[Show abstract][Hide abstract] ABSTRACT: Neuropilins and semaphorins are known as modulators of axon guidance, angiogenesis, and organogenesis in the developing nervous system, but have been recently evidenced as also playing a role in the immune system. Here we describe the expression and role of semaphorin 3F (SEMA3F) and its receptor neuropilin-2 (NRP2) in human T cell precursors. NRP2 and SEMA3F are expressed in the human thymus, in both lymphoid and non-lymphoid compartments. SEMA3F have a repulsive effect on thymocyte migration and inhibited CXCL12- and sphingosine-1-phosphate (S1P)-induced thymocyte migration by inhibiting cytoskeleton reorganization prior to stimuli. Moreover, NRP2 and SEMA3F are expressed in human T-cell acute lymphoblastic leukemia/lymphoma primary cells. In these tumor cells, SEMA3F also blocks their migration induced by CXCL12 and S1P. Our data show that SEMA3F and NRP2 are further regulators of human thymocyte migration in physiological and pathological conditions.
[Show abstract][Hide abstract] ABSTRACT: Classification of acute myeloid leukemia (AML) has undergone dramatic changes with the introduction of the WHO classification in 2001. This classification attempts to categorize AML into 4 major categories on the basis of morphologic, immunophenotypic, genetic and clinical features. All categories present a good intra-group homogeneity except for the subgroup with 11q23/MLL abnormalities11q23 abnormalities are generally associated with unfavorable prognosis. More than 50 partners have been described for MLL, and 35 of these partners have been cloned and analysed at the molecular level. The specific functional role of each specific fusion transcript on the progression and outcome of disease remains to be elucidated to be effective at the clinical level. Such heterogeneity is a technical challenge at the diagnostic level. Current standard diagnostic testing for patients with acute leukemia includes cytogenetics backed up by FISH and/or RT-PCR. This screening strategy can be cumbersome in the clinical setting, since identification of the fusion gene partner may involve multiple and time-consuming analysis. We present here the results of an international multi-center study aimed at assessing the clinical performance of the MLL FusionChip™ kit, a molecular device designed to confirm the 11q23 abnormality and identify the MLL fusion gene partner. A previous study showed that the analytical performance of this oncodiagnostic device is compatible with its claimed use. In the current study, sample inclusion criteria were made on the basis of the current standard diagnosis procedures. Overall agreement between routine diagnostic analysis and the MLL FusionChip™ kit was > 90%. These results collectively suggest that the MLL FusionChip™ may be a clinically feasible oncodiagnostic device to improve acute leukemia stratification and enrich minimal residual disease (MRD) follow-up. Further consequences of enhanced patient stratification could lead to personalized therapy expansion, and to optimized use of molecular target-based therapeutics.
[Show abstract][Hide abstract] ABSTRACT: With intensified pediatric-like therapy and genetic disease dissection, the field of adult acute lymphoblastic leukemia (ALL) has evolved recently. In this new context, we aimed to reassess the value of conventional risk factors with regard to new genetic alterations and early response to therapy, as assessed by Ig/TCR minimal residual disease (MRD) levels. The study was performed in 423 younger adults with Philadelphia chromosome-negative ALL in first remission (265 B-cell precursor [BCP] and 158 T-cell ALL), with cumulative incidence of relapse (CIR) as primary endpoint. In addition to conventional risk factors, the most frequent currently available genetic alterations were included in the analysis. A higher specific hazard of relapse was independently associated with post-induction MRD level ≥ 10(-4) and unfavorable genetic characteristics (i.e. MLL gene rearrangement or focal IKZF1 gene deletion in BCP-ALL; and no NOTCH1/FBXW7 mutation and/or N/K-RAS mutation and/or PTEN gene alteration in T-ALL). These two factors allowed definition of a new risk classification, which is strongly associated with higher CIR and shorter relapse-free and overall survival. These results indicate that genetic abnormalities are important predictors of outcome in adult ALL, not fully recapitulated by early response to therapy. Patients included in this study were treated in the multicenter GRAALL-2003 and 2005 trials. Both trials were registered at ClinicalTrials.gov (GRAALL-2003, NCT00222027; GRAALL-2005, NCT00327678).
[Show abstract][Hide abstract] ABSTRACT: Although purine analogues have significantly improved the outcome of hairy cell leukaemia (HCL) patients, 30-40% relapse, illustrating the need for minimal residual disease (MRD) markers that can aid personalized therapeutic management. Diagnostic samples from 34 HCL patients were used to design an 8-colour flow cytometry (8-FC) tube for blood MRD (B/RD) analysis (188 samples) which was compared to quantitative IGH polymerase chain reaction (Q-PCR) on 83 samples and to qualitative consensus IGH PCR clonality analysis on 165 samples. Despite heterogeneous HCL phenotypes at diagnosis, discrimination from normal B lymphocytes was possible in all cases using a single 8-FC tube, with a robust sensitivity of detection of 10(-4) , comparable to Q-PCR at this level, but preferable in terms of informativeness, simplicity and cost. B/RD assessment of 15 patients achieving haematological complete remission after purine analogues was predictive of a clinically significant relapse risk: with a median follow-up of 95 months; only one of the nine patients with reproducible 8-FC B/RD levels below 10(-4) (B/RD(neg) ) relapsed, compared to 5/6 in the B/RD(pos) group (P = 0·003). These data demonstrate the clinical interest of a robust 8-FC HCL B/RD strategy that could become a surrogate biomarker for therapeutic stratification and new drug assessment, which should be evaluated prospectively.
British Journal of Haematology 03/2014; · 4.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Minimal residual disease (MRD) is a major predictive factor of the cure rate of acute lymphoblastic leukaemia (ALL). Haematopoietic cell transplantation is a treatment option for patients at high risk of relapse. Between 2005 and 2008, we conducted a prospective study evaluating the feasibility and efficacy of the reduction of immunosuppressive medication shortly after a non-ex vivo T depleted myeloablative transplantation. Immunoglobulin (Ig)H/T-cell receptor MRD 30 d before transplant could be obtained in 122 of the 133 cases of high-risk paediatric ALL enrolled. There were no significant demographic differences except remission status (first or second complete remission) between the 95 children with MRD <10(-3) and the 27 with MRD ≥10(-3) . Multivariate analysis identified sex match and MRD as being significantly associated with 5-year survival. MRD ≥10(-3) compromised the 5-year cumulative incidence of relapse (43·6 vs. 16·7%). Complete remission status and stem cell source did not modify the relationship between MRD and prognosis. Thus, pre-transplant MRD is still a major predictor of outcome for ALL. The MRD-guided strategy resulted in survival for 72·3% of patients with MRD<10(-3) and 40·4% of those with MRD ≥10(-3) .
British Journal of Haematology 01/2014; · 4.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The SET-NUP214 (TAF1/CAN) fusion gene resulting from either cryptic t(9;9)(q34;q34) or del(9)(q34.11q34.13)is a rare genetic event in T-cell acute lymphoblastic leukemia (T-ALL). Eleven of 196 (6%) T-ALLs enrolled in the French GRAALL-2003 and -2005 trials harbored a SET-NUP214 transcript. SET-NUP214 positive patients were predominantly (10/11; 91%) T-cell receptor (TCR) negative and strikingly associated to TCRγδ lineage T-ALLs, as defined by expression of a TCRγδ, or TCRδ and/or TCRγ rearrangements but no complete TCRβ VDJ rearrangement in surface CD3/TCR negative cases. When compared to SET-NUP214 negative patients, SET-NUP214+ cases showed a significantly higher rate of corticosteroid resistance (91% versus 44%; p=0.003) and chemoresistance (100% versus 44%; p=0.0001). All but one SET-NUP214+ patients achieved complete remission and nine were allografted. Despite the poor early treatment sensitivity, the outcome of SET-NUP214+ patients was similar to that of SET-NUP214-cases (p=0.52 for event-free survival and p=0.86 for overall survival). This trial is registered at clinicaltrials.gov, identifier: NCT00327678.
[Show abstract][Hide abstract] ABSTRACT: Little is known about intestinal CD4+ T-cell lymphoma; this rare malignancy is frequently misdiagnosed. We evaluated diagnostic criteria and factors that might affect its development and outcome.
In a retrospective analysis, we analyzed medical records and intestinal specimens from 10 patients diagnosed with intestinal CD4+ T-cell lymphoma among 115 consecutive patients examined for severe enteropathy with villous atrophy. Samples were analyzed by histology, flow cytometry, and comparative genomic hybridization.
Small intestine epithelial and lamina propria tissues from patients who presented with chronic diarrhea and malnutrition had variable levels of infiltration of the by CD3+ CD4+ T cells. Flow cytometry revealed a high frequency of CD4+ intra-epithelial cells, which frequently expressed a specific Vβ chain. T-cell receptor β clonality was confirmed by DNA sequencing. Two patients had HLA and serology results compatible with celiac disease and autoimmune enteropathy, respectively. Two patients were found to have antibodies against human T-cell leukemia virus and 2 patients had signs of recent infection with herpes viruses. Comparative genomic hybridization analyses showed heterogeneous chromosomal abnormalities. Symptoms were reduced in patients treated with steroids (n=5), but not in patients given purine analogues or chemotherapy. Antibodies against CD52 produced clinical and histological responses in 2/2 patients, whereas severe adverse effects developed in 1 patient. At the latest follow up, all patients are alive.
There is much heterogeneity in onset and genetic features of intestinal CD4+ T cell lymphomas, despite their common presentation as indolent lymphoproliferations of the intestinal mucosa. Patients should be treated with steroids, and possibly antibodies against CD52 (for the most aggressive forms of this disorder).
Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 12/2013; · 5.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL) recently reported a significantly better outcome in T-cell acute lymphoblastic leukemia (T-ALL) harboring NOTCH1 and/or FBXW7 (N/F) mutations compared with unmutated T-ALL. Despite this, one third of patients with N/F-mutated T-ALL experienced relapse.
In a series of 212 adult T-ALLs included in the multicenter randomized GRAALL-2003 and -2005 trials, we searched for additional N/K-RAS mutations and PTEN defects (mutations and gene deletion).
N/F mutations were identified in 143 (67%) of 212 patients, and lack of N/F mutation was confirmed to be associated with a poor prognosis. K-RAS, N-RAS, and PTEN mutations/deletions were identified in three (1.6%) of 191, 17 (8.9%) of 191, and 21 (12%) of 175 patients, respectively. The favorable prognostic significance of N/F mutations was restricted to patients without RAS/PTEN abnormalities. These observations led us to propose a new T-ALL oncogenetic classifier defining low-risk patients as those with N/F mutation but no RAS/PTEN mutation (97 of 189 patients; 51%) and all other patients (49%; including 13% with N/F and RAS/PTEN mutations) as high-risk patients. In multivariable analysis, this oncogenetic classifier remained the only significant prognostic covariate (event-free survival: hazard ratio [HR], 3.2; 95% CI, 1.9 to 5.15; P < .001; and overall survival: HR, 3.2; 95% CI, 1.9 to 5.6; P < .001).
These data demonstrate that the presence of N/F mutations in the absence of RAS or PTEN abnormalities predicts good outcome in almost 50% of adult T-ALL. Conversely, the absence of N/F or presence of RAS/PTEN alterations identifies the remaining cohort of patients with poor prognosis.
Journal of Clinical Oncology 10/2013; · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Imatinib is the treatment of choice for FIP1L1/PDGFRA (F/P)-associated chronic eosinophilic leukemia (F/P CEL), but its optimal dosing, duration, and possibility of discontinuation are still a matter of debate. A retrospective multicenter study was conducted with 44 F/P CEL patients identified in the French Eosinophil Network and treated with imatinib. The most frequently involved systems were skin (57%), spleen (52%), and lung (45%), and eosinophilic heart disease was observed in 15 patients (34%). Complete hematologic response (CHR) was obtained in all patients, and complete molecular response (CMR) in 95% of patients (average initial imatinib dose, 165 mg/d). For 29 patients the imatinib dose was tapered with a maintenance dose of 58 mg/d (±34 mg/d), allowing sustained CHR and CMR. None of the patients developed resistance during a median follow-up of 52.3 months (range, 1.4-97.4 mo). Imatinib was stopped in 11 patients; 6 of the patients subsequently relapsed, but 5 remained in persistent CHR or CMR (range, 9-88 mo). These results confirm that an initial low-dose regimen of imatinib (100 mg/d) followed by a lower maintenance dose can be efficient for obtaining long-term CHR and CMR. Our data also suggest that imatinib can be stopped in some patients without molecular relapse.
[Show abstract][Hide abstract] ABSTRACT: CALM-AF10 (also known as PICALM-MLLT10) is the commonest fusion protein in T-cell acute lymphoblastic leukemia, but its prognostic impact remains unclear. Molecular screening at diagnosis identified CALM-AF10 in 30/431 (7%) T-cell acute lymphoblastic leukemia patients aged 16 years and over and 15/234 (6%) in those aged up to 15 years. CALM-AF10 positive patients were predominantly (72%) surface (s)CD3/T-cell receptor negative in adults, but predominantly (67%) T-cell receptor positive in children. Amongst 22 adult CALM-AF10+ patients treated according to the LALA94/GRAALL03-05 protocols, the poor prognosis for event-free survival (p=0.0017) and overall survival (p=0.0014) was restricted to the 15 T-cell receptor negative cases. Amongst CALM-AF10+ T-cell receptor negative patients, 82% demonstrated an early T-cell precursor phenotype, reported to be of poor prognosis in pediatric T-cell acute lymphoblastic leukemia. Early T-cell precursor acute lymphoblastic leukemia corresponded to 22% of adult LALA94/GRAALL03-05 T-cell acute lymphoblastic leukemias, but had no prognostic impact per se. CALM-AF10 fusion within early T-cell precursor acute lymphoblastic leukemia (21%) did, however, identify a poor prognostic group for event-free survival (p=0.04). CALM-AF10 therefore identifies a poor prognostic group within sCD3/T-cell receptor negative adult T-cell acute lymphoblastic leukemias and is over-represented within early T-cell precursor acute lymphoblastic leukemias, where it identifies those likely to fail treatment. Its prognosis and overlap with early T-cell precursor acute lymphoblastic leukemia in pediatric T-cell acute lymphoblastic leukemia merits analysis. The clinical trial GRAALL was registered at Clinical Trials.gov number NCT00327678.
[Show abstract][Hide abstract] ABSTRACT: Bone marrow flow cytometric analysis is a powerful and rapid tool for evaluating aberrant plasma cell. In this study, we have examined the utility of multiparameter flow cytometry (MFC) in 52 patients with multiple myeloma (MM) and in 45 patients with monoclonal gammopathy with unknown significance (MGUS) into routine evaluation for the management of patients with plasma cell-related disorders. The plasma cells (PC) were identified by their light scatter distribution and reactivity patterns to CD138, CD38, and CD45. The combination of these parameters was helpful for identifying distinct subpopulations of PCs. Moderate to bright expression of CD56, CD20, CD24, CD28, and CD117 was detected in 67%, 26%, 13%, 27%, and 57% of MM cases and in 58%, 20%, 11%, 43% and 44% of MGUS cases, respectively. In MGUS group, the median percentage abnormal PCs/total PCs was 88% with 37 patients out of 45 (82%) with ratio <95%. The median ratio of the MM group was 98.9% and a ratio ≥ 95% was observed in 37 samples out of 44 (84%). In conclusion, MFC immunophenotyping of PCs has obvious clinical relevance in differential diagnosis between MM and others monoclonal gammopathies, identification of high-risk MGUS and smouldering MM, and minimal residual disease monitoring of MM. Our results showed that this tool can be easily applied in haematology laboratories.
Annales de biologie clinique. 06/2013; 71(3):313-323.
[Show abstract][Hide abstract] ABSTRACT: Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL-rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene (B90%): AFF1/AF4, MLLT3/AF9, MLLT1/ENL,
[Show abstract][Hide abstract] ABSTRACT: INTRODUCTION: Prognosis of enteropathy-associated T cell lymphoma is poor but predictors of survival remain ill-defined. How clinical presentation, pathological features and therapies influence outcome was evaluated in 37 thoroughly characterized patients with celiac disease and T-cell lymphoma. PATIENTS AND METHODS: Medical files were studied retrospectively. Lymphoma and intestinal mucosa were analysed by histopathology, multiplex PCR and intestinal intraepithelial lymphocytes phenotyping. Survival and prognostic factors were analysed using Kaplan-Meier curves with Logrank test and Cox Model. RESULTS: Lymphoma complicated non clonal enteropathy, celiac disease (n=15) and type I refractory celiac disease (n=2) in 17 patients and clonal type II refractory celiac disease in 20 patients. Twenty-five patients underwent surgery with resection of the main tumour mass in 22 cases. In univariate analysis, non clonal celiac disease, serum albumin level>21.6g/L at diagnosis, chemotherapy and surgical resection predicted good survival (p=0.0007, p<0.0001, p<0.0001, p<0.0001, respectively). In multivariate analysis, serum albumin level>21.6g/L, chemotherapy and reductive surgery were all significantly associated with increased survival (p<0.002, p<0.03, p<0.03, respectively). CONCLUSIONS: Our study underlines the prognostic value of celiac disease type in patients with T-cell lymphoma, and suggests that a combination of nutritional, chemotherapy and reductive surgery may improve survival.
Digestive and Liver Disease 01/2013; · 3.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Capsule endoscopy (CE) allows for the assessment of the small bowel in numerous intestinal diseases, including celiac disease (CD). The main advantage of CE is the complete visualization of the intestinal mucosal surface. The objective of this study was to investigate whether CE can predict the severity of CD and detect complications.
We retrospectively studied the medical files of 9 patients with symptomatic CD, 11 patients with refractory celiac disease type I (RCDI) and 18 patients with refractory celiac disease type II (RCDII), and 45 patients without CD who were investigated both CE and upper endoscopy or enteroscopy. The type of CD was diagnosed on the basis of a centralized histological review, flow cytometry analysis of intraepithelial lymphocytes, and the analysis of T-cell receptor rearrangement by multiplex polymerase chain reaction.
A total of 47 CEs (10, 11, and 26 CEs in the symptomatic CD, RCDI, and RCDII groups, respectively) from the 38 celiac patients and 47 CEs from the 45 nonceliac patients were retrospectively reviewed. Villous atrophy, numerous, or distally located ulcers were more frequent in celiac patients than in controls. Among celiac patients, CE was of acceptable quality in 96% of cases and was complete in 62% of cases. The concordance of CE with histology for villous atrophy was better than that of optic endoscopy (κ coefficient =0.45 vs. 0.24, P<0.001). Extensive mucosal damage on CE was associated with low serum albumin (P=0.003) and the RCDII form (P=0.02). Three cases of overt lymphoma were detected by CE during the follow-up.
CE findings have a satisfactory concordance with histology and nutritional status in patients with symptomatic or refractory CD. Moreover, CE may predict the type of RCD and allows for the early detection of overt lymphoma.
The American Journal of Gastroenterology 09/2012; 107(10):1546-53. · 7.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chromosomal translocations involving the TCR loci represent one of the most recurrent oncogenic hallmarks of T-cell acute lymphoblastic leukemia (T-ALL) and are generally believed to result from illegitimate V(D)J recombination events. However, molecular characterization and evaluation of the extent of recombinase involvement at the TCR-oncogene junction has not been fully evaluated. In the present study, screening for TCRβ and TCRα/δ translocations by FISH and ligation-mediated PCR in 280 T-ALLs allowed the identification of 4 previously unreported TCR-translocated oncogene partners: GNAG, LEF1, NKX2-4, and IL2RB. Molecular mapping of genomic junctions from TCR translocations showed that the majority of oncogenic partner breakpoints are not recombinase mediated and that the regulatory elements predominantly used to drive oncogene expression differ markedly in TCRβ (which are exclusively enhancer driven) and TCRα/δ (which use an enhancer-independent cryptic internal promoter) translocations. Our data also imply that oncogene activation takes place at a very immature stage of thymic development, when Dδ2-Dδ3/Dδ3-Jδ1 and Dβ-Jβ rearrangements occur, whereas the bulk leukemic maturation arrest occurs at a much later (cortical) stage. These observations have implications for T-ALL therapy, because the preleukemic early thymic clonogenic population needs to be eradicated and its disappearance monitored.
[Show abstract][Hide abstract] ABSTRACT: Large granular lymphocyte leukemia (LGL) is characterized by clonal expansion of CD3+ T cells or CD3(-) natural killer cells and frequently is associated with autoimmune diseases. We describe 2 patients with celiac disease who no longer responded to gluten-free diets after they developed T-cell LGL, with intestinal localization of malignant lymphocytes. Flow cytometry phenotyping of isolated intestinal intraepithelial and lamina propria cells eliminated type II refractory celiac disease, identifying large-sized CD8(+)CD57(+) T cells. Treatment with a combination of cyclosporine and methotrexate restored the patients' sensitivity to gluten-free diets. LGL therefore might be a cause of refractory celiac disease that is sensitive to immunosuppressive therapy.
[Show abstract][Hide abstract] ABSTRACT: Minimal residual disease (MRD) quantification is widely used for therapeutic stratification in pediatric acute lymphoblastic leukemia (ALL). A robust, reproducible, sensitivity of at least 0.01% has been achieved for IG/TCR clonal rearrangements using allele-specific quantitative PCR (IG/TCR-QPCR) within the EuroMRD consortium. Whether multiparameter flow cytometry (MFC) can reach such inter-center performance in ALL MRD monitoring remains unclear. In a multicenter study, MRD was measured prospectively on 598 follow-up bone marrow samples from 102 high-risk children and 136 adult ALL patients, using IG/TCR-QPCR and 4/5 color MFC. At diagnosis, all 238 patients (100%) had at least one suitable MRD marker with 0.01% sensitivity, including 205/238 samples (86%) by using IG/TCR-QPCR and 223/238 samples (94%) by using MFC. QPCR and MFC were evaluable in 495/598 (83%) samples. Qualitative results (<0.01% or 0.01%) concurred in 96% of samples and overall positivity (including <0.01% and nonquantifiable positivity) was concurrent in 84%. MRD values 0.01% correlated highly (r(2)=0.87) and 69% clustered within half-a-log(10). QPCR and MFC can therefore be comparable if properly standardized, and are highly complementary. MFC strategies will benefit from a concerted approach, as does molecular MRD monitoring, and will contribute significantly to the achievement of 100% MRD informativity in adult and pediatric ALL.Leukemia advance online publication, 16 October 2012; doi:10.1038/leu.2012.234.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 08/2012; · 10.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Constitutively activated FLT3 signaling is common in acute myeloid leukemia, and is currently under evaluation for targeted therapy, whereas little data is available in T-cell acute lymphoblastic leukemia (T-ALL). We analyzed 357 T-ALL cases for FLT3 mutations and transcript expression. FLT3 mutations (3% overall) and overexpression (FLT3 high expresser (FLT3(High))) were restricted to immature/TCRγδ T-ALLs. In vitro FLT3 inhibition induced apoptosis in only 30% of FLT3(High) T-ALLs and did not correlate with mutational status. In order to investigate the mechanisms of primary resistance to FLT3 inhibition, a broad quantitative screen for receptor kinome transcript deregulation was performed by Taqman Low Density Array. FLT3 deregulation was associated with overexpression of a network of receptor kinases (RKs), potentially responsible for redundancies and sporadic response to specific FLT3 inhibition. In keeping with this resistance to FLT3 inhibition could be reversed by dual inhibition of FLT3 and KIT with a synergistic effect. We conclude that immature T-ALL may benefit from multitargeted RK inhibition and that exploration of the receptor kinome defines a rational strategy for testing multitarget kinase inhibition in malignant diseases.Leukemia advance online publication, 27 July 2012; doi:10.1038/leu.2012.177.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 07/2012; · 10.16 Impact Factor