-LMMC- chronic myelomonocytic leukemia (Chronic myelomonocytic leukemia -CMML-) - Genes RUNX1, PTPN11, USP16, HIP1, ASXL1 and JAK2

Chronic myelomonocytic leukemia (CMML) is a clonal disorder that results from altered stem cell of the bone marrow and is characterized by a persistent monocitosis in peripheral blood. Clinical, hematological and morphological characteristics are heterogeneous and can vary greatly among affected individuals. According to the latest ranking of the World Health Organization (WHO) in 2008, CMML is classified in the category of "Myeloproliferative Disorders / Chronic Myeloproliferative Neoplasms" (MDS / MPN), which features both overlap.

This may be due to genetic alterations in at least six genes identified: RUNX1, PTPN11, USP16, HIP1, ASXL1 and JAK2.

The RUNX1 gene, located on the long arm of chromosome 21 (21q22.3), encodes a protein transcription factor which interacts with the core binding factor beta or CBF? (encoded from CBFB gene), which contributes to the RUNX1 protein binds DNA and avoid decomposition. Together, these proteins form a version of a complex known as core binding factor (CBF). The RUNX1 protein activates genes that help control hematopoiesis. In particular, it plays an important role in the development of hematopoietic stem cells. Translocations and other types of mutations involving the RUNX1 gene have been associated with different types of leukemia and blood disorders related, including acute lymphoblastic leukemia (ALL), chronic myelomonocytic leukemia (CMML), familial platelet disorder with predisposition acute myeloid leukemia and myelodysplastic syndromes (MDS). Depending on the type of mutation, these processes may be related to an alteration in the regulation of gene activity or loss of normal function of the gene.

PTPN11 gene on the long arm of chromosome 12 (12q24) is an oncogene that encodes a two-tyrosine phosphatase with homology to Src (SHP2) containing two domains of Src homology-2 (N-SH2 C-SH2 ), and a catalytic domain phosphatase. Proteins tyrosine phosphatase family are known to be signaling molecules that regulate many cellular processes such as growth and cell differentiation, mitotic cycle and oncogenic transformation processes. SHP2, helps regulate the activation of the signaling pathway RAS / MAPK. Indeed SHP2 is a key component of many signal transduction pathways that control development processes protein, including the formation of cardiac semilunar valves and hematopoietic cell differentiation. Besides chronic myelomonocytic leukemia, somatic mutations in the PTPN11 gene are also associated with other blood disorders such as myelodysplastic syndrome, nonsyndromic acute myeloid leukemia, acute lymphocytic leukemia and juvenile myelomonocytic leukemia. Mutations in the PTPN11 gene result encoding a protein SHP2, overactive and disrupts pathways that control production of immature blood cells. As a result, overproduce certain white blood cells, leading to this type of leukemia.

Besides genetic alterations described above, we have identified certain chromosomal aberrations responsible for chronic myelomonocytic leukemia. Among them, in the USP16 gene, located on the long arm of chromosome 21 (21q22.11), investment inv (21) (q21; q22) with RUNX1 / AML1; in HIP1 gene, located on the long arm of chromosome 7 (7q11.23), t (5; 7) (q33; q11.2) with PDGFRB; and changes in the ASXL1 gene located on long arm of chromosome 20 (20q11). Furthermore, somatic mutation, V617F, in the 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 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 myelomonocytic leukemia (3-15%).

In general, chronic myelomonocytic leukemia (CMML) is not inherited but arises from genetic changes that occur in body cells after fertilization.

Tests performed in IVAMI: in IVAMI perform mutation detection associated with the development of myeloproliferative neoplasms or chronic myelomonocytic leukemia (CMML), by complete PCR amplification of the exons of the RUNX1, PTPN11, USP16, HIP1, ASXL1 and JAK2 genes, respectively, and subsequent sequencing.

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).