediate’ prognostic subgroup without
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