FLT3-ITD and TLR9 use Bruton tyrosine kinase to activate distinct transcriptional programs mediating AML cell survival and proliferation

Oellerich, Thomas; Mohr, Sebastian; Corso, Jasmin; Beck, Julia; Döbele, Carmen; Braun, Helene; Cremer, Anjali; Münch, Silvia; Wicht, Johannes; Oellerich, Mark F.; Bug, Gesine; Bohnenberger, Hanibal; Perske, Christina; Schütz, Ekkehard; Urlaub, Henning; Serve, Hubert

doi:10.1182/blood-2014-06-585216

Cited by 53 publications

(49 citation statements)

References 21 publications

(27 reference statements)

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“…However, the transient initial clinical response is followed by the appearance of resistant blasts. Recent efforts to identify alternative targets in FLT3-ITD AML lead to the identification of candidates such as PU.1 [21], NFATc1 [22], SIRT1 [23], PIM [24], FES [25], SYK [26], and BTK [27]. We describe here an essential pathway downstream of FLT3-ITD in AML cells.…”

Section: Discussionmentioning

confidence: 99%

An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia

et al. 2016

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CDK4/CDK6 and RB proteins drive the progression through the G1 phase of the cell cycle. In acute myeloid leukemia (AML), the activity of the CDK/Cyclin D complex is increased. The mechanism involved is unknown, as are the respective roles played by CDK4 or CDK6 in this process. Here, we report that AML cells carrying FLT3-ITD mutations are dependent on CDK6 for cell proliferation while CDK4 is not essential. We showed that FLT3-ITD signaling is responsible for CDK6 overexpression, through a pathway involving the SRC-family kinase HCK. Accordingly, FLT3-ITD failed to transform primary hematopoietic progenitor cells from Cdk6−/− mice. Our results demonstrate that CDK6 is the primary target of CDK4/CDK6 inhibitors in FLT3-ITD positive AML. Furthermore, we delineate an essential protein kinase pathway -FLT3/HCK/CDK6- in the context of AML with FLT3-ITD mutations.

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Section: Discussionmentioning

confidence: 99%

An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia

et al. 2016

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“…Lastly, KLF4 expression decreased BTK expression. BTK expression has recently been implicated in FLT3-ITD-dependent MYC activation in AML (64). It is possible that KLF4's effects on MYC expression are mediated in part by decreased BTK expression.…”

Section: Discussionmentioning

confidence: 99%

Deregulated KLF4 Expression in Myeloid Leukemias Alters Cell Proliferation and Differentiation through MicroRNA and Gene Targets

Morris

Cummings

Korb

et al. 2016

Molecular and Cellular Biology

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bAcute myeloid leukemia (AML) is characterized by increased proliferation and blocked differentiation of hematopoietic progenitors mediated, in part, by altered myeloid transcription factor expression. Decreased Krüppel-like factor 4 (KLF4) expression has been observed in AML, but how decreased KLF4 contributes to AML pathogenesis is largely unknown. We demonstrate decreased KLF4 expression in AML patient samples with various cytogenetic aberrations, confirm that KLF4 overexpression promotes myeloid differentiation and inhibits cell proliferation in AML cell lines, and identify new targets of KLF4. We have demonstrated that microRNA 150 (miR-150) expression is decreased in AML and that reintroducing miR-150 expression induces myeloid differentiation and inhibits proliferation of AML cells. We show that KLF family DNA binding sites are necessary for miR-150 promoter activity and that KLF2 or KLF4 overexpression induces miR-150 expression. miR-150 silencing, alone or in combination with silencing of CDKN1A, a well-described KLF4 target, did not fully reverse KLF4-mediated effects. Gene expression profiling and validation identified putative KLF4-regulated genes, including decreased MYC and downstream MYC-regulated gene expression in KLF4-overexpressing cells. Our findings indicate that decreased KLF4 expression mediates antileukemic effects through regulation of gene and microRNA networks, containing miR-150, CDKN1A, and MYC, and provide mechanistic support for therapeutic strategies increasing KLF4 expression.A cute myeloid leukemia (AML) is characterized by increased self-renewal of leukemia stem or progenitor cells and a failure of differentiation to mature myeloid cells. Normal hematopoietic cell differentiation and proliferation are regulated by the expression and interaction of specific transcription factors (1, 2), which are altered in AML (3-5). Elucidation of the genomic landscape of AML has further highlighted that alterations in myeloid transcription factors play a significant role in leukemogenesis (4). Recent attention has focused on the role of aberrant expression of the Krüppel-like factor (KLF) family of transcription factors in cancer (5). This family includes 17 different isoforms that bind to GCrich regions of DNA via three zinc finger domains and regulate the transcriptional activity of target genes by using two glutaminerich transactivation domains (5). KLF4 regulates differentiation of epidermal and vascular smooth muscle cells (6, 7), as well as cellular reprogramming to induce pluripotent stem cells (8). In normal hematopoiesis, KLF2 and KLF4 regulate myeloid differentiation and KLF4 expression induces CDKN1A (p21), which contributes to cell cycle arrest (9-13). In T-cell acute lymphoblastic leukemia (T-ALL) (14) and B-cell lymphomas, KLF4 has been described as a tumor suppressor regulating proliferation, apoptosis, and differentiation (15). A recent study showed that the homeobox transcription factor CDX2 represses KLF4 in myeloid leukemia cells (16). The investigators also observed that C...

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“…Tumor tissues were fixed and stained as described (Oellerich et al., 2015). Briefly, biopsy samples for histological stains were sliced and stained with antibodies against HOXA9 (Novus Biologicals; dilution 1:500), MEIS1 (Abcam; dilution 1:2500), PU.1/Spi1 (Abcam; dilution 1:200), SYK (Cell Signaling Technologies; dilution 1:100) and pY348-SYK (Abcam; dilution 1:100).…”

Section: Methodsmentioning

confidence: 99%

Hoxa9 and Meis1 Cooperatively Induce Addiction to Syk Signaling by Suppressing miR-146a in Acute Myeloid Leukemia

Mohr¹,

Doebele²,

Comoglio³

et al. 2017

Cancer Cell

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SummaryThe transcription factor Meis1 drives myeloid leukemogenesis in the context of Hox gene overexpression but is currently considered undruggable. We therefore investigated whether myeloid progenitor cells transformed by Hoxa9 and Meis1 become addicted to targetable signaling pathways. A comprehensive (phospho)proteomic analysis revealed that Meis1 increased Syk protein expression and activity. Syk upregulation occurs through a Meis1-dependent feedback loop. By dissecting this loop, we show that Syk is a direct target of miR-146a, whose expression is indirectly regulated by Meis1 through the transcription factor PU.1. In the context of Hoxa9 overexpression, Syk signaling induces Meis1, recapitulating several leukemogenic features of Hoxa9/Meis1-driven leukemia. Finally, Syk inhibition disrupts the identified regulatory loop, prolonging survival of mice with Hoxa9/Meis1-driven leukemia.

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FLT3-ITD and TLR9 use Bruton tyrosine kinase to activate distinct transcriptional programs mediating AML cell survival and proliferation

Cited by 53 publications

References 21 publications

An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia

An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia

Deregulated KLF4 Expression in Myeloid Leukemias Alters Cell Proliferation and Differentiation through MicroRNA and Gene Targets

Hoxa9 and Meis1 Cooperatively Induce Addiction to Syk Signaling by Suppressing miR-146a in Acute Myeloid Leukemia

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