Oncogenic Kinase Cascades Induce Molecular Mechanisms That Protect Leukemic Cell Models from Lethal Effects of De Novo dNTP Synthesis Inhibition

The ribonucleotide reductase inhibitor hydroxyurea suppresses de novo dNTP synthesis and attenuates the hyperproliferation of leukemic blasts. Mechanisms that determine whether cells undergo apoptosis in response to hydroxyurea are ill-defined. We used unbiased proteomics to uncover which pathways control the transition of the hydroxyurea-induced replication stress into an apoptotic program in chronic and acute myeloid leukemia cells. We noted a decrease in the serine/threonine kinase RAF1/c-RAF in cells that undergo apoptosis in response to clinically relevant doses of hydroxyurea. Using the RAF inhibitor LY3009120, we show that RAF activity determines the sensitivity of leukemic cells toward hydroxyurea. We further disclose that pharmacological inhibition of the RAF downstream target BCL-XL with the drug navitoclax and RNAi combine favorably with hydroxyurea against leukemic cells. BCR-ABL1 and hyperactive FLT3 are tyrosine kinases that causally contribute to the development of leukemia and induce RAF1 and BCL-XL. Accordingly, the ABL inhibitor imatinib and the FLT3 inhibitor quizartinib sensitize leukemic cells to pro-apoptotic effects of hydroxyurea. Moreover, hydroxyurea and navitoclax kill leukemic cells with mutant FLT3 that are resistant to quizartinib. These data reveal cellular susceptibility factors toward hydroxyurea and how they can be exploited to eliminate difficult-to-treat leukemic cells with clinically relevant drug combinations.

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CITED2 Affects Leukemic Cell Survival By Interfering with p53 Activation

Blood ◽

10.1182/blood.v128.22.1542.1542 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1542-1542

Author(s):

Katharina Mattes ◽

Gerbrig Berger ◽

Marjan Geugien ◽

Joost H.A. Martens ◽

Edo Vellenga ◽

...

Keyword(s):

De Novo ◽

Conflicts Of Interest ◽

Leukemic Cell ◽

Akt Signaling ◽

Leukemic Cells ◽

Dependent Manner ◽

Hematopoietic Stem ◽

Downstream Target ◽

Nsg Mice ◽

Cd34 Cells

Abstract Recently it was demonstrated that CITED2 (CBP/p300-interacting-transactivator-with-an ED-rich-tail 2) is upregulated in 70% of AML cases and that CITED2 levels are critical for the survival of leukemic stem cells. To address the role of CITED2 in leukemia maintenance, NSG mice were transplanted with human AML CD34+ cells transduced with a lentiviral construct for RNAi-mediated knockdown of CITED2. The results demonstrated that these mice had a significantly longer survival compared to mice transplanted with control AML cells (p<0.02). In order to identify the molecular pathways affected in hematopoietic stem and progenitor cells upon loss of CITED2, differential gene expression after CITED2 knockdown was analyzed using microarray. Gene ontology analysis revealed an enrichment of p53 targets among those genes. We observed increased levels of acetylated p53 and its downstream target p21 upon down-regulation of CITED2 in both primary CD34+ cord blood cells and in the leukemic cells lines NB4 and MOLM13, whereas levels of the anti-apoptotic protein BCL2 were strongly reduced. In line with these observations, we found increased levels of apoptosis in CITED2 knockdown cells, which could be rescued by simultaneous knockdown of p53. Further analysis of p53 targets by qPCR in CITED2 knockdown cells revealed an increased expression of PHLDA3. PHLDA3 is known as a repressor of the AKT signaling pathway, which promotes cell growth and survival. In line with this finding, we observed decreased AKT phosphorylation in CITED2 knockdown cells. Notably, we could rescue the CITED2 knockdown- mediated repression of AKT signaling by simultaneous knockdown of PHLDA3. Additionally, simultaneous knockdown of PHLDA3 led to a partial rescue of the apoptotic phenotype induced by CITED2 RNAi. Similar, knockdown of CITED2 in patient AML CD34+ cells (n=17) cultured on MS5 stromal layer led to impaired growth of AMLs cells, whereas a simultaneous knockdown of CITED2 and p53 could rescue this phenotype. These data suggest that de novo AML with p53 mutations will be resistant to CITED2 knockdown-mediated cell death and we currently investigate this hypothesis. Additionally, we aim to get insight into the mechanism of increased p53 acetylation and activation upon knockdown of CITED2. By performing immunoprecipitation studies, we found a mutually exclusive binding of CITED2 and p53 to p300, suggesting that knockdown of CITED2 potentially alters p300 protein stability and acetylation activity towards p53. Furthermore, ChIP-Seq data revealed that knockdown of CITED2 in AML cells causes a global increase of H3K27 acetylation, thereby providing further evidence for altered p300 activity. Our results demonstrate that knockdown of CITED2 triggers apoptosis in both normal hematopoietic- and leukemic cells in a p53-dependent manner. Therefore, CITED2 represents a highly interesting target for the treatment of p53 wild type AML patients. Disclosures No relevant conflicts of interest to declare.

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The pan-Bcl-2 inhibitor obatoclax promotes differentiation and apoptosis of acute myeloid leukemia cells

Investigational New Drugs ◽

10.1007/s10637-020-00931-4 ◽

2020 ◽

Vol 38 (6) ◽

pp. 1664-1676

Author(s):

Małgorzata Opydo-Chanek ◽

Iwona Cichoń ◽

Agnieszka Rak ◽

Elżbieta Kołaczkowska ◽

Lidia Mazur

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Treatment Strategies ◽

Leukemic Cell ◽

Leukemic Cells ◽

Dependent Manner ◽

Apoptotic Pathway ◽

Acute Myeloid Leukemia Cells ◽

Induced Apoptosis ◽

Acute Myeloid

Summary One of the key features of acute myeloid leukemia (AML) is the arrest of differentiation at the early progenitor stage of myelopoiesis. Therefore, the identification of new agents that could overcome this differentiation block and force leukemic cells to enter the apoptotic pathway is essential for the development of new treatment strategies in AML. Regarding this, herein we report the pro-differentiation activity of the pan-Bcl-2 inhibitor, obatoclax. Obatoclax promoted differentiation of human AML HL-60 cells and triggered their apoptosis in a dose- and time-dependent manner. Importantly, obatoclax-induced apoptosis was associated with leukemic cell differentiation. Moreover, decreased expression of Bcl-2 protein was observed in obatoclax-treated HL-60 cells. Furthermore, differentiation of these cells was accompanied by the loss of their proliferative capacity, as shown by G0/G1 cell cycle arrest. Taken together, these findings indicate that the anti-AML effects of obatoclax involve not only the induction of apoptosis but also differentiation of leukemic cells. Therefore, obatoclax represents a promising treatment for AML that warrants further exploration.

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Signal transduction and glycophosphatidylinositol-linked proteins (lyn, lck, CD4, CD45, G proteins, and CD55) selectively localize in Triton- insoluble plasma membrane domains of human leukemic cell lines and normal granulocytes

Blood ◽

10.1182/blood.v87.9.3783.bloodjournal8793783 ◽

1996 ◽

Vol 87 (9) ◽

pp. 3783-3794 ◽

Cited By ~ 134

Author(s):

I Parolini ◽

M Sargiacomo ◽

MP Lisanti ◽

C Peschle

Keyword(s):

Signal Transduction ◽

G Proteins ◽

Cell Lines ◽

Tyrosine Kinases ◽

Leukemic Cell ◽

Receptor Activation ◽

Leukemic Cells ◽

Human Leukemic Cell ◽

Leukemic Cell Lines ◽

B Lymphoid

Src-family nonreceptor protein tyrosine kinases (NRPTK) are associated with cell surface receptors in large detergent-resistant complexes: in epithelial cells, yes is selectively located in vesicle structures containing caveolin (“caveolae”). These formations are typically also endowed with glycophosphatidylinositol (GPI)-anchored proteins. In the present study, we observed lck, lyn, src, hck, CD4, CD45, G proteins, and CD55 (decay-accelerating factor) expression in the buoyant low- density Triton-insoluble (LDTI) fraction of selected leukemic cell lines and granulocytes. We provide a detailed analysis of the two most highly expressed NRPTK, p53/p56lyn and p56lck, which are involved in the transduction of signals for proliferation and differentiation of monocytes/B lymphocytes and T lymphocytes, respectively. We show that lyn is selectively recovered in LDTI complexes isolated from human leukemic cell lines (promyelocytic [HL-60], erythroid [K562] and B- lymphoid [697]) and from normal human granulocytes, and that lck is recovered from LDTI fractions of leukemic T- and B-lymphoid cell lines (CEM, 697). In LDTI fractions of leukemic cells, lck and lyn are enriched 100-fold as compared with the total cell lysates. Analysis of these fractions by electron microscopy shows the presence of 70- to 200- nm vesicles: lyn and lck are homogenously distributed in the vesicles, as revealed by an immunogold labeling procedure. These novel results propose a role for these vesicles in signal transduction mechanisms of normal and neoplastic hematopoietic cells. In support of this hypothesis, we further observed that molecules participating in B- and T-cell receptor activation cofractionate in the LDTI fractions, CD45/lyn (B cells) and CD45/lck/CD4 (T cells).

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A Novel Ring-Substituted Diindolylmethane 1,1-bis [3′-(5-methoxyindolyl)]-1-(p-t-butylphenyl) Methane Abrogates ERK Activation and Induces Apoptosis in Acute Myeloid Leukemia (AML).

Blood ◽

10.1182/blood.v104.11.3399.3399 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3399-3399

Author(s):

Rooha Contractor ◽

Ismael J. Samudio ◽

Zeev Estrov ◽

David Harris ◽

James A. McCubrey ◽

...

Keyword(s):

Cell Death ◽

Molecular Mechanisms ◽

Leukemic Cell ◽

Leukemic Cells ◽

Caspase 9 ◽

Apoptotic Pathway ◽

Erk Activation ◽

New Class ◽

Induced Apoptosis ◽

Extracellular Regulated Kinase

Abstract We investigated the antileukemic activity and molecular mechanisms of action of a newly synthesized ring-substituted diindolylmethane (DIM) derivative, named, 1,1-bis [3′-(5-methoxyindolyl)]-1-(p-t-butylphenyl) methane (DIM #34), in myeloid leukemic cells. DIM #34 inhibited leukemic cell growth via induction of apoptosis. DIM #34 inhibited clonogenic growth and induced apoptosis of AML CD34+ progenitor cells but spared normal progenitors. DIM #34 induced loss of mitochondrial membrane potential, which was accompanied by the release of cytochrome c into the cytosol and early cleavage of caspase-9 followed by the cleavage of caspases -8, and -3. Bcl-2 overexpression and caspase-9-deficient cells were partially protected against DIM #34-induced apoptosis, suggesting activation of the intrinsic apoptotic pathway. DIM #34 induced Bax cleavage, and Bax knockout cells were partially resistant to cell death. Furthermore, DIM #34 transiently inhibited the phosphorylation and the activity of the extracellular-regulated kinase (ERK) and abrogated Bcl-2 phosphorylation. Because other methylene substituted DIM analogs transactivate the nuclear receptor PPARγ, we studied the role of PPARγ in apoptosis induction. Although the co-treatment of cells with a selective PPARγ antagonist T007, and a low dose of DIM #34 partially diminished apoptosis, apoptosis was not inhibited at higher concentrations of DIM #34, suggesting the involvement of both, receptor-dependent and independent mechanisms. Co-treatment with RXR- and RAR-ligands enhanced DIM #34-induced cell death. Together, these findings showed that substituted DIMs represent a new class of compounds that selectively induce apoptosis in AML cells through interference with ERK and activation of PPARγ signaling pathways.

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Coagulopathy in HLA-DR Antigen-Negative Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v104.11.4457.4457 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4457-4457

Author(s):

Hideki Uchiumi ◽

Takafumi Matsushima ◽

Arito Yamane ◽

Hiroshi Handa ◽

Hiroyuki Irisawa ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

De Novo ◽

Myeloid Cell ◽

Leukemic Cell ◽

Leukemic Cells ◽

Hla Dr ◽

Risk Of Mortality ◽

Acute Myeloid

Abstract Background: HLA-DR antigen is present on hematopoietic progenitors and granulocyte/monocyte, erythrocyte and megakaryocytic precursors but absent at the promyelocytic stage during myeloid cell maturation. In accordance with this, majority of promyelocytic leukemia (APL) cells were negative for HLA-DR. Meanwhile, some of non-APL acute myeloid leukemia (AML) cells is found to express HLA-DR. However, the clinical significance of HLA-DR antigen on AML cells is currently unclear. Purpose: We sought to determine the prevalence and clinical characteristics of negativity in HLA-DR expression by retrospectively analyzing 181 consecutive patients with de novo adult AML. Patients and Methods: AML patients examined in the current study (aged 15–86 years) had been diagnosed between August 1995 and July 2004, and categorized to M0 (8 patients), M1 (35), M2 (74), M3 (20), M4 (25), M5 (15), and M6 (4), based on the FAB classification. Median follow-up time was 19.3 months. Phenotypic analyses of leukemic cells were performed using CD45 gating methods. HLA-DR-negative AML was defined as HLA-DR expression less than 20% of cells in the CD45 leukemic cell gate. Results: Among 181 patients, HLA-DR antigens were not detected on AML cells from 46 patients; 20 with APL and 26 with non-APL (non-APL/DR(−)), the latter of which included M0 (2 patients), M1 (15), M2 (7), M4 (2). Leukemic cells from other non-APL patients were HLA-DR-positive (non-APL/DR(+)). None of non-APL/DR(−) patients had t(15;17) nor PML/RARa rearrangement on cytogenetic analysis. Twenty out of 26 patients with non-APL/DR(−) had normal chromosome, and 6 had abnormal karyotypes. In the non-APL/DR(−) group, various degrees of nuclear folding, convolution, or lobulation were observed in 9 patients. Although treatment response and overall survival rate were similar in the three groups (APL, non-APL/DR(−), and non-APL/DR(+)), both FDP levels at diagnosis (57.3 vs 13.2, p<0.05) and maximal FDP levels (232.6 vs 43.8, p<0.01) were significantly higher in non-APL/DR(−) compared with non-APL/DR(+). The maximal FDP levels in the non-APL/DR(−) patients were comparable to those in the APL patients. FDP levels greater than 40 mg/ml were significantly more prevalent in the non-APL/DR(−) than in the the non-APL/DR(−) group. Logistic regression analysis demonstrated that low HLA-DR expression was an independent risk factor for FDP > 40 mg/ml. Conclusion: Our study suggests that AML with negative HLA-DR antigen tend to be associated with abnormality in coagulation and fibrinolysis even if they are genetically non-APL. We propose that more attention should be paied for HLA-DR expression to avoid a devastating coagulopathy which carries a high risk of mortality unless specifically addressed.

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Id1 is a common downstream target of oncogenic tyrosine kinases in leukemic cells

Blood ◽

10.1182/blood-2007-07-103010 ◽

2008 ◽

Vol 112 (5) ◽

pp. 1981-1992 ◽

Cited By ~ 30

Author(s):

Winnie F. Tam ◽

Ting-Lei Gu ◽

Jing Chen ◽

Benjamin H. Lee ◽

Lars Bullinger ◽

...

Keyword(s):

Cell Lines ◽

Tyrosine Kinases ◽

Target Genes ◽

Bone Marrow Cells ◽

Leukemic Cells ◽

Hematopoietic Malignancy ◽

Downstream Target ◽

Models Of Disease ◽

Induced Apoptosis

Abstract Oncogenic tyrosine kinases, such as BCR-ABL, TEL-ABL, TEL-PDGFβR, and FLT3-ITD, play a major role in the development of hematopoietic malignancy. They activate many of the same signal transduction pathways. To identify the critical target genes required for transformation in hematopoietic cells, we used a comparative gene expression strategy in which selective small molecules were applied to 32Dcl3 cells that had been transformed to factor-independent growth by these respective oncogenic alleles. We identified inhibitor of DNA binding 1 (Id1), a gene involved in development, cell cycle, and tumorigenesis, as a common target of these oncogenic kinases. These findings were prospectively confirmed in cell lines and primary bone marrow cells engineered to express the respective tyrosine kinase alleles and were also confirmed in vivo in murine models of disease. Moreover, human AML cell lines Molm-14 and K562, which express the FLT3-ITD and BCR-ABL tyrosine kinases, respectively, showed high levels of Id1 expression. Antisense and siRNA based knockdown of Id1-inhibited growth of these cells associated with increased p27Kip1 expression and increased sensitivity to Trail-induced apoptosis. These findings indicate that Id1 is an important target of constitutively activated tyrosine kinases and may be a therapeutic target for leukemias associated with oncogenic tyrosine kinases.

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The effects of dexamethasone and tetradecanoyl phorbol acetate on plasminogen activator release by human acute myeloid leukemia cells

Blood ◽

10.1182/blood.v61.3.561.561 ◽

1983 ◽

Vol 61 (3) ◽

pp. 561-567 ◽

Cited By ~ 20

Author(s):

EL Wilson ◽

P Jacobs ◽

EB Dowdle

Keyword(s):

Plasminogen Activator ◽

Glucocorticoid Receptors ◽

Leukemic Cell ◽

Biologically Active ◽

Leukemic Cells ◽

Tissue Type ◽

Cell Functions ◽

Tetradecanoyl Phorbol Acetate ◽

Acute Myeloid Leukemia Cells

Abstract This investigation was undertaken to examine the extent to which leukemic cell functions are susceptible to regulation in vitro and to investigate their heterogeneity in this regard. Since plasminogen activator release is known to be a modulatable cellular function that can be influenced by antiinflammatory steroids and tetradecanoyl phorbol acetate (TPA), the effect of these two compounds on the secretion of urokinase- or tissue-type enzymes by leukemic cells was studied. The release of both enzyme species could be stimulated or suppressed by these substances by mechanisms that were inhibitable by actinomycin-D and hence required transcription of new mRNA. Plasminogen activator release by cells from 41/45 patients with AML was either stimulated or inhibited by 10(-7) M dexamethasone, implying that most AML cells possess glucocorticoid receptors. In 26/45 cases, the enzyme was inhibited by this steroid to less than 25% of control values. Pronounced inhibition of this degree was not encountered with normal polymorphonuclear leukocytes. Plasminogen activator secretion by AML cells was profoundly inhibited in 20/41 cases by 1 ng/ml TPA and stimulated in 8/41 cases. Leukemic blasts varied considerably in their response to dexamethasone and TPA. Plasminogen activator release should prove a sensitive means of monitoring the responses of AML cells to biologically active compounds.

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Endothelial cell activation by myeloblasts: molecular mechanisms of leukostasis and leukemic cell dissemination

Blood ◽

10.1182/blood.v97.7.2121 ◽

2001 ◽

Vol 97 (7) ◽

pp. 2121-2129 ◽

Cited By ~ 160

Author(s):

Anne Stucki ◽

Anne-Sophie Rivier ◽

Milica Gikic ◽

Natacha Monai ◽

Marc Schapira ◽

...

Keyword(s):

Endothelial Cell ◽

Cell Activation ◽

Molecular Mechanisms ◽

Leukemic Cell ◽

Leukemic Cells ◽

Adhesion Assay ◽

Endothelial Cell Activation ◽

Adhesion Receptors ◽

Tnf Α ◽

Blast Cells

Abstract Leukostasis and tissue infiltration by leukemic cells are poorly understood life-threatening complications of acute leukemia. This study has tested the hypothesis that adhesion receptors and cytokines secreted by blast cells play central roles in these reactions. Immunophenotypic studies showed that acute myeloid leukemia (AML) cells (n = 78) of the M0 to M5 subtypes of the French-American-British Cooperative Group expressed various amounts of adhesion receptors, including CD11a, b, c/CD18, CD49d, e, f/CD29, CD54, sCD15, and L-selectin. The presence of functional adhesion receptors was evaluated using a nonstatic adhesion assay. The number of blast cells attached to unactivated endothelium increased by 7 to 31 times after a 6-hour exposure of endothelium to tumor necrosis factor (TNF)-α. Inhibition studies showed that multiple adhesion receptors—including L-selectin, E-selectin, VCAM-1, and CD11/CD18—were involved in blast cell adhesion to TNF-α–activated endothelium. Leukemic cells were then cocultured at 37°C on unactivated endothelial cell monolayers for time periods up to 24 hours. A time-dependent increase in the number of blasts attached to the endothelium and a concomitant induction of ICAM-1, VCAM-1, and E-selectin were observed. Additional experiments revealed that endothelial cell activation by leukemic myeloblasts was caused by cytokine secretion by blast cells, in particular TNF-α and IL-1β, and direct contacts between adhesion receptors expressed by blast cells and endothelial cells. Thus, leukemic cells have the ability to generate conditions that promote their own adhesion to vascular endothelium, a property that may have important implications for the pathophysiology of leukostasis and tissue infiltration by leukemic blast cells.

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Two types of C/EBPα mutations play distinct but collaborative roles in leukemogenesis: lessons from clinical data and BMT models

Blood ◽

10.1182/blood-2010-02-270181 ◽

2011 ◽

Vol 117 (1) ◽

pp. 221-233 ◽

Cited By ~ 41

Author(s):

Naoko Kato ◽

Jiro Kitaura ◽

Noriko Doki ◽

Yukiko Komeno ◽

Naoko Watanabe-Okochi ◽

...

Keyword(s):

Myeloid Leukemia ◽

Leucine Zipper ◽

Molecular Mechanisms ◽

De Novo ◽

Dominant Negative ◽

Leukemic Cells ◽

Basic Leucine Zipper ◽

Enhancer Binding Protein ◽

Type C ◽

De Novo Aml

Abstract Two types of mutations of a transcription factor CCAAT-enhancer binding protein α (C/EBPα) are found in leukemic cells of 5%-14% of acute myeloid leukemia (AML) patients: N-terminal mutations expressing dominant negative p30 and C-terminal mutations in the basic leucine zipper domain. Our results showed that a mutation of C/EBPα in one allele was observed in AML after myelodysplastic syndrome, while the 2 alleles are mutated in de novo AML. Unlike an N-terminal frame-shift mutant (C/EBPα-Nm)–transduced cells, a C-terminal mutant (C/EBPα-Cm)–transduced cells alone induced AML with leukopenia in mice 4-12 months after bone marrow transplantation. Coexpression of both mutants induced AML with marked leukocytosis with shorter latencies. Interestingly, C/EBPα-Cm collaborated with an Flt3-activating mutant Flt3-ITD in inducing AML. Moreover, C/EBPα-Cm strongly blocked myeloid differentiation of 32Dcl3 cells, suggesting its class II mutation-like role in leukemogenesis. Although C/EBPα-Cm failed to inhibit transcriptional activity of wild-type C/EBPα, it suppressed the synergistic effect between C/EBPα and PU.1. On the other hand, C/EBPα-Nm inhibited C/EBPα activation in the absence of PU.1, despite low expression levels of p30 protein generated by C/EBPα-Nm. Thus, 2 types of C/EBPα mutations are implicated in leukemo-genesis, involving different and cooperating molecular mechanisms.

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High-affinity neurotrophin receptors and ligands promote leukemogenesis

Blood ◽

10.1182/blood-2008-05-155200 ◽

2009 ◽

Vol 113 (9) ◽

pp. 2028-2037 ◽

Cited By ~ 34

Author(s):

Zhixiong Li ◽

Gernot Beutel ◽

Mathias Rhein ◽

Johann Meyer ◽

Christian Koenecke ◽

...

Keyword(s):

Tyrosine Kinases ◽

De Novo ◽

Point Mutations ◽

Surface Expression ◽

Leukemic Cells ◽

Receptor Protein ◽

Cell Surface Expression ◽

Clear Correlation ◽

High Affinity ◽

Induced Apoptosis

Abstract Neurotrophins (NTs) and their receptors play a key role in neurogenesis and survival. The TRK (tropomyosin-related kinase) receptor protein tyrosine kinases (TRKA, TRKB, TRKC) are high-affinity NT receptors that are expressed in a variety of human tissues. Their role in normal and malignant hematopoiesis is poorly understood. In a prospective study involving 94 adult patients we demonstrate for the first time cell-surface expression of the 3 TRKs and constitutive activation in blasts from patients with de novo or secondary acute leukemia. At least one TRK was expressed in 55% of the analyzed cases. We establish a clear correlation between the TRK expression pattern and FAB classification. Although only few point mutations were found in TRK sequences by reverse-transcriptase–polymerase chain reaction (RT-PCR), we observed coexpression of BDNF (ligand for TRKB) in more than 50% of TRKB+ cases (16/30). Activation of TRKA or TRKB by NGF and BDNF, respectively, efficiently rescued murine myeloid cells from irradiation-induced apoptosis. Coexpression of TRKB/BDNF or TRKA/NGF in murine hematopoietic cells induced leukemia. Moreover, activation of TRKs was important for survival of both human and murine leukemic cells. Our findings suggest that TRKs play an important role in leukemogenesis and may serve as a new drug target.

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