Internal tandem duplication mutation of FLT3 blocks myeloid differentiation through suppression of C/EBPα expression

Blood ◽  
2004 ◽  
Vol 103 (5) ◽  
pp. 1883-1890 ◽  
Author(s):  
Rui Zheng ◽  
Alan D. Friedman ◽  
Mark Levis ◽  
Li Li ◽  
Edward G. Weir ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Tandem Duplication ◽  
Myeloid Differentiation ◽  
Internal Tandem Duplication ◽  
Activating Mutations ◽  
Flt3 Inhibitor ◽  
Enhancer Binding Protein ◽  
Differentiation Block ◽  
Proliferative Signaling

AbstractConstitutively activating mutations of FMS-like tyrosine kinase 3 (FLT3) occur in approximately one third of patients with acute myeloid leukemia (AML) and are associated with poor prognosis. Altered FLT3 signaling leads to antiapoptotic and proliferative signaling pathways. We recently showed that these mutations can also contribute to the differentiation arrest that characterizes leukemia. In this report we investigated the mechanism by which internal tandem duplication (ITD) mutation of FLT3 signaling blocks differentiation. Normally, myeloid differentiation requires the induction of CCAAT/enhancer-binding protein α (C/EBPα) and PU.1 expression. Expression of both genes was repressed by FLT3/ITD signaling in 32Dcl3 (32D) cells and this repression was overcome by treatment with a FLT3 inhibitor, allowing differentiation to proceed. We also observed increased expression of C/EBPα and PU.1 accompanied by signs of differentiation in 2 of 3 primary AML samples from patients with FLT3/ITD mutations receiving a FLT3 inhibitor, CEP-701, as part of a clinical trial. Forced expression of C/EBPα was also able to overcome FLT3/ITD-mediated differentiation block, further proving the importance of C/EBPα in this process.

scholarly journals Block of C/EBPα function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations

2006 ◽  
Vol 203 (2) ◽  
pp. 371-381 ◽  
Author(s):  
Hanna S. Radomska ◽  
Daniela S. Bassères ◽  
Rui Zheng ◽  
Pu Zhang ◽  
Tajhal Dayaram ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Myelogenous Leukemia ◽  
Granulocytic Differentiation ◽  
Extracellular Signal Regulated Kinase ◽  
Activating Mutations ◽  
Flt3 Inhibitor ◽  
Extracellular Signal ◽  
Enhancer Binding Protein ◽  
Acute Myelogenous ◽  
Differentiation Block

Mutations constitutively activating FLT3 kinase are detected in ∼30% of acute myelogenous leukemia (AML) patients and affect downstream pathways such as extracellular signal–regulated kinase (ERK)1/2. We found that activation of FLT3 in human AML inhibits CCAAT/enhancer binding protein α (C/EBPα) function by ERK1/2-mediated phosphorylation, which may explain the differentiation block of leukemic blasts. In MV4;11 cells, pharmacological inhibition of either FLT3 or MEK1 leads to granulocytic differentiation. Differentiation of MV4;11 cells was also observed when C/EBPα mutated at serine 21 to alanine (S21A) was stably expressed. In contrast, there was no effect when serine 21 was mutated to aspartate (S21D), which mimics phosphorylation of C/EBPα. Thus, our results suggest that therapies targeting the MEK/ERK cascade or development of protein therapies based on transduction of constitutively active C/EBPα may prove effective in treatment of FLT3 mutant leukemias resistant to the FLT3 inhibitor therapies.

A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo

Blood ◽  
2002 ◽  
Vol 99 (11) ◽  
pp. 3885-3891 ◽  
Author(s):  
Mark Levis ◽  
Jeffrey Allebach ◽  
Kam-Fai Tse ◽  
Rui Zheng ◽  
Brenda R. Baldwin ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Point Mutations ◽  
Internal Tandem Duplication ◽  
Activating Mutations ◽  
Flt3 Inhibitor

Constitutively activating internal tandem duplication (ITD) and point mutations of the receptor tyrosine kinase FLT3 are present in up to 41% of patients with acute myeloid leukemia (AML). These FLT3/ITD mutations are likely to be important because their presence is associated with a poor prognosis. Both types of mutations appear to activate the tyrosine kinase activity of FLT3. We describe here the identification and characterization of the indolocarbazole derivative CEP-701 as a FLT3 inhibitor. This drug potently and selectively inhibits autophosphorylation of wild-type and constitutively activated mutant FLT3 in vitro in FLT3/ITD-transfected cells and in human FLT3-expressing myeloid leukemia–derived cell lines. We demonstrate that CEP-701 induces a cytotoxic effect on cells in a dose-responsive fashion that parallels the inhibition of FLT3. STAT5 and ERK1/2, downstream targets of FLT3 in the signaling pathway, are inhibited in response to FLT3 inhibition. In primary leukemia blasts from AML patients harboring FLT3/ITD mutations, FLT3 is also inhibited, with an associated cytotoxic response. Finally, using a mouse model of FLT3/ITD leukemia, we demonstrate that the drug inhibits FLT3 phosphorylation in vivo and prolongs survival. These findings form the basis for a planned clinical trial of CEP-701 in patients with AML harboring FLT3- activating mutations.

Isavuconazole therapy in an FLT3 mutated acute myeloid leukemia patient receiving midostaurin: A case report

2018 ◽  
Vol 25 (4) ◽  
pp. 987-989 ◽  
Author(s):  
Eris Tollkuci
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Tandem Duplication ◽  
Cyp3a4 Inhibitor ◽  
Internal Tandem Duplication ◽  
Flt3 Inhibitor ◽  
Cyp3a4 Substrate ◽  
Cyp3a4 Inhibitors ◽  
Flt3 Internal Tandem Duplication ◽  
Acute Myeloid

Midostaurin is the first approved FMS-related tyrosine kinase 3 (FLT3) inhibitor indicated for FLT3 mutated acute myeloid leukemia. Midostaurin is a major cytochrome P450 3A4 (CYP3A4) substrate. Coadministration with a strong CYP3A4 inhibitor or inducer can lead to a potential increase or decrease in midostaurin exposure. This report describes a 43-year-old patient with FLT3-internal tandem duplication (FLT3-ITD) positive acute myeloid leukemia who initially presented with leukocytosis and concern for acute leukemia. Following the initiation of induction chemotherapy, the patient developed lung nodules concerning for a fungal infection. Isavuconazole, a moderate CYP3A4 inhibitor, was successfully initiated and maintained, while midostaurin therapy was also administered. Clinicians should be aware and exercise caution when using midostaurin with CYP3A4 inhibitors and inducers.

scholarly journals Terminal myeloid differentiation in vivo is induced by FLT3 inhibition in FLT3/ITD AML

Blood ◽  
2012 ◽  
Vol 120 (20) ◽  
pp. 4205-4214 ◽  
Author(s):  
Amy Sexauer ◽  
Alexander Perl ◽  
Xiaochuan Yang ◽  
Michael Borowitz ◽  
Christopher Gocke ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Normal Karyotype ◽  
Myeloid Differentiation ◽  
Internal Tandem Duplication ◽  
Cycle Arrest ◽  
Flt3 Inhibitor ◽  
Differentiation Block

Abstract A hallmark of cancer is the disruption of differentiation within tumor cells. Internal tandem duplication mutations of the FLT3 kinase (FLT3/ITD) occur commonly in acute myeloid leukemia (AML) and are associated with poor survival, leading to efforts to develop FLT3 kinase inhibitors. However, FLT3 inhibitors have thus far met with limited success, inducing only a clearance of peripheral blasts with minimal BM responses. Quizartinib is a novel potent and selective FLT3 inhibitor currently being studied in clinical trials. In 13 of 14 FLT3/ITD AML patients with normal karyotype treated with quizartinib, we observed terminal myeloid differentiation of BM blasts in association with a clinical differentiation syndrome. The single patient whose blasts failed to differentiate had a preexisting C/EBPα mutation and another developed a C/EBPα mutation at disease progression, suggesting a mechanism of resistance to FLT3 inhibition. In vitro, in primary blasts cocultured with human BM stroma, FLT3 inhibition with quizartinib induced cell-cycle arrest and differentiation rather than apoptosis. The present study is the first description of terminal differentiation of cancer cells in patients treated with a tyrosine kinase inhibitor. These data highlight the importance of the differentiation block in the patho-genesis of AML.

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