RESUMEN
BACKGROUND: Measurable/minimal residual disease (MRD) monitoring can predict imminent hematological relapse in acute myeloid leukemia (AML). The majority of childhood AML patients do not harbor fusion genes or mutations applicable as MRD markers and overexpression of Wilms tumor gene 1 (WT1) may constitute a useful monitoring target. However, age-specific reference values in healthy hematopoiesis and standardization of WT1 assessment are prerequisites for clinical utility. PROCEDURE: We investigated WT1 expression across age in hematologically healthy controls (n = 109), during suspected infection (n = 90) and bone marrow (BM) regeneration (n = 13). WT1 expression in AML at diagnosis (n = 91) and during follow-up (n = 30) was compared with age-specific reference values. RESULTS: WT1 expression correlated with age and showed higher levels in both BM and peripheral blood (PB) in children compared with adults (P < 0.001 and P = 0.01). WT1 expression from healthy hematopoiesis was lower in PB compared with BM (WT1BM /WT1PB = 8.6, 95% CI: 5.3-13.7) and not influenced by infection nor BM regeneration. At AML diagnosis, 66% had more than 20-fold WT1 overexpression in PB or BM (PB 74%; BM 45%). WT1 was quantified in 279 PB samples during follow-up. All 11 patients with PB sampling within 4 months of disease recurrence displayed WT1 overexpression by a median of 1.9 months (range, 0.7-9.7) before hematological relapse. CONCLUSIONS: This study defines child-specific reference values for WT1 expression in healthy hematopoiesis and demonstrates that WT1 expression in PB is a useful post-treatment monitoring tool in childhood AML. Based on these observations, we propose definitions for childhood AML molecular relapse using WT1 overexpression.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Médula Ósea/metabolismo , Leucemia Mieloide Aguda/patología , Recurrencia Local de Neoplasia/patología , Neoplasia Residual/patología , Proteínas WT1/metabolismo , Adolescente , Adulto , Biomarcadores de Tumor/sangre , Médula Ósea/patología , Estudios de Casos y Controles , Niño , Preescolar , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Lactante , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/terapia , Masculino , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/terapia , Neoplasia Residual/metabolismo , Neoplasia Residual/terapia , Pronóstico , Valores de Referencia , Proteínas WT1/sangreRESUMEN
Relapse after hematopoietic stem cell transplantation in pediatric acute myeloid leukemia is a fatal event in the majority of cases. Immunotherapy may prevent an impending relapse if instituted at first molecular evidence of disease recurrence. Wilms tumor gene 1 (WT1) is overexpressed in the majority of children and may constitute a useful molecular marker of measurable residual disease applicable for disease monitoring in peripheral blood where the background amplification from healthy hematopoiesis is less prevalent compared with bone marrow. We report the measurable residual disease kinetics from a child with FLT3-internal tandem duplication acute myeloid leukemia where sequential WT1 monitoring in peripheral blood-guided withdrawal of immunosuppression.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Terapia de Inmunosupresión/métodos , Leucemia Mieloide Aguda/terapia , Neoplasia Residual/diagnóstico , Proteínas WT1/sangre , Monitoreo Biológico/métodos , Niño , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Mutación , Recurrencia , Secuencias Repetidas en Tándem , Factores de Tiempo , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
Mantle cell lymphoma (MCL) is a malignancy arising from naive B lymphocytes with common bone marrow (BM) involvement. Although t(11;14) is a primary event in MCL development, the highly diverse molecular etiology and causal genomic events are still being explored. We investigated the transcriptome of CD19+ BM cells from eight MCL patients at single-cell level. The transcriptomes revealed marked heterogeneity across patients, while general homogeneity and clonal continuity was observed within the patients with no clear evidence of subclonal involvement. All patients were SOX11+CCND1+CD20+. Despite monotypic surface immunoglobulin (Ig) κ or λ protein expression in MCL, 10.9% of the SOX11 + malignant cells expressed both light chain transcripts. The early lymphocyte transcription factor SOX4 was expressed in a fraction of SOX11 + cells in two patients and co-expressed with the precursor lymphoblastic marker, FAT1, in a blastoid case, suggesting a potential prognostic role. Additionally, SOX4 was found to identify non-malignant SOX11- pro-/pre-B cell populations. Altogether, the observed expression of markers such as SOX4, CD27, IgA and IgG in the SOX11+ MCL cells, may suggest that the malignant cells are not fixed in the differentiation state of naïve mature B cells, but instead the patients carry B lymphocytes of different differentiation stages.