RESUMO
Classical myeloproliferative diseases can be divided into Philadelphia chromosome-positive chronic myeloid leukemia and Philadelphia chromosome-negative myeloproliferative neoplasm. The driver mutations of the latter occur in the Janus kinase 2 or calreticulin genes. The coincidence of Philadelphia chromosome-negative and -positive myeloproliferative neoplasms in the same patient is exceptionally rare in the literature. During the long-term follow-up of our 120 patients with chronic myeloid leukemia, we investigated the clinical data of patients in whom Philadelphia chromosome-negative myeloproliferative disease was also confirmed. Philadelphia chromosome was detected by classical cytogenetic methods and/or fluorescence in situ hybridization. The amount of BCR-ABLI fusion RNA was monitored by quantitative real-time polymerase chain reaction. Mutations in the Janus kinase 2 and calreticulin genes were detected by quantitative allele-specific polymerase chain reaction and fragment analysis. The dynamics of disease development were inferred from the change in the amount of mutant clones over time and from the clinical data. We identified four cases carrying both Philadelphia chromosome and Janus kinase 2/calreticulin gene mutation. In some cases, competition between the clones, in other cases their co-occurrence in a common clone was observed. Isolated thrombocytosis at the time of diagnosis or persisting thrombocytosis during targeted therapy with good molecular response may call attention to the possibility of the co-occurrence of the two diseases. Co-occurrence of Philadelphia chromosome-positive and -negative myeloproliferative neoplasms is more frequent than the literature suggests. If the disease has an unusual appearance, the association of the two myeloproliferative dieseases may be suspected.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Transtornos Mieloproliferativos , Trombocitose , Calreticulina/genética , Calreticulina/uso terapêutico , Humanos , Hibridização in Situ Fluorescente , Janus Quinase 2/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Mutação , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Cromossomo FiladélfiaRESUMO
One characteristic type of the common somatic mutations causing myeloproliferative neoplasias is the frameshift mutation of the calreticulin gene that leads to proteins of abnormal structure. The pathologic protein induces novel cell biological processes that are fundamental to the onset and maintenance of myeloproliferative diseases. In this review, an insight is provided into these processes, aiding better understanding of the underlining pathobiological processes and eventually to more effective therapy in the future.
Assuntos
Calreticulina , Transtornos Mieloproliferativos , Calreticulina/genética , Calreticulina/metabolismo , Mutação com Ganho de Função , Humanos , Mutação , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Transtornos Mieloproliferativos/patologiaRESUMO
Összefoglaló. Az autoimmun lymphoproliferativ szindróma egy ritka, immundeficientiával járó genetikai betegség. Hátterében az extrinszik apoptotikus útvonal génjeinek örökletes vagy szerzett mutációi és a következményesen kialakuló, aktivált lymphocyták negatív szelekciójának a defektusa áll. Az autoimmun lymphoproliferativ szindróma klinikai megjelenésére jellemzo a jóindulatú lymphocytaburjánzás következtében kialakuló lymphadenopathia és lépmegnagyobbodás. Gyakran társul olyan autoimmun kórképekkel, mint az autoimmun haemolyticus anaemia vagy az autoimmun thrombocytopenia. A betegségben jellemzo laboratóriumi eltérések a következok: az αß+ CD4-/CD8- kettos negatív T-sejtek szaporulata, a szolúbilis Fas-ligand, az interleukin-10 és interleukin-18, valamint a B12-vitamin szérumszintjének emelkedése. A kórkép diagnózisához hozzátartozik az in vitro Fas-mediált apoptózis funkciójának vizsgálata, valamint a genetikai vizsgálat. Differenciáldiagnosztikai szempontból fontos elkülöníteni a lymphomáktól, valamint az autoimmun lymphoproliferativ szindrómaszeru betegségektol. A kezelés alapja a társuló autoimmun kórképek tüneteinek csökkentése immunszuppresszív terápiával. Orv Hetil. 2022; 163(4): 123-131. Summary. The autoimmune lymphoproliferative syndrome is a rare genetic disorder causing immunodeficiency. In the background of the disease, germline or somatic mutations of genes participating in the extrinsic apoptotic pathway and the consequential defect in the negative selection of activated lymphocytes were discovered. The clinical appearance of autoimmune lymphoproliferative syndrome consists of non-malignant lymphoproliferation, lymphadenopathy and splenomegaly, it is frequently accompanied by autoimmune disorders such as autoimmune haemolytic anaemia or autoimmune thrombocytopenia. The main diagnostic laboratory findings of this disease are the following: an elevation in αß+, CD4-/CD8- double-negative T cell count, elevated serum levels of soluble Fas-ligand, interleukin-10, interleukin-18 and vitamin B12. Other useful laboratory tests are the in vitro Fas-mediated apoptotic functional assay and the genetic screening for gene mutations. Differential diagnosis should exclude malignant lymphoproliferation in lymphomas and non-malignant autoimmune lymphoprolipherative syndrome-like diseases. The main aim of the treatment is the amelioration of the accompanying autoimmune disease with immunosuppressive therapy. Orv Hetil. 2022; 163(4): 123-131.
