Tandem duplication of the FLT3 gene is found in acute lymphoblastic leukaemia as well as acute myeloid leukaemia but not in myelodysplastic syndrome or juvenile chronic myelogenous leukaemia in children

Abstract

We examined mRNA expression and internal tandem duplication of the Fms-like tyrosine kinase 3 (FLT3) gene in haematological malignancies by reverse transcriptase-polymerase chain reaction (RT-PCR) and genomic PCR followed by sequencing. By RT-PCR, expression of FLT3 was detected in 45/74 (61%) leukaemia cell lines and the frequency of expression of FLT3 was significantly higher in undifferentiated type (B-precursor acute lymphoblastic leukaemia; ALL) than in differentiated type cell lines (B-ALL) (P = 0.0076). Using the genomic PCR method, 194 fresh samples including 87 acute myeloid leukaemias, 60 ALLs, 32 myelodysplastic syndromes (MDSs) and 15 juvenile chronic myelogenous leukaemias (JCMLs) were examined. Tandem duplication was found in 12 (13.8%) AMLs and two (3.3%) ALLs. Sequence analyses of the 14 samples with the duplication revealed that eight showed a simple tandem duplication and six a tandem duplication with insertion. Most of these tandem duplications occurred within exon 11, and two duplications occurred from exon 11 to intron 11 and exon 12. No tandem duplications of FLT3 gene were detected in MDS or JCML. The frequency of tandem duplication of FLT3 gene in childhood AML was lower than that in adult AML so far reported. All of the 12 AML patients with the duplication died within 47 months after diagnosis, whereas two ALL patients with the duplication have survived 44 and 72 months, respectively. These two ALL patients expressed both lymphoid and myeloid antigens and were considered to have biphenotypic leukaemia. These results suggest that tandem duplication is involved in ALL in addition to AML, but not in childhood MDS or JCML, and that childhood AML patients with the tandem duplication have a poor prognosis.

Mutations of FLT3, NRAS, KRAS, and PTPN11 are frequent and possibly mutually exclusive in high hyperdiploid childhood acute lymphoblastic leukemia

“…In ALL, ITDs are very rare, with only a handful of pediatric cases having been reported (Xu et al, 1999;Yamamoto et al, 2006). In contrast, 7-9% of the cases harbor Asp835/Ile836 mutations, with an increased frequency in infant ALLs with translocations involving the MLL gene and in high hyperdiploid cases.…”

Biological characteristics and prognosis of adult acute myeloid leukemia with internal tandem duplications in the Flt3 gene

“…In ALL, Flt3/ITDs have only been reported in two patients which at closer examination were considered to be biphenotypic leukemia. 20 Though Flt3/ITDs are also observed in childhood AML their frequency is significantly lower when compared to adult AML. Frequencies reported for the Japanese childhood AML population vary between 11% (Kondo et al, seven out of 64 cases studied) 21 and 5.3% (Iwai et al, five out of 94 cases studied).…”

Prognostic significance of FLT3 mutational status and expression levels in MLL-AF4+ and MLL-germline acute lymphoblastic leukemia

“…Several groups reported the presence of FLT3/tyrosine kinase domain (TKD) mutations in 3-20% of MLL-rearranged ALLs, 6,[12][13][14] whereas Stam et al 15,16 together with Bardini et al, 17,18 using high-resolution genomic analysis, showed that FLT3 mutations in MLL-rearranged ALLs do not occur. Despite this emerging controversy, FLT3 is consistently highly expressed in MLLrearranged ALL, and therefore it is not fully resolved whether the constitutive activation of FLT3 in MLL-rearranged ALL is due to the presence of activating FLT3 mutations, or simply due to a transcriptional increased expression of FLT3 in an attempt to provide blast cells with survival and proliferative advantage.…”