RESUMEN
BACKGROUND: Infants with Noonan syndrome (NS) are predisposed to developing juvenile myelomonocytic leukaemia (JMML) or JMML-like myeloproliferative disorders (MPD). Whereas sporadic JMML is known to be aggressive, JMML occurring in patients with NS is often considered as benign and transitory. However, little information is available regarding the occurrence and characteristics of JMML in NS. METHODS AND RESULTS: Within a large prospective cohort of 641 patients with a germline PTPN11 mutation, we identified MPD features in 36 (5.6%) patients, including 20 patients (3%) who fully met the consensus diagnostic criteria for JMML. Sixty percent of the latter (12/20) had severe neonatal manifestations, and 10/20 died in the first month of life. Almost all (11/12) patients with severe neonatal JMML were males. Two females who survived MPD/JMML subsequently developed another malignancy during childhood. Although the risk of developing MPD/JMML could not be fully predicted by the underlying PTPN11 mutation, some germline PTPN11 mutations were preferentially associated with myeloproliferation: 10/48 patients with NS (20.8%) with a mutation in codon Asp61 developed MPD/JMML in infancy. Patients with a p.Thr73Ile mutation also had more chances of developing MPD/JMML but with a milder clinical course. SNP array and whole exome sequencing in paired tumoral and constitutional samples identified no second acquired somatic mutation to explain the occurrence of myeloproliferation. CONCLUSIONS: JMML represents the first cause of death in PTPN11-associated NS. Few patients have been reported so far, suggesting that JMML may sometimes be overlooked due to early death, comorbidities or lack of confirmatory tests.
Asunto(s)
Leucemia Mielomonocítica Juvenil/complicaciones , Leucemia Mielomonocítica Juvenil/genética , Síndrome de Noonan/complicaciones , Síndrome de Noonan/genética , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Estimación de Kaplan-Meier , Leucemia Mielomonocítica Juvenil/mortalidad , Leucemia Mielomonocítica Juvenil/fisiopatología , Masculino , Mutación , Síndrome de Noonan/mortalidad , Síndrome de Noonan/fisiopatología , Estudios Prospectivos , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genéticaAsunto(s)
Péptidos y Proteínas de Señalización Intracelular/genética , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/fisiopatología , Proteínas de la Membrana/genética , Proteínas Adaptadoras Transductoras de Señales , Niño , Predisposición Genética a la Enfermedad , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Leucemia Mielomonocítica Juvenil/metabolismo , Proteínas de la Membrana/metabolismoRESUMEN
Juvenile myelomonocytic leukemia (JMML) is a rare hematopoietic malignancy of early childhood with features characteristic of both myelodysplastic and myeloproliferative disorders. Recent studies clearly show that the deregulated activation of the RAS signaling pathway plays a central role in the pathogenesis of JMML. Somatic defects in either RAS, PTPN11 or NF1 genes involved in this pathway are detected in 70-80% of JMML patients, allowing a molecular diagnosis to be made in the majority of cases. Patients with JMML respond poorly to chemotherapy, and the probability of survival without allogeneic hematopoietic stem cell transplantation (HSCT) is less than 10%. Recent studies show that the event-free survival after HSCT is between 24 and 54%, with no difference between transplants using matched family donors and those using unrelated donors. The use of therapies such as intensive chemotherapy and splenectomy prior to HSCT does not improve the outcome. The relapse rate following HSCT is over 30%, which is unacceptably high. Cumulative evidence suggests that a graft-versus-leukemia effect occurs in JMML. Donor leukocyte infusion is not usually successful in JMML, but the outcome of second HSCT is generally favorable. Based on recent advances in the understanding of the pathogenesis of JMML, the development of novel targeted therapies, which might improve the outcome of patients, is keenly awaited.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mielomonocítica Juvenil/fisiopatología , Leucemia Mielomonocítica Juvenil/terapia , Pediatría , Antineoplásicos/uso terapéutico , Diagnóstico Diferencial , Progresión de la Enfermedad , Genes de Neurofibromatosis 1/fisiología , Genes ras/fisiología , Predisposición Genética a la Enfermedad , Humanos , Leucemia Mielomonocítica Juvenil/diagnóstico , Mutación Puntual , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , RecurrenciaRESUMEN
The t(7;11)(p15;p15) translocation has been reported as a rare and recurrent chromosomal abnormality in acute myeloid leukemia (AML) patients. The NUP98-HOXA9 fusion gene with t(7;11)(p15;p15) was identified and revealed to be essential for leukemogenesis and myeloproliferative disease. To date, t(7;11)(p15;p15) with NUP98-HOXA11 fusion has been reported only in one case of ph-negative chronic myeloid leukemia (CML). Here, we report a case of a 3-year-old girl with juvenile myelomonocytic leukemia (JMML) carrying t(7;11)(p15;p15) abnormality with NUP98-HOXA11 fusion. AML chemotherapy followed by bone marrow transplantation (BMT) was found to be effective in treating this disorder, and she remains in complete remission for 3 years after BMT. We suggest the possibility that AML chemotherapy might be effective for treating JMML with t(7;11)(p15;p15) abnormality and NUP98-HOXA11 fusion.