Chronic neutrophilic leukemia (Chronic neutrophilic leukemia -CNL-) - Genes JAK2 and CSF3R

Chronic neutrophilic leukemia is a rare disease classified in chronic myeloproliferative neoplasms. Figures and their impact forecasts vary widely, partly because of the difficulties of diagnosis. But in any case, the prognosis is usually poor, with an average age of diagnosis of 63 years and a median survival around two years (28% have increased survival of 5 years). Generally, diagnosis is made by exclusion. The presence of persistent neutrophilia, splenomegaly and hyperplasia of the affected bone marrow without evidence of chronic myeloid leukemia or basophilia valued.

Somatic mutation V617F JAK2 gene, located on the short arm of chromosome 9 (9p24), affects a highly conserved domain (JH2) involved in negative regulation and therefore causes uncontrolled activation of the tyrosine kinase encoded by JAK2, whose function is key signal transduction multiple recipients hematopoietic growth factors. This mutation has been widely detected in some myeloproliferative neoplasms - see myeloproliferative neoplasms (Polycythemia vera, Essential thrombocytosis, idiopathic myelofibrosis) -gene JAK2- and also manifested in some cases of chronic neutrophilic leukemia (20% of patients). Detection of this genetic alteration can be important because JAK2 is a promising candidate for targeted and specific, yet investigational molecular therapies.

Recently, we have identified somatic mutations in the CSF3R gene, located on the short arm of chromosome 1 (1p35-p34.3). The protein encoded by this gene is the receptor for colony stimulating factor 3, a cytokine that controls the production, differentiation and function of granulocytes. The encoded protein, which is a member of the family of cytokine receptors, may also act in some processes of adhesion or recognition of the cell surface. The most common genetic mutation CSF3R identified in affected individuals, approximately 76% of cases, T618I mutation is affecting the extracellular domain (exon 14). In an identified for mutation T618I patient a mutation was also identified in exon 17 (2341_2342insC; cytoplasmic domain), which introduces a stop codon 7 residues from the insertion site. Other mutations identified include I598I and M696T.

Genetic changes that lead to the development of chronic neutrophilic leukemia, arising from somatic mutations occurring in the body cells after conception, which means that are acquired during the lifetime of a person and are present only in certain types cell.

Tests in IVAMI: IVAMI performed in detecting mutations associated with the development of chronic neutrophilic leukemia (CNL), by complete PCR amplification of the exons of JAK2 and CSF3R genes, respectively, and subsequent sequencing. It is recommended to begin the study by exon 14, where found most genetic abnormalities and, in case of negative result, the study of exon 12, where there have been other mutations associated suggested JAK2 some of these disorders . If not, it is recommended to continue the study for exon 14 and 17 of the CSF3R gene, where the most frequent genetic alterations are located.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).