RESUMO
Acute promyelocytic leukemia (APL) is a special disease entity of acute myeloid leukemia (AML). The clinical use of all-trans retinoic acid (ATRA) has transformed APL into the most curable form of AML. The majority of APL cases are characterized by the fusion gene PML-RARA. Although the PML-RARA fusion gene can be detected in almost all APL cases, translocation variants of APL have been reported. To date, this is the most comprehensive review of these translocations, discussing 15 different variants. Reviewed genes involved in APL variants include: ZBTB16, NPM, NuMA, STAT5b, PRKAR1A, FIP1L1, BCOR, NABP1, TBLR1, GTF2I, IRF2BP2, FNDC3B, ADAMDTS17, STAT3, and TFG. The genotypic and phenotypic features of APL translocations are summarized. All reported studies were either case reports or case series indicating the rarity of these entities and limiting the ability to drive conclusions regarding their characteristics. However, reported variants have shown variable clinical and morphological features, with diverse responsiveness to ATRA.
Assuntos
Genótipo , Leucemia Promielocítica Aguda , Proteínas de Neoplasias , Translocação Genética , Humanos , Leucemia Promielocítica Aguda/classificação , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismoAssuntos
Antineoplásicos/uso terapêutico , Trióxido de Arsênio/uso terapêutico , Leucemia Promielocítica Aguda/terapia , Guias de Prática Clínica como Assunto , Tretinoína/uso terapêutico , Humanos , Quimioterapia de Indução , Leucemia Promielocítica Aguda/classificação , Leucemia Promielocítica Aguda/etiologia , Leucemia Promielocítica Aguda/genética , Terapia de Alvo MolecularRESUMO
Diagnosis and classification of acute myeloid leukaemia (AML) require cytogenetic and molecular genetic investigation. However, while these evaluations are pending, morphology supplemented by immunophenotyping can provide clues to the diagnosis of specific cytogenetic/genetic categories of AML. Most importantly, acute promyelocytic leukaemia can be diagnosed with a high degree of certainty. However, provisional identification of cases associated with t(8; 21), inv(16), t(1; 22), and NPM1 mutation may also be possible. In addition, transient abnormal myelopoiesis of Down's syndrome can generally be diagnosed morphologically.
Assuntos
Inversão Cromossômica , Cromossomos Humanos/genética , Leucemia Promielocítica Aguda , Mielopoese/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Translocação Genética , Síndrome de Down/genética , Humanos , Leucemia Promielocítica Aguda/classificação , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/terapia , Nucleofosmina , Organização Mundial da SaúdeRESUMO
BACKGROUND: Acute lymphoblastic leukemia (ALL) is a malignant disease in which early lymphoid precursors proliferate and replace the normal hematopoiesis. It has distinctive clinical and biological features. In respect to adult ALL, available data from Pakistan are limited. Therefore we reviewed the demographical and clinico- hematological profiles along with FAB stratification of adult patients with ALL presented at our hospital. MATERIALS AND METHODS: In this cross sectional study, 51 adults (≥15 years) patients with ALL were enrolled from January 2010 to December 2014. RESULTS: The mean age was 23.8±12.9 years with the median age of 18.0 years. The male to female ratio was 2:1. The major complaints were fever (60.7%), generalized weakness (47.0%), overt bleeding (19.6%) and weight loss (13.7%). Physical examination revealed lymphodenopathy as a predominant finding detected in 43.1% followed by splenomegaly and hepatomegaly in 23.5% and 21.5%, respectively. The mean hemoglobin level was 9.0±2.75g/dl with a mean MCV of 82.2±15.4 fl, a mean total leukocyte count of 31.1±64.0x109/l, a mean ANC of 2.1±3.0 x109/l and a mean platelet count of 71.7±85.7x109/l. According to FAB classification, 47.1% were L1 type, 45.1% L2 and 7.8% L3 variant. CONCLUSIONS: Clinico-pathological features appeared comparable to published data. Febrile illness associated with lymphodenopathy was the commonest presentation. FAB classification revealed a predominance of ALL-L1 variant in Pakistani adult patients with ALL.
Assuntos
Leucemia Promielocítica Aguda/epidemiologia , Leucemia Promielocítica Aguda/patologia , Adolescente , Adulto , Idoso , Estudos Transversais , Demografia , Feminino , Seguimentos , Humanos , Leucemia Promielocítica Aguda/classificação , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paquistão/epidemiologia , Prognóstico , Centros de Atenção Terciária , Adulto JovemRESUMO
OBJECTIVE: To investigate the immunophenotype of leukemia promyelocytes (LP) in bone marrow of patients with acute promyelocytic leukemia (APL) and to explore their characteristics and significance. METHODS: The immunophenotypes of leukemia cells in 43 patients with APL were analyzed by means of 4 color immunophenotypes; the cell population in which CD45 strength localized at 10(2) and the SSC strength locatized at 10(2) was defined as R3, the cell population in which CD45 strength localized at 10(3) and the SSC strength localized at 10(2) was defined as R5, moreover the ratio of positive cells >80% was defined as strong positive expression, the ratio of positive cells between 20%-80% was difined as weak positive expression, the ratio of positive cells <20% was difined as negative by gating method of CD45/SSC. RESULTS: There was a abnormal cell population (R3) in 79.07% cases; the immunophenotypes of R3 was cheracteried by high SSC, weaker expression of CD45, the rate of CD38, CD9 and CD13 all was 100%, moreover their bright expression (>80%) was 86.05%, 90.70% and 86.05%, respectively; the positive expression rate of CD33, CD117 and CD64 was 97.67%, 95.35% and 83.80% respectively, moreover thier bright expression was 84.04%, 69.77% and 30.23% respectively; the CD15 was weakly expressed in 39.53% cases, the CD34 and HLA-DR were weakly expression in 16.28% and 6.98% cases respectively. All the cases did not express CD116. There were 2 cell populations (R3 and R5) in 20.93% cases, the immunophenotypic features of R3 were cosistant with above mentioning, while the immunophenotypes of R5 were lower than those of R3 SSC; the fluorescence intensity of CD45 was higher, but lower than that in normal lymphycytes, the positive rate of CD9, CD13, MPO was 100%, moreover thier fluorescence intensity was high; they did not expressed CD123, CD25, CD22, CD4, CD64 and CD14. Thereby it can be concluded that the typical immunophenotypes is characterized by CD13(+) CD9(+) CD38(+) CD33(+) CD117(+) CD64(+) CD11b(-) CD34(-) HLA-DR(-) in APL. There was a special immunophenotype in the APL with basophilic granules. Conclusoin: APL has a characteristic immunophenotypic profile, whose typical immunophenotype is characterized by CD13(+) CD9(+) CD38(+) CD33(+) CD117(+) CD64(+) CD11b(-) CD34(-) HLA-DR(-). The special immunophenotype exists in the APL with basophilic granules. Flow cytometric immunophenotyping may be a useful for rapid recognition of APL and has significant for prognosis.
Assuntos
Imunofenotipagem , Leucemia Promielocítica Aguda/imunologia , Antígenos CD/metabolismo , Contagem de Células , Citometria de Fluxo , Células Precursoras de Granulócitos/classificação , Antígenos HLA-DR/metabolismo , Humanos , Leucemia Promielocítica Aguda/classificação , Antígenos Comuns de Leucócito/metabolismo , PrognósticoRESUMO
The French-American-British (FAB) and WHO classifications provide important guidelines for the diagnosis, treatment, and prognostic prediction of acute leukemia, but are incapable of accurately differentiating all subtypes, and not well correlated with the clinical outcomes. In this study, we performed the protein profiling of the bone marrow mononuclear cells from the patients with acute leukemia and the health volunteers (control) by surface enhanced laser desorption/ionization-time of flight mass spectrometry (SELDI_TOF_MS). The patients with acute leukemia were analyzed as unitary by the profiling that were grouped into acute promyelocytic leukemia (APL), acute myeloid leukemia-granulocytic (AML-Gran), acute myeloid leukemia-monocytic (AML-Mon) acute lymphocytic leukemia (ALL), and control. Based on 109 proteomic signatures, the classification models of acute leukemia were constructed to screen the predictors by the improvement of the proteomic signatures and to detect their expression characteristics. According to the improvement and the expression characteristics of the predictors, the proteomic signatures (M3829, M1593, M2121, M2536, M1016) characterized successively each group (CON, APL, AML-Gra, AML-Mon, ALL) were screened as target molecules for identification. Meanwhile, the proteomic-based class of determinant samples could be made by the classification models. The credibility of the proteomic-based classification passed the evaluation of Biomarker Patterns Software 5.0 (BPS 5.0) scoring and validated application in clinical practice. The results suggested that the proteomic signatures characterized by different blasts were potential for developing new treatment and monitoring approaches of leukemia blasts. Moreover, the classification model was potential in serving as new diagnose approach of leukemia.
Assuntos
Biomarcadores Tumorais/análise , Leucemia Mieloide Aguda/metabolismo , Leucemia Promielocítica Aguda/metabolismo , Proteínas de Neoplasias/análise , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Análise Serial de Proteínas , Proteômica/métodos , Adulto , Estudos de Casos e Controles , Biologia Computacional , Árvores de Decisões , Feminino , Humanos , Leucemia Mieloide Aguda/classificação , Leucemia Mieloide Aguda/patologia , Leucemia Promielocítica Aguda/classificação , Leucemia Promielocítica Aguda/patologia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/classificação , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Validação de Programas de Computador , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
OBJECTIVE: To screen the potential protein biomarkers in minimal residual disease (MRD) of the acute promyelocytic leukemia (APL) by comparison of differentially expressed serum protein between APL patients at diagnosis and after complete remission (CR) and healthy controls, and to establish and verify a diagnostic model. METHODS: Serum proteins from 36 cases of primary APL, 29 cases of APL during complete remission and 32 healthy controls were purified by magnetic beads and then analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The spectra were analyzed statistically using FlexAnalysis(TM) and ClinProt(TM) software. RESULTS: Two prediction model of primary APL/healthy control, primary APL/APL CR were developed. Thirty four statistically significant peptide peaks were obtained with the m/z value ranging from 1000 to 10 000 (P < 0.001) in primary APL/healthy control model. Seven statistically significant peptide peaks were obtained in primary APL/APL CR model (P < 0.001). Comparison of the protein profiles between the two models, three peptides with m/z 4642, 7764 and 9289 were considered as the protein biomarker of APL MRD. A diagnostic pattern for APL CR using m/z 4642 and 9289 was established. Blind validation yielded correct classification of 6 out of 8 cases. CONCLUSIONS: The MALDI-TOF MS analysis of APL patients serum protein can be used as a promising dynamic method for MRD detection and the two peptides with m/z 4642 and 9289 may be better biomarkers.
Assuntos
Leucemia Promielocítica Aguda/diagnóstico , Neoplasia Residual/diagnóstico , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Humanos , Leucemia Promielocítica Aguda/classificação , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/classificação , Prognóstico , Adulto JovemRESUMO
A total of 97 acute promyelocytic leukemia (APL) patients with adequate flow cytometry (FC) data, bone marrow aspirates and presence of t(15;17)/PML-RARA by cytogenetics and/or FISH studies were analyzed for immunophenotypic pattern. Leukemic cells had the following phenotype: CD11b-, CD11c-, CD13+, CD33+, CD45+, CD64+/-, CD117+, and HLA-DR-. A subset of cases showed also an expression of CD2, CD4, CD34, and CD56. Based on the immunophenotype and side scatter properties (SSC), four FC patterns were recognized. The majority of cases represented classical (hypergranular) APL and were characterized by high SSC, positive CD117, lack of CD34, heterogeneous CD13, and bright CD33 (pattern 1). Second most common type, corresponding to the hypogranular (microgranular) variant of APL differed from classical APL by low SSC and frequent co-expression of CD2 and CD34 (pattern 2). Rare cases of APL (pattern 3) showed a mixture of neoplastic cells (low SSC/CD2+/CD13+/CD33+/CD34+/CD117+) and prominent population of benign granulocytes/maturing myeloid precursors (high SSC/CD10+/-/CD16+/-/ CD117-). One case showed two APL populations, one with hypogranular and one with hypergranular characteristics (pattern 4). Apart from a well-known FC pattern of hypergranular APL, we presented less common immunophenotypic variants of APL, which helps to identify an additional group of patients who would benefit from fast confirmatory FISH and/or PCR testing for t(15;17)/PML-RARA.
Assuntos
Antígenos CD/análise , Biomarcadores Tumorais/análise , Leucemia Promielocítica Aguda/classificação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Separação Celular , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Hibridização in Situ Fluorescente , Leucemia Promielocítica Aguda/genética , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto JovemAssuntos
Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adulto , Fatores Etários , Anemia/etiologia , Antineoplásicos/uso terapêutico , Proteínas Estimuladoras de Ligação a CCAAT/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Diploide , Coagulação Intravascular Disseminada/etiologia , Transplante de Células-Tronco Hematopoéticas , Hepatomegalia/etiologia , Humanos , Cariótipo , Leucemia Mieloide Aguda/classificação , Leucemia Mieloide Aguda/etiologia , Leucemia Promielocítica Aguda/classificação , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/etiologia , Leucemia Promielocítica Aguda/terapia , Contagem de Leucócitos , Leucostasia/etiologia , Doenças Linfáticas/etiologia , Mutação , Proteínas Nucleares/genética , Nucleofosmina , Pancitopenia/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/classificação , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Fatores de Risco , Punção Espinal , Esplenomegalia/etiologia , Trombocitopenia/etiologia , Translocação Genética , Tirosina Quinase 3 Semelhante a fms/genética , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
We aimed to explore the expression of CD34 and its impact on the disease outcome in patients with APL. The study comprised 40 de novo APL patients. Diagnostic tools included peripheral blood and bone marrow morphology and cytochemistry, immunophenotyping, cytogenetic studies, and PML/RARα fusion gene detection using RT-PCR. CD34 was expressed in 13 (32.5%) of cases with higher expression in M3v compared to M3 subtype. All M3v cases were CD34+, while only 7.4% of M3 cases were CD34+. CD34+ cases were associated with significant higher white blood cell count and peripheral blood promyelocytes. No significant association was found between PML/RAR-α isoform and molecular remission. CD34+ expression was significantly associated with decreased incidence of molecular remission and increased incidence of early death. The overall survival of patients with WBC count >11 × 103/µl was inferior to patients with WBC count <11 × 103/µl, but no significant differences were observed in overall survival between CD34- and CD34+ or between bcr1 and bcr3 groups. Immunophenotypic analysis for CD34 could distinguish an APL subset with different biological characteristics and adverse prognostic outcome.
Assuntos
Antígenos CD34/metabolismo , Leucemia Promielocítica Aguda/classificação , Leucemia Promielocítica Aguda/metabolismo , Adolescente , Adulto , Idoso , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Leucemia Promielocítica Aguda/mortalidade , Leucemia Promielocítica Aguda/terapia , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Isoformas de Proteínas , Indução de Remissão , Taxa de Sobrevida , Resultado do Tratamento , Adulto JovemAssuntos
Medula Óssea/patologia , Grânulos Citoplasmáticos/ultraestrutura , Imunofenotipagem , Leucemia Promielocítica Aguda/patologia , Complicações Neoplásicas na Gravidez/patologia , Adulto , Antígenos CD34/análise , Biomarcadores Tumorais/sangue , Testes de Coagulação Sanguínea , Núcleo Celular/ultraestrutura , Cromossomos Humanos Par 15/ultraestrutura , Cromossomos Humanos Par 17/ultraestrutura , Grânulos Citoplasmáticos/química , Feminino , Antígenos HLA-DR/análise , Humanos , Leucemia Promielocítica Aguda/classificação , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/genética , Proteínas Nucleares/sangue , Gravidez , Complicações Neoplásicas na Gravidez/diagnóstico , Proteína da Leucemia Promielocítica , Fatores de Transcrição/sangue , Translocação Genética , Proteínas Supressoras de Tumor/sangueRESUMO
Few studies have examined the outcome of large numbers of patients with the microgranular variant (M3V) of acute promyelocytic leukemia (APL) in the all-trans retinoic acid era. Here, the outcome of 155 patients treated with all-trans retinoic acid-based therapy on 3 clinical trials, North American Intergroup protocol I0129 and Programa para el Estudio de la Terapéutica en Hemopatía Maligna protocols LPA96 and LPA99, are reported. The complete remission rate for all 155 patients was 82%, compared with 89% for 748 patients with classical M3 disease. The incidence of the APL differentiation syndrome was 26%, compared with 25% for classical M3 patients, and the early death rate was 13.6% compared with 8.4% for patients with classical M3 morphology. With a median follow-up time among survivors of 7.6 years (range 3.6-14.5), the 5-year overall survival, disease-free survival, and cumulative incidence of relapse for patients with M3V were 70%, 73%, and 24%, respectively. With a median follow-up time among survivors of 7.6 years (range 0.6-14.3), the 5-year overall survival, disease-free survival, and cumulative incidence of relapse among patients with classical M3 morphology were 80% (P = .006 compared with M3V), 81% (P = .07), and 15% (P = .005), respectively. When outcomes were adjusted for the white blood cell count or the relapse risk score, none of these outcomes were significantly different between patients with M3V and classical M3 APL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Lactente , Leucemia Promielocítica Aguda/classificação , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Taxa de Sobrevida , Resultado do Tratamento , Tretinoína/administração & dosagem , Adulto JovemRESUMO
This cases series describes the profile of adult patients with acute promyelocytic leukaemia (APt) at a referral hospital in Qatar. Of 34 acute myeloid leukaemia (AML) cases diagnosed, 11(32%) were classified as APt. Disseminated intravascular coagulation was common at presentation (91%). Severe thrombocytopenia was seen in 73%, leukocytosis in 55% and severe anaemia in 45%. Only 2 patients were of the classic hypergranular type. In the remaining 9 patients, 3 morphological subtypes were recognized: microgranular variant (6 patients), hyperbasophilic (2 patients) and regular nuclear outline M3r (1 patient). Translocation t(15;17) was detected in 63% of cases. APL constitutes a high proportion of AML cases in Qatar, with considerable morphological heterogeneity and a oredominance of APL variants with unfavourable oresenting features.
Assuntos
Leucemia Promielocítica Aguda/epidemiologia , Leucemia Promielocítica Aguda/patologia , Adolescente , Anemia/epidemiologia , Anemia/etiologia , Exame de Medula Óssea , Institutos de Câncer , Análise Citogenética , Feminino , Citometria de Fluxo , Variação Genética/genética , Humanos , Imunofenotipagem , Cariotipagem , Leucemia Promielocítica Aguda/classificação , Leucemia Promielocítica Aguda/etiologia , Leucocitose/epidemiologia , Leucocitose/etiologia , Masculino , Pessoa de Meia-Idade , Vigilância da População , Catar/epidemiologia , Trombocitopenia/epidemiologia , Trombocitopenia/etiologia , Translocação Genética , Adulto JovemRESUMO
We describe here a unique chromosomal abnormality found in a patient with M(3r) subtype of APL. Neither t(15;17) nor rearrangement of RARalpha was detected by routine R-banded chromosome as well as fluorescence in situ hybridization (FISH) analysis using PML/RARalpha dual-color dual-fusion translocation probe and RARalpha dual-color break apart rearrangement probe. Instead of the typical rearrangement between chromosomes 15 and 17, all cells analyzed had a translocation between X and 17 as the sole karyotypic anomaly. The translocation was conformed by whole chromosome painting (WCP) with painting probes of chromosomes X and 17. To our knowledge, this is the first documented APL with a novel translocation involving chromosomes X and 17 without RARalpha gene rearrangement.
Assuntos
Cromossomos Humanos Par 17 , Cromossomos Humanos X , Leucemia Promielocítica Aguda/genética , Receptores do Ácido Retinoico/genética , Translocação Genética , Humanos , Cariotipagem , Leucemia Promielocítica Aguda/classificação , Receptor alfa de Ácido RetinoicoRESUMO
This review focuses on the treatment of acute promyelocytic leukemia (APL) in elderly patients and offers recommendations for improving outcomes. Nineteen percent of patients with APL are > or =60 years. Rates of response and survival are lower in elderly compared with younger patients, owing to a higher incidence of early deaths or deaths in remission. However, relapse-free survival rates are similar in both groups. Ongoing trials assess the role of reduced-intensity regimens. All-trans retinoic acid (ATRA) and concurrent arsenic trioxide is associated with high rates of response and molecular remission and low rates of induction deaths. We propose this combination as the treatment of choice in patients with APL, including the elderly. Patients with elevated leukocyte counts may also benefit from gemtuzumab ozogamicin therapy, with or without leukapheresis. Monitoring major organ function and toxicity is essential. Patients should be assessed for minimal residual disease using polymerase chain reaction testing for promyelocytic leukemia-retinoic acid receptor alpha. If molecular relapse is evident, treatment with ATRA and idarubicin, with or without gemtuzumab ozogamicin, is recommended.
Assuntos
Antineoplásicos/uso terapêutico , Arsenicais/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Óxidos/uso terapêutico , Tretinoína/uso terapêutico , Idoso , Trióxido de Arsênio , Quimioterapia Combinada , Humanos , Leucemia Promielocítica Aguda/classificação , Leucemia Promielocítica Aguda/patologia , PrognósticoRESUMO
Acute promyelocytic leukaemia (APL) is a well-defined disease characterized by a typical morphology of leukaemic cells, the presence of t(15;17) translocation and the unique sensitivity to the differentiating effect of all-trans retinoic acid. Nevertheless, some aspects are variable among APL patients, with differences substantially related to morphological variants, peripheral leukocytes count, the presence of a disseminated intravascular coagulopathy, different PML/RARalpha isoforms (long, variable or short) and Fms-like tyrosine kinase 3 (Flt3) mutations. In order to better define this variability, we investigated the gene expression profiles of 18 APL cases revealing, besides a high uniformity in gene expression pattern, the presence of few robust differences among patients able to identify, by an unsupervised analysis, two major clusters of patients characterized by different phenotypes (hypogranular M3v vs classical M3) and by the presence or absence of Flt3 internal tandem duplications (ITDs). Further supervised analysis confirmed that Flt3 status was the APL parameter best associated with these two subgroups. We identified, between Flt3 wild-type and Flt3-ITDs subsets, 147 differentially expressed genes that were involved in the cytoskeleton organization, in the cell adhesion and migration, in the proliferation and the coagulation/inflammation pathways as well as in differentiation and myeloid granules constitution suggesting a role of Flt3 mutations in the pathogenesis and clinical manifestations of APL.
Assuntos
Perfilação da Expressão Gênica , Leucemia Promielocítica Aguda/genética , Família Multigênica , Tirosina Quinase 3 Semelhante a fms/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise por Conglomerados , Éxons , Feminino , Humanos , Leucemia Promielocítica Aguda/classificação , Leucemia Promielocítica Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Mutação , FenótipoRESUMO
Acute promyelocytic leukemia (APL) with t(15;17) appears in two phenotypes: AML M3, with abnormal promyelocytes showing heavy granulation and bundles of Auer rods, and AML M3 variant (M3v), with non- or hypogranular cytoplasm and a bilobed nucleus. We investigated the global gene expression profiles of 35 APL patients (19 AML M3, 16 AML M3v) by using high-density DNA-oligonucleotide microarrays. First, an unsupervised approach clearly separated APL samples from other AMLs characterized genetically as t(8;21) (n = 35), inv(16) (n = 35), or t(11q23)/MLL (n = 35) or as having a normal karyotype (n = 50). Second, we found genes with functional relevance for blood coagulation that were differentially expressed between APL and other AMLs. Furthermore, a supervised pairwise comparison between M3 and M3v revealed differential expression of genes that encode for biological functions and pathways such as granulation and maturation of hematologic cells, explaining morphologic and clinical differences. Discrimination between M3 and M3v based on gene signatures showed a median classification accuracy of 90% by use of 10-fold CV and support vector machines. Additional molecular mutations such as FLT3-LM, which were significantly more frequent in M3v than in M3 (P < 0.0001), may partly contribute to the different phenotypes. However, linear regression analysis demonstrated that genes differentially expressed between M3 and M3v did not correlate with FLT3-LM.
Assuntos
Perfilação da Expressão Gênica , Leucemia Promielocítica Aguda/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Coagulação Sanguínea/genética , Cromossomos Humanos Par 15 , Cromossomos Humanos Par 17 , Feminino , Humanos , Leucemia Promielocítica Aguda/classificação , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Translocação GenéticaRESUMO
Se presenta un caso con leucemia aguda promielocítica (LAP) en el que se demostró la presencia del gen híbrido PML/RARa y la duplicación interna en tandem del gen FLT3 (DIT/FLT3) al momento del diagnóstico. Después de recibir tratamiento de inducción con ácido transretinoico (ATRA) y quimioterapia, el estudio citomorfológico de la médula ósea mostró una transformación a leucemia monocítica aguda (LMA-M5). En el estudio molecular desapareció el transcripto PML/RARa, pero se mantuvo la DIT/FLT3. Estos resultados sugieren la coexistencia de 2 clones leucémicos independientes, un clon promielocítico (M3) con el gen quimérico PML/RARa y otro monocítico (M5) con DIT/FLT3. Aunque la evolución hematológica y molecular apoya esta sugerencia, no se puede excluir la presencia de la DIT/FLT3 en el clon M3, pues no es un marcador específico de la LMA-M5
Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Quimera , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/classificação , Leucemia Monocítica AgudaRESUMO
To investigate the value of bone marrow morphology, immunology, cytogenetics and molecular biology (MICM) examination in the diagnosis of acute promyelocytic leukemia (APL) and their relations of each other, the MICM data of 55 APL patients were analyzed retrospectively. The result showed that the accuracy rate of morphological diagnosis based on FAB classification could reach 96.4%; CD33 and CD13 antigen were co-expressed the highest in immunophenotyping (CD33(+)CD13(+) occupied 96.4%); cytogenetic abnormality containing t (15; 17)(q22; 21) accounted for 87.3%, translocation of chromosomes (simple type) of 100% t (15; 17)(q22; 21) occupied 75%, other involved chromosomes included 1, 8, 9, 11, 12, 21; the positive rate of PML/RARalpha gene also reached 96.4%; the accuracy rate of APL diagnosis by combining MICM measure was 100%. In conclusion, the bone marrow morphology still remains to be base for diagnosis of APL, but the combined analysis of MICM could obviously enhance the accuracy of diagnosis for APL. The MICM examination may provide a new approach to find subtype of APL.
Assuntos
Aberrações Cromossômicas , Leucemia Promielocítica Aguda/classificação , Adolescente , Adulto , Feminino , Humanos , Imunofenotipagem , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Fusão Oncogênica/genéticaRESUMO
Recent progress has demonstrated that acute myelogenous leukaemia (AML) can be classified by chromosomal aberrations and leukaemia-specific molecular gene rearrangements into homogeneous biological subgroups. However, descriptive epidemiological reports on AML consider the disease as a single entity. Acute promyelocytic leukaemia (APL) is an example of a truly unique AML subtype that has an easy-to-recognize morphology associated uniformly with distinct chromosomal and gene rearrangement aberration. Thus, APL is amenable to epidemiological studies as a model of human AML with a specific and well-characterized chromosomal and molecular abnormality. This chapter shows that epidemiological characteristics of APL are different from those of non-APL AML using data from the Los Angeles tumour registry and other sources. The principal distinct APL epidemiological features that so far have been described are the constant incidence with age after age 20, equal incidence in males and females and higher frequency among patients originating in Latin America. The APL-specific PML/RARalpha gene rearrangement is different in Latinos and non-Latinos. Therapy-related APL has the same response to treatment and outcome as de novo APL. It is therefore likely that aetiological factors for APL are different from those of other AML subtypes. So far no environmental and/or occupational risk factors have been found for APL. Future molecular studies of the APL-specific fusion gene combined with epidemiological and environmental investigations might lead to better understanding of specific aetiological factors in APL patients.