Acute promyelocytic leukemia with t(15;17): frequency of additional clonal chromosome abnormalities and FLT3 mutations

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) characterised by t(15;17)(q22;q21), a balanced reciprocal translocation involving PML and RARA genes. Rarely the following variant translocations are also observed: t(5;17)(q32;q12), where RARA is fused to nucleophosmin gene; t(11;17)(q13;q12), where RARA is fused to the gene nuclear matrix-associated; t(11;17)(q23;q21), where a fusion of promyelocytic zinc finger gene and RARA is formed, and dup(17q11;q21), which generates a STAT5bRARA fusion [1]. Clonal chromosomal abnormalities in addition to t(15;17), like trisomy 8 and others are observed in around 20 to 40% of cases at diagnosis [2]. The meaning of additional chromosomal aberrations is so far controversial, considering prognosis as well as a possible pathophysiologic role. Studies conducted in animal models with PML/ RARA suggest that this gene rearrangement is not sufficient for the development of APL, emphasising the importance of additional mutations [3]. Another gene that could be involved in APL leukemogenesis is FLT3, a Fms-like tyrosine kinase receptor which mutations have been observed in different AML subtypes as the internal tandem duplications (ITD), in around 18–37% of APL cases [1,4] or less frequently, the D835Y mutation [5]. The association of FLT3/ITD in APL gave rise to the proposition that it could provide a common class of cooperative mutation in the development of the disease. As previously observed by Douer [2], APL has a higher incidence among certain ethnic groups such as the Latin Americans [6]. Indeed, APL represents 21% of all cases of AML with successful karyotype in our institution, located in São Paulo, Southeast region of Brazil. This study was conducted in order to determine the frequencies of additional chromosome abnormalities and FLT3 mutations, including FLT3/ITD and D835. A putative association between cytogenetics and FLT3 mutations was also investigated. At diagnosis, bone marrow samples from 92 consecutive APL patients were enrolled in the study. Mean age was 29.5, varying from 4 months to 67 years old, with the following age distribution: 35.7% of the patients were younger than 20 years old; 55.2% were between 20 and 49 years old and only 17.2% were older than 50 years (Figure 1). There were 50 males and 42 females. Most frequent clinical symptoms were mucosal bleeding and fever. The white blood cell (WBC) count demonstrated a wide variation, from marked leukopenia (5500 leukocytes/mL) until evident leukocytosis (174.600/mL), most of them presenting circulating blasts. Hemoglobin level varied from 3.7 to 14 g/dL and platelets counts were frequently low. The APL diagnosis was made according to WHO classification and included morphology of peripheral blood and bone marrow cells and immunephenotyping with a panel of specific markers [7]. Cases included five (5.4%) microgranular variant patients. The G banding karyotype was performed as described elsewhere [8] from bone marrow samples after 24–48 h cultures. At least 20 metaphases were analysed in each case and the