Role of GRB2-associated binder 1 in epidermal growth factor receptor-induced signaling in head and neck squamous cell carcinoma.

The epidermal growth factor receptor (EGFR) plays an important role in the pathogenesis of head and neck squamous cell carcinoma (HNSCC). Despite the high expression of EGFR in HNSCC, EGFR inhibitors have only limited success as monotherapy. The Grb2-associated binder (GAB) family of adaptor proteins acts as docking/scaffolding molecules downstream of tyrosine kinase receptors. We hypothesized that GAB1 may amplify EGFR-induced signaling in HNSCCs and therefore could play a role in the reduced sensitivity of HNSCC to EGFR inhibitors. We used representative human HNSCC cell lines overexpressing wild type EGFR, and expressing GAB1 but not GAB2. We demonstrated that baseline Akt and MAPK signaling were reduced in HNSCC cells in which GAB1 expression was reduced. Furthermore, the maximal EGF-induced activation of the Akt and MAPK pathway was reduced and delayed, and the duration of the EGF-induced activation of these pathways was reduced in cells with GAB1 knock-down. In agreement with this, HNSCC cells in which GAB1 levels were reduced showed an increased sensitivity to the EGFR inhibitor gefitinib. Our work demonstrates that GAB1 plays an important role as part of the mechanism of by which EGFR induces induced activation of the MAPK and AKT pathway. Our results identify GAB1 as an amplifier of the EGFR-initiated signaling, which may also interfere with EGFR degradation. These findings support the emerging notion that reducing GAB1 function may sensitize HNSCC to EGFR inhibitors, hence representing a new therapeutic target HNSCC treatment in combination with EGFR targeting agents.

Gene expression profiling reveals clear differences between EBV-positive and EBV-negative posttransplant lymphoproliferative disorders.

Posttransplant patients are at risk of developing a potentially life-threatening posttransplantation lymphoproliferative disorder (PTLD), most often of diffuse large B cell lymphoma (DLBCL) morphology and associated with Epstein-Barr Virus (EBV) infection. The aim of this study was to characterize the clinicopathological and molecular-genetic characteristics of posttransplant DLBCL and to elucidate whether EBV(+) and EBV(-) posttransplant DLBCL are biologically different. We performed gene expression profiling studies on 48 DLBCL of which 33 arose posttransplantation (PT-DLBCL; 72% EBV+) and 15 in immunocompetent hosts (IC-DLBCL; none EBV+). Unsupervised hierarchical analysis showed clustering of samples related to EBV-status rather than immune status. Except for decreased T cell signaling these cases were inseparable from EBV(-) IC-DLBCL. In contrast, a viral response signature clearly segregated EBV(+) PT-DLBCL from EBV(-) PT-DLBCL and IC-DLBCL cases that were intermixed. The broad EBV latency profile (LMP1+/EBNA2+) was expressed in 59% of EBV(+) PT-DLBCL and associated with a more elaborate inflammatory response compared to intermediate latency (LMP1+/EBNA2-). Inference analysis revealed a role for innate and tolerogenic immune responses (including VSIG4 and IDO1) in EBV(+) PT-DLBCL. In conclusion we can state that the EBV signature is the most determining factor in the pathogenesis of EBV(+) PT-DLBCL.

Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia.

In T-cell acute lymphoblastic leukemia (T-ALL), transcription factors are known to be deregulated by chromosomal translocations, but mutations in protein tyrosine kinases have only rarely been identified. Here we describe the extrachromosomal (episomal) amplification of ABL1 in 5 of 90 (5.6%) individuals with T-ALL, an aberration that is not detectable by conventional cytogenetics. Molecular analyses delineated the amplicon as a 500-kb region from chromosome band 9q34, containing the oncogenes ABL1 and NUP214 (refs. 5,6). We identified a previously undescribed mechanism for activation of tyrosine kinases in cancer: the formation of episomes resulting in a fusion between NUP214 and ABL1. We detected the NUP214-ABL1 transcript in five individuals with the ABL1 amplification, in 5 of 85 (5.8%) additional individuals with T-ALL and in 3 of 22 T-ALL cell lines. The constitutively phosphorylated tyrosine kinase NUP214-ABL1 is sensitive to the tyrosine kinase inhibitor imatinib. The recurrent cryptic NUP214-ABL1 rearrangement is associated with increased HOX expression and deletion of CDKN2A, consistent with a multistep pathogenesis of T-ALL. NUP214-ABL1 expression defines a new subgroup of individuals with T-ALL who could benefit from treatment with imatinib.

Identification and characterization of novel oncogenes in chronic eosinophilic leukemia and T-cell acute lymphoblastic leukemia.

Research conducted in my group in the period 2006-2009 has led to a better understanding of the oncogenic mechanisms of the FIP1L1-PDGFRA and NUP214-ABL1 oncogenes. Insights into these mechanisms may help us to design novel strategies to treat leukemia. In addition, we have identified the small molecule inhibitor sorafenib as a potent inhibitor of the FIP1L1-PDGFRA and its T674I imatinib resistant mutant. Sorafenib was originally developed as a BRAF inhibitor, but our work demonstrates that sorafenib can also be used to treat FIP1L1-PDGFRA positive leukemia, demonstrating that new therapies to treat rare leukemias may be simply found by testing drugs that are already in use for the treatment of other diseases. Finally, using genome-wide screening approaches, we have identified the MYB gene as a novel oncogene implicated in the pathogenesis of T-ALL, and we suggest that MYB may represent a novel target for therapy in T-ALL as well as in other cancers.

FIP1L1-PDGFRA in chronic eosinophilic leukemia and BCR-ABL1 in chronic myeloid leukemia affect different leukemic cells.

We investigated genetically affected leukemic cells in FIP1L1-PDGFRA+ chronic eosinophilic leukemia (CEL) and in BCR-ABL1+ chronic myeloid leukemia (CML), two myeloproliferative disorders responsive to imatinib. Fluorescence in situ hybridization specific for BCR-ABL1 and for FIP1L1-PDGFRA was combined with cytomorphology or with lineage-restricted monoclonal antibodies and applied in CML and CEL, respectively. In CEL the amount of FIP1L1-PDGFRA+ cells among CD34+ and CD133+ cells, B and T lymphocytes, and megakaryocytes were within normal ranges. Positivity was found in eosinophils, granulo-monocytes and varying percentages of erythrocytes. In vitro assays with imatinib showed reduced survival of peripheral blood mononuclear cells but no reduction in colony-forming unit growth medium (CFU-GM) growth. In CML the BCR-ABL1 fusion gene was detected in CD34+/CD133+ cells, granulo-monocytes, eosinophils, erythrocytes, megakaryocytes and B-lymphocytes. Growth of both peripheral blood mononuclear cells and CFU-GM was inhibited by imatinib. This study provided evidence for marked differences in the leukemic masses which are targeted by imatinib in CEL or CML, as harboring FIP1L1-PDGFRA or BCR-ABL1.

Clinical, cytogenetic and molecular characteristics of 14 T-ALL patients carrying the TCRbeta-HOXA rearrangement: a study of the Groupe Francophone de Cytogénétique Hématologique.

Recently, we and others described a new chromosomal rearrangement, that is, inv(7)(p15q34) and t(7;7)(p15;q34) involving the T-cell receptor beta (TCRbeta) (7q34) and the HOXA gene locus (7p15) in 5% of T-cell acute lymphoblastic leukemia (T-ALL) patients leading to transcriptional activation of especially HOXA10. To further address the clinical, immunophenotypical and molecular genetic findings of this chromosomal aberration, we studied 330 additional T-ALLs. This revealed TCRbeta-HOXA rearrangements in five additional patients, which brings the total to 14 cases in 424 patients (3.3%). Real-time quantitative PCR analysis for HOXA10 gene expression was performed in 170 T-ALL patients and detected HOXA10 overexpression in 25.2% of cases including all the cases with a TCRbeta-HOXA rearrangement (8.2%). In contrast, expression of the short HOXA10 transcript, HOXA10b, was almost exclusively found in the TCRbeta-HOXA rearranged cases, suggesting a specific role for the HOXA10b short transcript in TCRbeta-HOXA-mediated oncogenesis. Other molecular and/or cytogenetic aberrations frequently found in subtypes of T-ALL (SIL-TAL1, CALM-AF10, HOX11, HOX11L2) were not detected in the TCRbeta-HOXA rearranged cases except for deletion 9p21 and NOTCH1 activating mutations, which were present in 64 and 67%, respectively. In conclusion, this study defines TCRbeta-HOXA rearranged T-ALLs as a distinct cytogenetic subgroup by clinical, immunophenotypical and molecular genetic characteristics.

Defining the molecular basis of oncogenic cooperation between TAL1 expression and Pten deletion in T-ALL using a novel pro-T-cell model system.

T-cell acute lymphoblastic leukemia (T-ALL) is caused by the accumulation of multiple mutations combined with the ectopic expression of transcription factors in developing T cells. However, the molecular basis underlying cooperation between transcription factor expression and additional oncogenic mutations in driving T-ALL has been difficult to assess due to limited robust T-cell model systems. Here we utilize a new ex vivo pro-T-cell model to study oncogenic cooperation. Using a systems biological approach we first dissect the pro-T-cell signaling network driven by interleukin-7, stem cell factor and Notch1 and identify key downstream Akt, Stat, E2f and Myc genetic signaling networks. Next, this pro-T-cell system was used to demonstrate that ectopic expression of the TAL1 transcription factor and Pten deletion are bona-fide cooperating events resulting in an increased stem cell signature, upregulation of a specific E2f signaling network and metabolic reprogramming with higher influx of glucose carbons into the tricarboxylic acid cycle. This ex vivo pro-T-cell system thereby provides a powerful new model system to investigate how normal T-cell signaling networks are perturbed and/or hijacked by different oncogenic events found in T-ALL.

Mutant JAK3 phosphoproteomic profiling predicts synergism between JAK3 inhibitors and MEK/BCL2 inhibitors for the treatment of T-cell acute lymphoblastic leukemia.

Mutations in the interleukin-7 receptor (IL7R) or the Janus kinase 3 (JAK3) kinase occur frequently in T-cell acute lymphoblastic leukemia (T-ALL) and both are able to drive cellular transformation and the development of T-ALL in mouse models. However, the signal transduction pathways downstream of JAK3 mutations remain poorly characterized. Here we describe the phosphoproteome downstream of the JAK3(L857Q)/(M511I) activating mutations in transformed Ba/F3 lymphocyte cells. Signaling pathways regulated by JAK3 mutants were assessed following acute inhibition of JAK1/JAK3 using the JAK kinase inhibitors ruxolitinib or tofacitinib. Comprehensive network interrogation using the phosphoproteomic signatures identified significant changes in pathways regulating cell cycle, translation initiation, mitogen-activated protein kinase and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT signaling, RNA metabolism, as well as epigenetic and apoptotic processes. Key regulatory proteins within pathways that showed altered phosphorylation following JAK inhibition were targeted using selumetinib and trametinib (MEK), buparlisib (PI3K) and ABT-199 (BCL2), and found to be synergistic in combination with JAK kinase inhibitors in primary T-ALL samples harboring JAK3 mutations. These data provide the first detailed molecular characterization of the downstream signaling pathways regulated by JAK3 mutations and provide further understanding into the oncogenic processes regulated by constitutive kinase activation aiding in the development of improved combinatorial treatment regimens.

Correction: Mutant JAK3 phosphoproteomic profiling predicts synergism between JAK3 inhibitors and MEK/BCL2 inhibitors for the treatment of T-cell acute lymphoblastic leukemia.

Following the publication of this article the authors noted that data describing precisely where phosphorylation sites in proteins modulated following JAK1 or JAK3 inhibition in mutant T-ALL samples was not clearly annotated. Therefore an additional sheet has been added to Supplementary Table 2.

The T-cell leukemia-associated ribosomal RPL10 R98S mutation enhances JAK-STAT signaling.

Several somatic ribosome defects have recently been discovered in cancer, yet their oncogenic mechanisms remain poorly understood. Here we investigated the pathogenic role of the recurrent R98S mutation in ribosomal protein L10 (RPL10 R98S) found in T-cell acute lymphoblastic leukemia (T-ALL). The JAK-STAT signaling pathway is a critical controller of cellular proliferation and survival. A proteome screen revealed overexpression of several Jak-Stat signaling proteins in engineered RPL10 R98S mouse lymphoid cells, which we confirmed in hematopoietic cells from transgenic Rpl10 R98S mice and T-ALL xenograft samples. RPL10 R98S expressing cells displayed JAK-STAT pathway hyper-activation upon cytokine stimulation, as well as increased sensitivity to clinically used JAK-STAT inhibitors like pimozide. A mutually exclusive mutation pattern between RPL10 R98S and JAK-STAT mutations in T-ALL patients further suggests that RPL10 R98S functionally mimics JAK-STAT activation. Mechanistically, besides transcriptional changes, RPL10 R98S caused reduction of apparent programmed ribosomal frameshifting at several ribosomal frameshift signals in mouse and human Jak-Stat genes, as well as decreased Jak1 degradation. Of further medical interest, RPL10 R98S cells showed reduced proteasome activity and enhanced sensitivity to clinical proteasome inhibitors. Collectively, we describe modulation of the JAK-STAT cascade as a novel cancer-promoting activity of a ribosomal mutation, and expand the relevance of this cascade in leukemia.

Chronic myeloproliferative disorders: a tyrosine kinase tale.

Chronic myeloproliferative diseases (CMPDs) are characterized by the abnormal proliferation and survival of one or more myeloid cell types. The archetype of this class of hematological diseases is chronic myeloid leukemia (CML), characterized by the presence of the Philadelphia (Ph) chromosome, the result of t(9;22)(q34;q11), and the associated BCR-ABL1 oncogene. Some of the Ph-negative myeloproliferative diseases are characterized by other chromosomal translocations involving a variety of tyrosine kinase genes, including ABL1, ABL2, PDGFRA, PDGFRB, FGFR1, and JAK2. The majority of Ph-negative CMPDs, however, such as chronic eosinophilic leukemia, polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis are not characterized by the presence of recurrent chromosomal abnormalities. Recent studies have identified the FIP1L1-PDGFRA fusion gene, generated due to a small cryptic deletion on chromosome 4q12, and the activating V617F mutation in JAK2 in a significant fraction of Ph-negative CMPDs. These results show that abnormalities in tyrosine kinase genes are central to the molecular pathogenesis of CMPDs. Genome-wide screenings to identify novel tyrosine kinase abnormalities in CMPDs may contribute to further improvement of the diagnosis and the treatment of these diseases.

Cytogenetics and molecular genetics of T-cell acute lymphoblastic leukemia: from thymocyte to lymphoblast.

For long, T-cell acute lymphoblastic leukemia (T-ALL) remained in the shadow of precursor B-ALL because it was more seldom, and showed a normal karyotype in more than 50% of cases. The last decennia, intense research has been carried out on different fronts. On one side, development of normal thymocyte and its regulation mechanisms have been studied in multiple mouse models and subsequently validated. On the other side, molecular cytogenetics (fluorescence in situ hybridization) and mutation analysis revealed cytogenetically cryptic aberrations in almost all cases of T-ALL. Also, expression microarray analysis disclosed gene expression signatures that recapitulate specific stages of thymocyte development. Investigations are still very much actual, fed by the discovery of new genetic aberrations. In this review, we present a summary of the current cytogenetic changes associated with T-ALL. The genes deregulated by translocations or mutations appear to encode proteins that are also implicated in T-cell development, which prompted us to review the 'normal' and 'leukemogenic' functions of these transcription regulators. To conclude, we show that the paradigm of multistep leukemogenesis is very much applicable to T-ALL and that the different genetic insults collaborate to maintain self-renewal capacity, and induce proliferation and differentiation arrest of T-lymphoblasts. They also open perspectives for targeted therapies.

Molecular cytogenetic study of 126 unselected T-ALL cases reveals high incidence of TCRbeta locus rearrangements and putative new T-cell oncogenes.

Chromosomal aberrations of T-cell receptor (TCR) gene loci often involve the TCRalphadelta (14q11) locus and affect various known T-cell oncogenes. A systematic fluorescent in situ hybridization (FISH) screening for the detection of chromosomal aberrations involving the TCR loci, TCRalphadelta (14q11), TCRbeta (7q34) and TCRgamma (7p14), has not been conducted so far. Therefore, we initiated a screening of 126 T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma cases and 19 T-ALL cell lines using FISH break-apart assays for the different TCR loci. Genomic rearrangements of the TCRbeta locus were detected in 24/126 cases (19%), most of which (58.3%) were not detected upon banding analysis. Breakpoints in the TCRalphadelta locus were detected in 22/126 cases (17.4%), whereas standard cytogenetics only detected 14 of these 22 cases. Cryptic TCRalphadelta/TCRbeta chromosome aberrations were thus observed in 22 of 126 cases (17.4%). Some of these chromosome aberrations target new putative T-cell oncogenes at chromosome 11q24, 20p12 and 6q22. Five patients and one cell line carried chromosomal rearrangements affecting both TCRbeta and TCRalphadelta loci. In conclusion, this study presents the first inventory of chromosomal rearrangements of TCR loci in T-ALL, revealing an unexpected high number of cryptic chromosomal rearrangements of the TCRbeta locus and further broadening the spectrum of genes putatively implicated in T-cell oncogenesis.

KIAA1509 is a novel PDGFRB fusion partner in imatinib-responsive myeloproliferative disease associated with a t(5;14)(q33;q32).

We report the cloning of a novel PDGFRB fusion gene partner in a patient with a chronic myeloproliferative disorder characterized by t(5;14)(q33;q32), who responded to treatment with imatinib mesylate. Fluorescence in situ hybridization demonstrated that PDGFRB was involved in the translocation. Long distance inversion PCR identified KIAA1509 as the PDGFRB fusion partner. KIAA1509 is an uncharacterized gene with a predicted coiled-coil oligomerization domain with homology to the HOOK family of proteins. The predicted KIAA1509-PDGFRbeta fusion protein contains the KIAA1509 coiled-coil domain fused to the cytoplasmic domain of PDGFRbeta that includes the tyrosine kinase domain. Imatinib therapy resulted in rapid normalization of the patient's blood counts, and subsequent bone marrow biopsies and karyotypic analysis were consistent with sustained complete remission.

A new recurrent inversion, inv(7)(p15q34), leads to transcriptional activation of HOXA10 and HOXA11 in a subset of T-cell acute lymphoblastic leukemias.

Chromosomal translocations with breakpoints in T-cell receptor (TCR) genes are recurrent in T-cell malignancies. These translocations involve the TCRalphadelta gene (14q11), the TCRbeta gene (7q34) and to a lesser extent the TCRgamma gene at chromosomal band 7p14 and juxtapose T-cell oncogenes next to TCR regulatory sequences leading to deregulated expression of those oncogenes. Here, we describe a new recurrent chromosomal inversion of chromosome 7, inv(7)(p15q34), in a subset of patients with T-cell acute lymphoblastic leukemia characterized by CD2 negative and CD4 positive, CD8 negative blasts. This rearrangement juxtaposes the distal part of the HOXA gene cluster on 7p15 to the TCRbeta locus on 7q34. Real time quantitative PCR analysis for all HOXA genes revealed high levels of HOXA10 and HOXA11 expression in all inv(7) positive cases. This is the first report of a recurrent chromosome rearrangement targeting the HOXA gene cluster in T-cell malignancies resulting in deregulated HOXA gene expression (particularly HOXA10 and HOXA11) and is in keeping with a previous report suggesting HOXA deregulation in MLL-rearranged T- and B cell lymphoblastic leukemia as the key factor in leukaemic transformation. Finally, our observation also supports the previous suggested role of HOXA10 and HOXA11 in normal thymocyte development.

[A man with FIP1L1/PDGFRA-positive chronic eosinophilic leukemia]. / Een man met FIP1L1-PDGFRA-positieve chronische eosinofiele leukemie.

A 39-year-old man was referred from Surinam to the Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands, for a right ventricular tumour, hypereosinophilia and mild thrombocytopenia. He appeared to have chronic eosinophilic leukaemia that was positive for the 'FIP1-like-1-platelet-derived growth factor receptor alpha' (FIP1L1-PDGFRA) gene. In addition, he had signs of a right ventricular thrombus that had existed for at least 6 months. The patient was treated with oral anticoagulants and the tyrosine kinase inhibitor imatinib. The latter therapy resulted in normalisation of leukocyte count and differential values. After 3 months of therapy, the FIP1L1-PDGFRA fusion transcript was no longer detectable in peripheral blood. After 1 year of follow up, the patient was in complete haematological and molecular remission for chronic eosinophilic leukaemia. The cardiac mass remained unchanged, but caused no haemodynamic problems.

Clinical and molecular features of FIP1L1-PDFGRA (+) chronic eosinophilic leukemias.

Detection of the FIP1L1-PDGFRA fusion gene or the corresponding cryptic 4q12 deletion supports the diagnosis of chronic eosinophilic leukemia (CEL) in patients with chronic hypereosinophilia. We retrospectively characterized 17 patients fulfilling WHO criteria for idiopathic hypereosinophilic syndrome (IHES) or CEL, using nested RT-PCR and interphase fluorescence in situ hybridization (FISH). Eight had FIP1L1-PDGFRA (+) CEL, three had FIP1L1-PDGFRA (-) CEL and six had IHES. FIP1L1-PDGFRA (+) CEL responded poorly to steroids, hydroxyurea or interferon-alpha, and had a high probability of eosinophilic endomyocarditis (n=4) and disease-related death (n=4). In FIP1L1-PDGFRA (+) CEL, palpable splenomegaly was present in 5/8 cases, serum vitamin B(12) was always markedly increased, and marrow biopsies revealed a distinctively myeloproliferative aspect. Imatinib induced rapid complete hematological responses in 4/4 treated FIP1L1-PDGFRA (+) cases, including one female, and complete molecular remission in 2/3 evaluable cases. In the female patient, 1 log reduction of FIP1L1-PDGFRA copy number was reached as by real-time quantitative PCR (RQ-PCR). Thus, correlating IHES/CEL genotype with phenotype, FIP1L1-PDGFRA (+) CEL emerges as a homogeneous clinicobiological entity, where imatinib can induce molecular remission. While RT-PCR and interphase FISH are equally valid diagnostic tools, the role of marrow biopsy in diagnosis and of RQ-PCR in disease and therapy monitoring needs further evaluation.

FIP1L1-PDGFR alpha, a therapeutic target for the treatment of chronic eosinophilic leukemia.

The identification of the FIP1L1-PDGFRA fusion gene provides a molecular explanation for the pathogenesis of approximately half of the patients with the hypereosinophilic syndrome (HES). A diagnostic test to identify FIP1L1-PDGFRA positive HES cases (subsequently reclassified as chronic eosinophilic leukemia, CEL) is now available. FIP1L1-PDGFR alpha is a novel therapeutic target of the kinase inhibitor imatinib (Glivec, Novartis), which provides the basis for the treatment of these patients with this drug. FIP1L1-PDGFRA positive CEL patients respond very well to imatinib therapy, some of which are remarkable responses with normalization of the blood counts within 2 weeks after start of the therapy. Imatinib is well tolerated with minimal side effects, and most CEL patients respond to low doses of imatinib (100 mg/day), being important for lowering both the cost of therapy and drug related toxicity. All imatinib treated FIP1L1-PDGFRA positive CEL patients achieve hematological and cytogenetic remission, and the majority of patients also achieve a molecular remission with the fusion gene no longer detectable in blood, even by the most sensitive PCR techniques.

Characterization of the genome-wide TLX1 binding profile in T-cell acute lymphoblastic leukemia.

The TLX1 transcription factor is critically involved in the multi-step pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) and often cooperates with NOTCH1 activation during malignant T-cell transformation. However, the exact molecular mechanism by which these T-cell specific oncogenes cooperate during transformation remains to be established. Here, we used chromatin immunoprecipitation followed by sequencing to establish the genome-wide binding pattern of TLX1 in human T-ALL. This integrative genomics approach showed that ectopic TLX1 expression drives repression of T cell-specific enhancers and mediates an unexpected transcriptional antagonism with NOTCH1 at critical target genes, including IL7R and NOTCH3. These phenomena coordinately trigger a TLX1-driven pre-leukemic phenotype in human thymic precursor cells, reminiscent of the thymus regression observed in murine TLX1 tumor models, and create a strong genetic pressure for acquiring activating NOTCH1 mutations as a prerequisite for full leukemic transformation. In conclusion, our results uncover a functional antagonism between cooperative oncogenes during the earliest phases of tumor development and provide novel insights in the multi-step pathogenesis of TLX1-driven human leukemia.

A new family of small, palmitoylated, membrane-associated proteins, characterized by the presence of a cysteine-rich hydrophobic motif.

We recently cloned the CHIC2 gene (previously BTL) by virtue of its involvement in a chromosomal translocation t(4;12)(q11;p13) occurring in acute myeloid leukemias. In this study we show that CHIC2 is a member of a highly conserved family of proteins characterized by the presence of a striking cysteine-rich hydrophobic (CHIC) motif. Our data illustrate that cysteines in this central CHIC motif are palmitoylated and that CHIC2 is associated with vesicular structures and the plasma membrane. The CHIC proteins thus resemble the cysteine string proteins, which function in regulated exocytosis.