FLT3 mutations in a 10 year consecutive series of 177 childhood acute leukemias and their impact on global gene expression patterns

Abstract

During 1995-2004, 209 children/adolescents were diagnosed with acute lymphoblastic or myeloid leukemia (ALL, AML) in Southern Sweden, of which 177 (85%), comprising 128 B-lineage ALL, 34 AML, and 15 T-cell ALL, could be analyzed for internal tandem duplications (ITD) and activating point mutations in the second tyrosine kinase domain (ATKD) of FLT3. Seventeen (10%) FLT3 mutations (6 ITD, 11 ATKD; mutually exclusive) were detected. None of the T-cell ALL harbored any mutations. ITD and ATKD were found in 2% and 6% of the B-lineage ALL and in 12% and 9% of the AML, being particularly common in high hyperdiploid ALL (14%), ALL (20%), and AML (23%) with 11q23/MLL rearrangements, and in AML with a normal karyotype (60%). All ATKD-positive AML with MLL rearrangements harbored the t(9;11)(p21;q23). Global gene expression data were available for 76 of the B-lineage ALL and 19 of the AML, of which 6 (8%) and 3 (16%) had FLT3 mutations, respectively. No distinct expression pattern associated with FLT3 mutations was identified.

Frequency of FLT3 mutations in childhood acute lymphoblastic leukemia

“…Point mutations within the activation loop region of the tyrosine kinase domain (D835) were identified in 2.3% (2/86) of the total ALL cases. These findings are in line with previous investigations [6,7,13].…”

“…This is in agreement with previous studies that proposed a high incidence of FLT3/AL mutations in hypediploid ALL subgroups (16-24%) [2,5,7]. More recent studies with larger patient groups, have demonstrated lower frequency of FLT3/AL mutations (14% and 7.7%, respectively) [6,13].…”

Flt3 Internal Tandem Duplication and D835 Mutations in Patients With Acute Lymphoblastic Leukemia and Its Clinical Significance

“…As this is a rare occurrence, the limited sample size of this study is the most likely cause of the difference. Similarly, neither FLT3/ITD nor FLT3/D835 mutations were evident in any case of CML transforming to ALL or in T-All (0/11) which is consistent with the study by Anderson et al 2008 (0% in 15 T-ALL patients) 13. Some larger studies have reported a low frequency of FLT3/ITD and/or FLT3/D835 mutations ranging from 3.3% to 5.5% among T-ALL patients 18,39,46…”

“…Recent studies have indicated a low overall frequency in childhood ALL (in the 1–8% range) while consistently demonstrating a higher incidence among those with MLL gene rearrangement and high hyperdiploidy 13–17. In adult ALL, FLT3 mutations are even rarer 18…”

FLT3 is implicated in cytarabine transport by human equilibrative nucleoside transporter 1 in pediatric acute leukemia

“…FLT3 mutations and overexpression have emerged as negative prognostic biomarkers in acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML) [3, 7–10]. FLT3 is expressed in the majority of ALL and AML cases, but the highest levels have been observed in ALL with MLL gene rearrangements (ALL-MLL+) and hyperdiploid ALL (51–67 chromosomes, HeH) [6, 10]. FLT3 overexpression correlates with unfavorable prognosis in adult AML cases as well as in infant leukemias [8].…”