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

Abstract

There is barely any information about the prognostic significance of FLT3 expression and mutational status in cytogenetically distinct subgroups of acute lymphoblastic leukemia (ALL). We analyzed the presence of FLT3-tyrosine kinase domain (TKD) and FLT3-internal tandem duplication (ITD) mutations as well as FLT3 expression levels in 54 newly diagnosed patients with B-ALL (n ¼ 49) or T-ALL (n ¼ 5). All B/T-ALL samples tested negative for the presence of FLT3-TKD or FLT3-ITD. None of the T-ALL and E2A-PBX1 þ B-ALL overexpressed FLT3. In contrast, mainly MLL-AF4 þ B-ALL but also ETV6-RUNX1 þ , BCR-ABL þ or B-ALL displaying normal cytogenetics exhibited significantly higher FLT3 expression levels than normal bone marrow, supporting that aberrantly increased transcription of FLT3, rather than activating FLT3 mutations, contributes to the pathogenesis of these B-ALL. Using the median FLT3 expression as cut-off value we found that high-level FLT3 expression is associated with an extremely poor 1-year overall survival (OS; 0 vs 71%; P ¼ 0.002) and disease-free survival (DFS; 0 vs 43%; P ¼ 0.03) in MLL-AF4 þ B-ALL but not in MLL-germline B-ALL. Cox regression analysis with OS/DFS as end points showed that age414 years and high-level FLT3 expression were independent prognostic factors when all ALL patients were analyzed together. Importantly, when the MLL-AF4 þ B-ALL subgroup was analyzed separately, high-level FLT3 expression was the only independent prognostic factor for OS and treatment outcome. These findings indicate that high FLT3 expression identifies MLL-AF4 þ ALL patients at very high risk of treatment failure and poor survival, emphasizing the value of ongoing/future clinical trials for FLT3 inhibitors.

FLT3 activation cooperates with MLL-AF4 fusion protein to abrogate the hematopoietic specification of human ESCs

“…Several other groups suggest, however, that FLT3 mutations are not common in MLL-AF41 pro-B-ALL, and that an increased transcriptional expression of FLT3 may act as a secondary cooperating hit. 17,[19][20][21] The latter is supported by Guenther et al 19 , who reported that FLT3 is a direct transcriptional target of MLL-AF4.…”

“…Moreover, it was shown that other MLL-rearranged leukemias display FLT3 mutations (FLT3-tyrosine kinase domain [TKD] or FLT3-internal tandem duplication [ITD]) in up to 20% of the cases, suggesting that they may represent candidate cooperating events. [15][16][17] Accordingly, Yamaguchi et al 18 have reported that FLT3-TKD cooperates with MLL-AF4 to induce in vitro aggressive proliferation of the mouse cell line 32Dc. Several other groups suggest, however, that FLT3 mutations are not common in MLL-AF41 pro-B-ALL, and that an increased transcriptional expression of FLT3 may act as a secondary cooperating hit.…”

“…17 cDNA was used for conventional (MLL-AF4) and quantitative (FLT3) polymerase chain reaction (PCR). MLL-AF4 expression was confirmed using the following primers (Fw:59-C AGGTCCAGAGCAGAGCAAAC-39 and Rw:59-GAGCACTTGGAGGT GCAGATG-39) and PCR conditions (95°C for 10 minutes followed by 40 cycles of 95°C for 15 seconds and 60°C for 60 seconds).…”

Activated KRAS Cooperates with MLL-AF4 to Promote Extramedullary Engraftment and Migration of Cord Blood CD34+ HSPC But Is Insufficient to Initiate Leukemia

“…In sharp contrast with its dismal clinical evolution, independent recent WGSeq studies have revealed a silent mutational landscape in MLL-r infant B-ALL (9-12), supporting the possibility that MA4 functions as a single oncogenic driver that suffices to spawn aggressive B-ALL. Despite the paucity of mutations observed in WGSeq studies, activation of FLT-3 and/or RAS was subclonally found in 30% to 50% of patients (9)(10)(11)(12) and correlated with poor outcome (36,47). Using CB-CD34…”

A Phase I Study of Quizartinib Combined with Chemotherapy in Relapsed Childhood Leukemia: A Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study

“…Therefore, the current standard of care for children with FLT3-ITD mutations is intensive induction chemotherapy followed by hematopoietic stem cell transplantation (HSCT). High levels of FLT3 wild-type receptor (FLT3-WT) also promote constitutive activation of the FLT3 receptor and carry poor prognosis similar to those with FLT3-ITD mutations (7,8). Among children with AML, about 30 percent have FLT3 disease: FLT3-ITD mutations (15%), kinase domain (KD) mutations (5%), or overexpression of FLT3-WT (10%; refs.…”