Dissection of PIM serine/threonine kinases in FLT3-ITD–induced leukemogenesis reveals PIM1 as regulator of CXCL12–CXCR4-mediated homing and migration

Grundler, Rebekka; Brault, Laurent; Gasser, Christelle; Bullock, Alex N.; Dechow, Tobias; Woetzel, Sabine; Pogačić, Vanda; Villa, Antonello; Ehret, Sabine; Berridge, G.; Spoo, Anke; Dierks, Christine; Biondi, Andrea; Knapp, Stefan; Duyster, Justus; Schwaller, Juerg

doi:10.1083/jcb1864oia7

Cited by 36 publications

(64 citation statements)

References 18 publications

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“…30 We and others have previously shown that transplantation of retroviral FLT3-ITD expressing progenitors can cause a myeloproliferative disease in vivo. 14,15 In contrast to those experiments, we here transplanted in vitro selected and expanded progenitors. As shown in Figures 1B and 2, expression of FLT3-ITD alone resulted in a poor selfrenewal capacity and was associated with differentiation of bone marrow progenitors towards monocytes/ macrophages and mast cells, which most probably abrogated their leukemogenic potential in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…15,23 In vitro transduction, proliferation and immortalization assays 1.5 × 10 5 lineage-surface marker negative (Lin-) bone marrow cells (MagCellect Kit, R&D systems, Minneapolis, USA) from 6-10 week old Balb/C or C57BL/6 mice were transduced with retrovirus on a 48-well fibronectin-coated plate according to the manufacturer's protocol (Retronectin TM , TaKaRa, Bio Inc., Shiga, Japan). The cells were selected with neomycin (0.8 mg/mL, Life Technologies, Paisley, UK) and cultured in medium containing murine stem cell factor (mSCF), FLT3 ligand, IL-11, thrombopoietin (PeproTech, Rocky Hill, NJ, USA).…”

Section: Retroviral Expression Vectorsmentioning

confidence: 99%

“…[7][8][9][10][11][12][13] Several studies have shown that FLT3-ITD alone can cause a myeloproliferative disorder in mice, but is not sufficient to induce AML. [14][15][16] NUP98-NSD1 is the product of a cytogenetically silent chromosomal translocation t(5;11) (q35;p15.5) that generates a fusion between the N-terminus of nucleoporin 98 (NUP98) and the C-terminal part of the nuclear receptor-binding SETdomain-containing protein NSD1. NUP98-NSD1 is the most frequent gene fusion in cytogenetically normal (CN) pediatric AML, and is generally associated with an aggressive disease and poor prognosis.…”

Section: Introductionmentioning

confidence: 99%

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Potent co-operation between the NUP98-NSD1 fusion and the FLT3-ITD mutation in acute myeloid leukemia induction

2014

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The NUP98-NSD1 fusion, product of the t(5;11)(q35;p15.5) chromosomal translocation, is one of the most prevalent genetic alterations in cytogenetically normal pediatric acute myeloid leukemias and is associated with poor prognosis. Co-existence of an FLT3-ITD activating mutation has been found in more than 70% of NUP98-NSD1-positive patients. To address functional synergism, we determined the transforming potential of retrovirally expressed NUP98-NSD1 and FLT3-ITD in the mouse. Expression of NUP98-NSD1 provided mouse strain-dependent, aberrant self-renewal potential to bone marrow progenitor cells. Co-expression of FLT3-ITD increased proliferation and maintained self-renewal in vitro. Transplantation of immortalized progenitors co-expressing NUP98-NSD1 and FLT3-ITD into mice resulted in acute myeloid leukemia after a short latency. In contrast, neither NUP98-NSD1 nor FLT3-ITD single transduced cells were able to initiate leukemia. Interestingly, as reported for patients carrying NUP98-NSD1, an increased Flt3-ITD to wild-type Flt3 mRNA expression ratio with increased FLT3-signaling was associated with rapidly induced disease. In contrast, there was no difference in the expression levels of the NUP98-NSD1 fusion or its proposed targets HoxA5, HoxA7, HoxA9 or HoxA10 between animals with different latencies to develop disease. Finally, leukemic cells co-expressing NUP98-NSD1 and FLT3-ITD were very sensitive to a small molecule FLT3 inhibitor, which underlines the significance of aberrant FLT3 signaling for NUP98-NSD1-positive leukemias and suggests new therapeutic approaches that could potentially improve patient outcome. Potent co-operation between the NUP98-NSD1 fusion and the FLT3-ITD mutation in acute myeloid leukemia induction

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Section: Discussionmentioning

confidence: 99%

Section: Retroviral Expression Vectorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Potent co-operation between the NUP98-NSD1 fusion and the FLT3-ITD mutation in acute myeloid leukemia induction

2014

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“…Pim1 knockout mice displayed defects in hematopoietic stem cell (HSC) homing to the bone marrow and the spleen by downregulation of the CXCR4 surface expression. Furthermore, PIM kinase inhibition in primary AML blasts induced downregulation of the CXCR4 receptor on the cell surface and PIM1 transcript levels correlated with CXCR4 surface expression in AML (37).…”

Section: Introductionmentioning

confidence: 99%

PIM Kinases Are Essential for Chronic Lymphocytic Leukemia Cell Survival (PIM2/3) and CXCR4-Mediated Microenvironmental Interactions (PIM1)

Decker

Finter

Forde

et al. 2014

Molecular Cancer Therapeutics

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Overexpression of the CXCR4 receptor is a hallmark of chronic lymphocytic leukemia (CLL) and is important for CLL cell survival, migration, and interaction with their protective microenvironment. In acute myelogenous leukemia (AML), PIM1 was shown to regulate the surface expression of the CXCR4 receptor. Here, we show that PIM (proviral integration site for Moloney murine leukemia virus) kinases 1-3 are overexpressed and that the CXCR4 receptor is hyperphosphorylated on Ser339 in CLL compared with normal lymphocytes. Furthermore, CXCR4 phosphorylation correlates with PIM1 protein expression and PIM1 transcript levels in CLL. PIM kinase inhibition with three different PIM kinase inhibitors induced apoptosis in CLL cells independent of the presence of protective stromal cells. In addition, PIM inhibition caused dephosphorylation of the CXCR4 receptor on Ser339, resulting in enhanced ligand-dependent CXCR4 internalization and reduced re-externalization after withdrawal of CXCL12. Furthermore, PIM inhibition in CLL cells blocked CXCR4 functions, such as migration toward CXCL12-or CXCL12-induced extracellular signal-regulated kinase (ERK) phosphorylation. In concordance, pretreatment of CLL cells with PIM kinase inhibitors strongly reduced homing of CLL cells toward the bone marrow and the spleen of Rag2

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“…Another promising strategy would be to target pathways that regulate receptor recycling. A recent paper (Grundler et al, 2009) suggests that PIM kinase mediates surface expression of CXCR4, which suggests that targeting PIM/FLT3 would be a more efficient therapy for targeting the bone marrow microenvironment. Thus, the use of CXCR4 inhibitors may be a potentially useful approach to overriding stromalmediated chemoresistance.…”

Section: Targeting Bone Marrow Microenvironmentmentioning

confidence: 99%

Drug resistance in mutant FLT3-positive AML

et al. 2010

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Mutant Fms-Like Tyrosine kinase-3 (FLT3), which is expressed in the leukemic cells of a subpopulation of acute myeloid leukemia (AML) patients, represents an attractive target for the therapy of AML. There are several FLT3 inhibitors presently in clinical trials with sufficient efficacy and toxicity features to warrant further testing in combination with standard therapies. However, the transient and partial responses observed in AML patients treated with FLT3 inhibitors, coupled with the discovery of drug-resistant leukemic blast cells in AML patients, have made resistance to FLT3 inhibitors a growing concern. In this study, we provide an overview of the role of mutant FLT3 in AML, FLT3 inhibitors under clinical and preclinical investigation, mechanisms of resistance to FLT3 inhibitors, and possible therapeutic approaches to overcoming this resistance.

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Dissection of PIM serine/threonine kinases in FLT3-ITD–induced leukemogenesis reveals PIM1 as regulator of CXCL12–CXCR4-mediated homing and migration

Abstract: CORRESPONDENCE

Cited by 36 publications

References 18 publications

Potent co-operation between the NUP98-NSD1 fusion and the FLT3-ITD mutation in acute myeloid leukemia induction

Potent co-operation between the NUP98-NSD1 fusion and the FLT3-ITD mutation in acute myeloid leukemia induction

PIM Kinases Are Essential for Chronic Lymphocytic Leukemia Cell Survival (PIM2/3) and CXCR4-Mediated Microenvironmental Interactions (PIM1)

Drug resistance in mutant FLT3-positive AML

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