Axl, a prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of leukemia cells with bone marrow stroma

Ben-Batalla, Isabel; Schultze, Alexander; Wroblewski, Mark; Erdmann, Robert; Heuser, Michael; Waizenegger, Jonas; Riecken, Kristoffer; Binder, Mascha; Schewe, Denis; Sawall, Stefan; Witzke, Victoria; Cubas-Cordova, Miguel; Janning, Melanie; Wellbrock, Jasmin; Fehse, Boris; Hagel, Christian; Krauter, Jürgen; Ganser, Arnold; Lorens, James B.; Fiedler, Walter; Carmeliet, Peter; Pantel, Klaus; Bokemeyer, Carsten; Loges, Sonja

doi:10.1182/blood-2013-03-491431

Cited by 184 publications

(214 citation statements)

References 46 publications

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“…In these models, the tumor microenvironment stimulated the upregulation of GAS6 in leukocytes, which in turn mediate the growth and metastasis of GAS6-deficient tumor cells. Similar findings were observed in AML cells (45). Thus, our findings indicate that sAXL therapy may inhibit both autocrine and paracrine GAS6/AXL signaling in tumors.…”

Section: Discussionsupporting

confidence: 77%

Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET

Rankin

Fuh

Castellini

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

242

210

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Dysregulation of the von Hippel-Lindau/hypoxia-inducible transcription factor (HIF) signaling pathway promotes clear cell renal cell carcinoma (ccRCC) progression and metastasis. The protein kinase GAS6/AXL signaling pathway has recently been implicated as an essential mediator of metastasis and receptor tyrosine kinase crosstalk in cancer. Here we establish a molecular link between HIF stabilization and induction of AXL receptor expression in metastatic ccRCC. We found that HIF-1 and HIF-2 directly activate the expression of AXL by binding to the hypoxia-response element in the AXL proximal promoter. Importantly, genetic and therapeutic inactivation of AXL signaling in metastatic ccRCC cells reversed the invasive and metastatic phenotype in vivo. Furthermore, we define a pathway by which GAS6/AXL signaling uses lateral activation of the met proto-oncogene (MET) through SRC proto-oncogene nonreceptor tyrosine kinase to maximize cellular invasion. Clinically, AXL expression in primary tumors of ccRCC patients correlates with aggressive tumor behavior and patient lethality. These findings provide an alternative model for SRC and MET activation by growth arrest-specific 6 in ccRCC and identify AXL as a therapeutic target driving the aggressive phenotype in renal clear cell carcinoma.targeted therapy | kidney cancer | VHL | hepatocellular carcinoma K idney cancer is a leading cause of cancer-related deaths in the United States. Metastasis to distant organs including the lung, bone, liver, and brain is the primary cause of death in kidney cancer patients, as only 12% of patients with metastatic kidney cancer will survive past 5 y, in comparison with 92% of patients with a localized disease (1). Because kidney cancer is chemo-and radiation-resistant, targeted therapies are needed for the prevention and management of metastatic kidney cancer.The von Hippel-Lindau (VHL)-hypoxia-inducible transcription factor (HIF) pathway is a critical regulator of clear cell renal cell carcinoma (ccRCC) tumor initiation and metastasis. VHL is a classic tumor suppressor controlling tumor initiation in ∼90% of ccRCC tumors (2, 3). VHL is the substrate recognition component of an E3 ubiquitin ligase complex containing the elongins B and C (4, 5), Cullin-2 (6), and Rbx1 (7) that targets the hydroxylated, oxygen-sensitive α-subunits of HIFs (HIF-1, -2, and -3) for ubiquitination and degradation by the 26S proteasome (8, 9). Thus, the primary function ascribed to VHL is the regulation of HIF protein stability. In VHL-deficient tumors, HIF transcriptional activity is constitutively active and contributes to both ccRCC tumor initiation and metastasis (8-11). Although many downstream HIF targets controlling ccRCC tumor initiation have been defined, key targets involved in ccRCC metastasis remain to be identified.AXL, a member of the TAM family of receptor tyrosine kinases (RTKs), has recently been described as an essential mediator of cancer metastasis. Additionally, AXL has been reported to mediate RTK crosstalk and resistance to targeted kina...

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Section: Discussionsupporting

confidence: 77%

Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET

Rankin

Fuh

Castellini

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

242

210

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“…The contribution of MDMs to hematoma resolution and the effect on disease progression requires further investigation in other models. AXL and MERTK function are critical to immune homeostasis (20) and have been shown to promote immunoregulatory functions in infection (76), atherosclerosis (28), cancer (77), and autoimmune disease (78). Notably, these receptors have been implicated in controlling inflammatory responses in the CNS, including in multiple sclerosis (79) and Parkinson's disease (55), suggesting that they may direct immune function in a wide range of neurological diseases.…”

Section: Discussionmentioning

confidence: 99%

Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage

Chang¹,

Goods²,

Askenase³

et al. 2017

Journal of Clinical Investigation

138

161

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-/-bone marrow chimeras (BMCs) at days 7 and 15 after ICH. Right: Quantification of residual hematoma volume in the WT and Ccr2 -/-BMCs. n = 11 at day 7; n = 9 at day 15. *P < 0.05 by Student's t test. (B) Cylinder test and apomorphine turning test from WT and Ccr2 -/-BMCs at day 15 after ICH. n = 6/group for cylinder test; n = 8/ group for apomorphine turning test. *P < 0.05 by Student's t test. (C) Cylinder test, neurological deficit score, and corner test in control-and anti-CCR2 antibody-treated mice at days 1 and 3 after collagenase ICH. n = 7/group. *P < 0.05 by 1-way repeated-measures ANOVA and Bonferroni's post hoc test. (D) Top: Representative coronal sections show hematoma from control-and anti-CCR2 antibody-treated WT mice after blood injection ICH at 7 days. Bottom: Quantification of hematoma volume, n = 3/ group. *P < 0.05 versus control by Student's t test. (E) Top: Representative coronal sections show hematoma in the isotype control-and anti-CCR2 antibody-treated mice from collagenase model at day 12. Bottom: Quantification of hematoma volume. n = 8/group. *P < 0.05 versus control by Student's t test. (F) The cylinder test, neurological deficit score, and corner test in isotype control-and anti-CCR2 antibody-treated ICH mice at days 3, 5, 7, 9, and 11 after collagenase ICH surgery. n = 8/group. *P < 0.05 versus isotype control group by 1-way repeated-measures ANOVA and Bonferroni's post hoc test. αCCR2, anti-CCR2 antibody.

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“…Gas6, a major activator of Mer signaling, is usually secreted in the bone marrow and considered a pro-proliferative signal. 1,12 In contrast to MSC cells, U343 cells did not secrete Gas6 ( Figure 3A). No paracrine effects between ALL and U343 cells potentiating Gas6 secretion 1 could be observed as supernatants of U343 cocultures contained low or no Gas6 (supplemental Figure 2A).…”

Section: Expression Of Mer In All Cell Lines Correlates With a Quiescmentioning

confidence: 99%

“…[1][2][3] The TAM receptor family consists of Tyro3, Axl, and Mer 4 which all have been found to have transforming properties. [5][6][7] Mer expression has been shown on macrophages, natural killer (NK) cells, dendritic cells, megakaryocytes, and platelets, 8 but it is not known to be present on normal T and B lymphocytes at any stage of differentiation.…”

Section: Introductionmentioning

confidence: 99%

Mer tyrosine kinase promotes the survival of t(1;19)-positive acute lymphoblastic leukemia (ALL) in the central nervous system (CNS)

Krause¹,

Pfeiffer²,

Strube³

et al. 2015

Blood

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Key Points• Mer mediates quiescence and chemotherapy resistance in a CNS coculture model and causes CNS infiltration in immunodeficient mice.• Mer expression correlates with CNS positivity upon initial diagnosis in t(1;19)-positive pediatric ALL patients.Patients with t(1;19)-positive acute lymphoblastic leukemia (ALL) are prone to central nervous system (CNS) relapses, and expression of the TAM (Tyro3, Axl, and Mer) receptor Mer is upregulated in these leukemias. We examined the functional role of Mer in the CNS in preclinical models and performed correlative studies in 64 t(1;19)-positive and 93 control pediatric ALL patients. ALL cells were analyzed in coculture with human glioma cells and normal rat astrocytes: CNS coculture caused quiescence and protection from methotrexate toxicity in Mer high ALL cell lines, which was antagonized by short hairpin RNA-mediated knockdown of Mer. Mer expression was upregulated, prosurvival Akt and mitogen-activated protein kinase signaling were activated, and secretion of the Mer ligand Galectin-3 was stimulated. Mer high t(1;19) primary cells caused CNS involvement to a larger extent in murine xenografts than in their Mer low counterparts.Leukemic cells from Mer high xenografts showed enhanced survival in coculture.Treatment of Mer high patient cells with the Mer-specific inhibitor UNC-569 in vivo delayed leukemia onset, reduced CNS infiltration, and prolonged survival of mice. Finally, a correlation between high Mer expression and CNS positivity upon initial diagnosis was observed in t(1;19) patients. Our data provide evidence that Mer is associated with survival in the CNS in t(1;19)-positive ALL, suggesting a role as a diagnostic marker and therapeutic target. (Blood. 2015;125(5):820-830) Introduction TAM (Tyro3, Axl, and Mer) receptors have been advocated as therapeutic targets in human cancers including leukemia. 1-3 The TAM receptor family consists of Tyro3, Axl, and Mer 4 which all have been found to have transforming properties. [5][6][7] Mer expression has been shown on macrophages, natural killer (NK) cells, dendritic cells, megakaryocytes, and platelets, 8 but it is not known to be present on normal T and B lymphocytes at any stage of differentiation. Aberrant Mer expression was detected in not only acute myeloid leukemia (AML), 9 but also lymphocytic malignancies as T-cell acute lymphoblastic leukemia (T-ALL).10 Studies overexpressing Mer in fibroblasts found that it can induce extracellular signalregulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38, nuclear factor-kB (NF-kB) and enhance cell survival via phosphatidylinositol 3-kinase (PI3K)/AKT. 2,11 Linger et al 12 reported that Mer is overexpressed on pre-B-cell ALL (B-ALL) cells of pediatric patients with t(1;19)(q23;p13) translocation. Furthermore, inhibition of Mer by RNA interference (RNAi) reduced survival and chemoresistance of pre-B-ALL cell lines and prolonged survival of xenografts.12 Pediatric ALL with t(1;19)(q23;p13) translocation is found in about 3% to 5% of ALL patients and has ...

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Axl, a prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of leukemia cells with bone marrow stroma

Abstract: Key Points Axl inhibition by BGB324 is active in FLT3-mutated and FLT3 wild-type AML, and presence of Axl and Gas6 are required for therapeutic efficacy. AML cells educate BMDSCs to secrete Gas6, which mediates leukemia cell proliferation and therapy resistance.

Cited by 184 publications

References 46 publications

Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET

Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET

Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage

Mer tyrosine kinase promotes the survival of t(1;19)-positive acute lymphoblastic leukemia (ALL) in the central nervous system (CNS)

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