ABSTRACT
Despite tremendous improvements in the outcome of patients with multiple myeloma in the past decade, high-risk patients have not benefited from the approval of novel drugs. The most important prognostic factor is the loss of parts of the short arm of chromosome 17, known as deletion 17p (del(17p)). A recent publication (on a small number of patients) suggested that these patients are at very high-risk only if del(17p) is associated with TP53 mutations, the so-called "double-hit" population. To validate this finding, we designed a much larger study on 121 patients presenting del(17p) in > 55% of their plasma cells, and homogeneously treated by an intensive approach. For these 121 patients, we performed deep next generation sequencing targeted on TP53. The outcome was then compared with a large control population (2505 patients lacking del(17p)). Our results confirmed that the "double hit" situation is the worst (median survival = 36 months), but that del(17p) alone also confers a poor outcome compared with the control cohort (median survival = 52.8 months vs 152.2 months, respectively). In conclusion, our study clearly confirms the extremely poor outcome of patients displaying "double hit," but also that del(17p) alone is still a very high-risk feature, confirming its value as a prognostic indicator for poor outcome.
Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 17/genetics , Multiple Myeloma/genetics , Tumor Suppressor Protein p53/genetics , Adult , Aged , Female , Humans , Male , Middle Aged , Multiple Myeloma/diagnosis , Mutation , Prognosis , Young AdultABSTRACT
Germline GATA2 mutations predispose to myeloid malignancies resulting from the progressive acquisition of additional somatic mutations. Here we describe clinical and biological features of 78 GATA2-deficient patients. Hematopoietic stem and progenitor cell phenotypic characterization revealed an exhaustion of myeloid progenitors. Somatic mutations in STAG2, ASXL1 and SETBP1 genes along with cytogenetic abnormalities (monosomy 7, trisomy 8, der(1;7)) occurred frequently in patients with GATA2 germline mutations. Patients were classified into three hematopoietic spectra based on bone marrow cytomorphology. No somatic additional mutations were detected in patients with normal bone marrow (spectrum 0), whereas clonal hematopoiesis mediated by STAG2 mutations was frequent in those with a hypocellular and/or myelodysplastic bone marrow without excess blasts (spectrum 1). Finally, SETBP1, RAS pathway and RUNX1 mutations were predominantly associated with leukemic transformation stage (spectrum 2), highlighting their implications in the transformation process. Specific somatic alterations, potentially providing distinct selective advantages to affected cells, are therefore associated with the clinical/hematological evolution of GATA2 syndrome. Our study not only suggests that somatic genetic profiling will help clinicians in their management of patients, but will also clarify the mechanism of leukemogenesis in the context of germline GATA2 mutations.
Subject(s)
GATA2 Deficiency , Myeloproliferative Disorders , Humans , GATA2 Deficiency/diagnosis , GATA2 Deficiency/genetics , Myeloproliferative Disorders/genetics , Mutation , Bone Marrow , Germ-Line Mutation , GATA2 Transcription Factor/geneticsABSTRACT
The oncogenic events involved in breast implant-associated anaplastic large cell lymphoma (BI-ALCL) remain elusive. To clarify this point, we have characterized the genomic landscape of 34 BI-ALCLs (15 tumor and 19 in situ subtypes) collected from 54 BI-ALCL patients diagnosed through the French Lymphopath network. Whole-exome sequencing (n = 22, with paired tumor/germline DNA) and/or targeted deep sequencing (n = 24) showed recurrent mutations of epigenetic modifiers in 74% of cases, involving notably KMT2C (26%), KMT2D (9%), CHD2 (15%), and CREBBP (15%). KMT2D and KMT2C mutations correlated with a loss of H3K4 mono- and trimethylation by immunohistochemistry. Twenty cases (59%) showed mutations in ≥1 member of the JAK/STAT pathway, including STAT3 (38%), JAK1 (18%), and STAT5B (3%), and in negative regulators, including SOCS3 (6%), SOCS1 (3%), and PTPN1 (3%). These mutations were more frequent in tumor-type samples than in situ samples (P = .038). All BI-ALCLs expressed pSTAT3, regardless of the mutational status of genes in the JAK/STAT pathway. Mutations in the EOMES gene (12%) involved in lymphocyte development, PI3K-AKT/mTOR (6%), and loss-of-function mutations in TP53 (12%) were also identified. Copy-number aberration (CNA) analysis identified recurrent alterations, including gains on chromosomes 2, 9p, 12p, and 21 and losses on 4q, 8p, 15, 16, and 20. Regions of CNA encompassed genes involved in the JAK/STAT pathway and epigenetic regulators. Our results show that the BI-ALCL genomic landscape is characterized by not only JAK/STAT activating mutations but also loss-of-function alterations of epigenetic modifiers.
Subject(s)
Breast Implants/adverse effects , Epigenesis, Genetic , Janus Kinases/metabolism , Lymphoma, Large-Cell, Anaplastic/etiology , Lymphoma, Large-Cell, Anaplastic/genetics , STAT Transcription Factors/metabolism , Signal Transduction , Adult , Aged , Aged, 80 and over , DNA Copy Number Variations , Female , Genome, Human , Humans , Lymphoma, Large-Cell, Anaplastic/pathology , Middle Aged , Mutation/geneticsABSTRACT
PAX5 is a well-known haploinsufficient tumor suppressor gene in human B-cell precursor acute lymphoblastic leukemia (B-ALL) and is involved in various chromosomal translocations that fuse a part of PAX5 with other partners. However, the role of PAX5 fusion proteins in B-ALL initiation and transformation is ill-known. We previously reported a new recurrent t(7;9)(q11;p13) chromosomal translocation in human B-ALL that juxtaposed PAX5 to the coding sequence of elastin (ELN). To study the function of the resulting PAX5-ELN fusion protein in B-ALL development, we generated a knockin mouse model in which the PAX5-ELN transgene is expressed specifically in B cells. PAX5-ELN-expressing mice efficiently developed B-ALL with an incidence of 80%. Leukemic transformation was associated with recurrent secondary mutations on Ptpn11, Kras, Pax5, and Jak3 genes affecting key signaling pathways required for cell proliferation. Our functional studies demonstrate that PAX5-ELN affected B-cell development in vitro and in vivo featuring an aberrant expansion of the pro-B cell compartment at the preleukemic stage. Finally, our molecular and computational approaches identified PAX5-ELN-regulated gene candidates that establish the molecular bases of the preleukemic state to drive B-ALL initiation. Hence, our study provides a new in vivo model of human B-ALL and strongly implicates PAX5 fusion proteins as potent oncoproteins in leukemia development.
Subject(s)
Elastin/genetics , Oncogene Proteins, Fusion/genetics , PAX5 Transcription Factor/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Animals , B-Lymphocytes/pathology , B-Lymphocytes/physiology , Elastin/metabolism , Gene Expression Regulation, Leukemic , Gene Knock-In Techniques , Janus Kinase 3/genetics , Mice, Transgenic , Mutation , Neoplasms, Experimental , Oncogene Proteins, Fusion/metabolism , PAX5 Transcription Factor/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics , Proto-Oncogene Proteins p21(ras)/geneticsSubject(s)
Germ-Line Mutation , PAX5 Transcription Factor/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adult , Child , Female , Genetic Predisposition to Disease , Humans , Male , Pedigree , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/congenital , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathologyABSTRACT
Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder of remarkable heterogeneity as demonstrated by cytogenetics and molecular analyses. Complex karyotype (CK), TP53 deletions and/or mutations (TP53 disruption), IGVH mutational status, and, more recently, recurrent somatic mutations have been identified as prognostic markers in CLL. On a cohort of 110 patients with CLL treated with first-line fludarabin, cyclophosphamide, and rituximab treatment compared with 33 untreated (watch and wait) patients with CLL, we report more frequent complex karyotypes (34 vs 15%; P = .05), unmutated IGHV (70 vs 21%; P < .0001), ATM deletion (25 vs 6%, P = .02), and NOTCH mutation (3 vs 17%, P = .04). Among treated patients, 39 relapsed during the follow-up period. These patients were characterized before treatment by a higher incidence of trisomy 12 (38 vs 11%, P < .001) and TP53 disruption (31 vs 4%, P = .0002). A significantly shorter 5-year overall survival was found for treated patients with CK (72.4 vs 85.8%; P = .007), unmutated IGHV (70 vs 100%; P = .04), or TP53 disruption (55.7 vs 82.7%; P < .0001). Three risk groups were defined based on the status of TP53 disruption or unmutated IGVH, which differed significantly in terms of 5-year overall survival. Moreover, the presence of CK impacted pejoratively 5-year overall survival and progression-free survival in all these 3 groups. Conventional karyotyping therefore appears to be of value, CK being an additional factor, undetectable in classical FISH, in patients with CLL at the stage when therapy becomes required.
Subject(s)
Immunoglobulin Heavy Chains/genetics , Immunoglobulin Variable Region/genetics , Karyotype , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Mutation , Tumor Suppressor Protein p53/genetics , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor , Cohort Studies , Drug Resistance, Neoplasm , Female , Humans , In Situ Hybridization, Fluorescence , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Male , Prognosis , Recurrence , Survival AnalysisABSTRACT
UNLABELLED: Congenital neutropenia is a group of genetic disorders that involve chronic neutropenia and susceptibility to infections. These neutropenias may be isolated or associated with immunologic defects or extra-hematopoietic manifestations. Complications may occur as infectious diseases, but also less frequently as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Recently, the transcription factor GATA2 has been identified as a new predisposing gene for familial AML/MDS. In the present study, we describe the initial identification by exome sequencing of a GATA2 R396Q mutation in a family with a history of chronic mild neutropenia evolving to AML and/or MDS. The subsequent analysis of the French Severe Chronic Neutropenia Registry allowed the identification of 6 additional pedigrees and 10 patients with 6 different and not previously reportedGATA2 mutations (R204X, E224X, R330X, A372T, M388V, and a complete deletion of the GATA2 locus). The frequent evolution to MDS and AML in these patients reveals the importance of screening GATA2 in chronic neutropenia associated with monocytopenia because of the frequent hematopoietic transformation, variable clinical expression at onset, and the need for aggressive therapy in patients with poor clinical outcome. KEY POINTS: Mutations of key transcription factor in myeloid malignancies.
Subject(s)
GATA2 Transcription Factor/genetics , Genetic Diseases, Inborn/genetics , Leukemia, Myeloid, Acute/genetics , Mutation, Missense , Myelodysplastic Syndromes/genetics , Neutropenia/genetics , Adolescent , Adult , Amino Acid Substitution , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/pathology , Child , Child, Preschool , Female , France , GATA2 Transcription Factor/metabolism , Genetic Diseases, Inborn/metabolism , Genetic Diseases, Inborn/pathology , Genetic Diseases, Inborn/therapy , Genetic Loci , Humans , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Leukemia, Myeloid, Acute/therapy , Male , Myelodysplastic Syndromes/metabolism , Myelodysplastic Syndromes/pathology , Myelodysplastic Syndromes/therapy , Neutropenia/metabolism , Pedigree , RegistriesABSTRACT
Anaplastic large-cell lymphomas (ALCLs) bearing the t(2;5) translocation (ALK(+)ALCLs) are frequently characterized by skin colonization and associated with a poor prognosis. Using conditional transgenic models of anaplastic lymphoma kinase-positive (ALK(+)) lymphomas and human ALK(+)ALCL cell lines, in the present study, we show that high-mobility-group box-1 (HMGB-1), a proinflammatory cytokine, is released by ALK(+) cells, and demonstrate extracellular HMGB-1-stimulated secretion of the IL-8 chemokine by HaCaT keratinocytes through the involvement of MMP-9, PAR-2, and the NF-κB pathway. Furthermore, we demonstrate that, in vitro, IL-8 is able to induce the invasiveness of ALK(+) cells, which express the IL-8 receptors CXCR1 and CXCR2. In vitro and in vivo, HMGB-1 inhibition achieved by glycyrrhizin treatment led to a drastic reduction in ALK(+) cell invasiveness. The pathophysiological relevance of our observations was confirmed by demonstrating that the HMGB-1 and IL-8 receptors are expressed in ALK(+)ALCL biopsies. We have also shown that IL-8 secretion is correlated with leukemic dissemination of ALK(+) cells in a significant number of patients. The results of the present study demonstrate for the first time a relationship among the pro-inflammatory mediators HMGB-1, MMP-9, PAR-2, and IL-8. We propose that these mediators create a premetastatic niche within the skin, thereby participating in ALK(+) lymphoma epidermotropism.
Subject(s)
HMGB1 Protein/physiology , Interleukin-8/metabolism , Keratinocytes/metabolism , Lymphoma, Large-Cell, Anaplastic/pathology , NF-kappa B/metabolism , Receptor Protein-Tyrosine Kinases/metabolism , Skin/metabolism , Anaplastic Lymphoma Kinase , Animals , Cells, Cultured , Female , HMGB1 Protein/genetics , HMGB1 Protein/metabolism , Humans , Keratinocytes/pathology , Leukemic Infiltration/genetics , Leukemic Infiltration/metabolism , Leukemic Infiltration/pathology , Lymphoma, Large-Cell, Anaplastic/genetics , Lymphoma, Large-Cell, Anaplastic/metabolism , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/metabolism , Matrix Metalloproteinase 9/physiology , Mice , Mice, Inbred C57BL , Mice, SCID , Mice, Transgenic , NF-kappa B/genetics , Receptor Protein-Tyrosine Kinases/genetics , Receptor, PAR-2/genetics , Receptor, PAR-2/metabolism , Receptor, PAR-2/physiology , Signal Transduction/physiology , Skin/pathology , Stem Cell Niche/genetics , Stem Cell Niche/immunologyABSTRACT
B cell acute lymphoblastic leukemia (B-ALL) is a multistep disease characterized by the hierarchical acquisition of genetic alterations. However, the question of how a primary oncogene reprograms stem cell-like properties in committed B cells and leads to a preneoplastic population remains unclear. Here, we used the PAX5::ELN oncogenic model to demonstrate a causal link between the differentiation blockade, the self-renewal, and the emergence of preleukemic stem cells (pre-LSCs). We show that PAX5::ELN disrupts the differentiation of preleukemic cells by enforcing the IL7r/JAK-STAT pathway. This disruption is associated with the induction of rare and quiescent pre-LSCs that sustain the leukemia-initiating activity, as assessed using the H2B-GFP model. Integration of transcriptomic and chromatin accessibility data reveals that those quiescent pre-LSCs lose B cell identity and reactivate an immature molecular program, reminiscent of human B-ALL chemo-resistant cells. Finally, our transcriptional regulatory network reveals the transcription factor EGR1 as a strong candidate to control quiescence/resistance of PAX5::ELN pre-LSCs as well as of blasts from human B-ALL.
Subject(s)
Burkitt Lymphoma , Leukemia , Humans , Janus Kinases , STAT Transcription Factors , Signal Transduction , Stem CellsABSTRACT
Global transcriptional technologies have revolutionised the study of lymphoid cell populations, but human γδ T lymphocytes specific for phosphoantigens remain far less deeply characterised by these methods despite the great therapeutic potential of these cells. Here we analyse the transcriptome of circulating TCRVγ(+) γδ T cells isolated from healthy individuals, and their relation with those from other lymphoid cell subsets. We report that the gene signature of phosphoantigen-specific TCRVγ(+) γδ T cells is a hybrid of those from αß T and NK cells, with more 'NK-cell' genes than αß T cells have and more 'T-cell' genes than NK cells. The expression profile of TCRVγ(+) γδ T cells stimulated with phosphoantigen recapitulates their immediate physiological functions: Th1 cytokine, chemokine and cytotoxic activities reflect their high mitotic activity at later time points and do not indicate antigen-presenting functions. Finally, such hallmarks make the transcriptome of γδ T cells, whether resting or clonally expanding, clearly distinctive from that of NK/T or peripheral T-cell lymphomas of the γδ subtype.
Subject(s)
Cytokines/immunology , Epitopes, T-Lymphocyte/immunology , Killer Cells, Natural/immunology , Receptors, Antigen, T-Cell, alpha-beta/immunology , Receptors, Antigen, T-Cell, gamma-delta/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocytes/immunology , Animals , Cytokines/genetics , Data Mining , Epitopes, T-Lymphocyte/genetics , Flow Cytometry , Gene Expression Profiling/methods , Humans , Immunophenotyping/methods , Oligonucleotide Array Sequence Analysis , Phosphoproteins/immunology , RNA/chemistry , RNA/genetics , Receptors, Antigen, T-Cell, alpha-beta/genetics , Receptors, Antigen, T-Cell, gamma-delta/genetics , Reverse Transcriptase Polymerase Chain Reaction , Statistics, NonparametricABSTRACT
Acute basophilic leukemia (ABL) is a rare subtype of acute leukemia with clinical features and symptoms related to hyperhistaminemia because of excessive growth of basophils. No known recurrent cytogenetic abnormality is associated with this leukemia. Rare cases of t(X;6)(p11;q23) translocation have been described but these were sporadic. We report here 4 cases of ABL with a t(X;6)(p11;q23) translocation occurring in male infants. Because of its location on chromosome 6q23, MYB was a good candidate gene. Our molecular investigations, based on fluorescence in situ hybridization and rapid amplification of cDNA ends, revealed that the translocation generated a MYB-GATA1 fusion gene. Expression of MYB-GATA1 in mouse lineage-negative cells committed them to the granulocyte lineage and blocked at an early stage of differentiation. Taken together, these results establish, for the first time, a link between a recurrent chromosomal translocation and the development of this particular subtype of infant leukemia.
Subject(s)
GATA1 Transcription Factor/genetics , Leukemia, Basophilic, Acute/genetics , Oncogene Proteins, Fusion/genetics , Oncogenes/genetics , Proto-Oncogene Proteins c-myb/genetics , Animals , Blotting, Western , Chromosomes, Human, Pair 6/genetics , Chromosomes, Human, X/genetics , Female , Humans , In Situ Hybridization, Fluorescence , Infant , Karyotyping , Male , Mice , Mice, Inbred C57BL , Prognosis , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction , Translocation, Genetic , Tumor Stem Cell AssayABSTRACT
PAX5 is the main target of somatic mutations in acute B lymphoblastic leukemia (B-ALL). We analyzed 153 adult and child B-ALL harboring karyotypic abnormalities at chromosome 9p, to determine the frequency and the nature of PAX5 alterations. We found PAX5 internal rearrangements in 21% of the cases. To isolate fusion partners, we used classic and innovative techniques (rolling circle amplification-rapid amplification of cDNA ends) and single nucleotide polymorphism-comparative genomic hybridization arrays. Recurrent and novel fusion partners were identified, including NCoR1, DACH2, GOLGA6, and TAOK1 genes showing the high variability of the partners. We noted that half the fusion genes can give rise to truncated PAX5 proteins. Furthermore, malignant cells carrying PAX5 fusion genes displayed a simple karyotype. These data strongly suggest that PAX5 fusion genes are early players in leukemogenesis. In addition, PAX5 deletion was observed in 60% of B-ALL with 9p alterations. Contrary to cases with PAX5 fusions, deletions were associated with complex karyotypes and common recurrent translocations. This supports the hypothesis of the secondary nature of the deletion. Our data shed more light on the high variability of PAX5 alterations in B-ALL. Therefore, it is probable that gene fusions occur early, whereas deletions should be regarded as a late/secondary event.
Subject(s)
Cytogenetic Analysis , Mutation/genetics , PAX5 Transcription Factor/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Chromosome Breakpoints , Chromosomes, Human, Pair 9/genetics , Cloning, Molecular , Cohort Studies , Female , France , Gene Expression Regulation, Leukemic , Humans , Karyotyping , Male , Middle Aged , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/metabolism , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Young AdultABSTRACT
Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis leading to peripheral cytopenias and in a substantial proportion of cases to acute myeloid leukemia. The deletion of the long arm of chromosome 11, del(11q), is a rare but recurrent clonal event in MDS. Here, we detail the largest series of 113 cases of MDS and myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) harboring a del(11q) analyzed at clinical, cytological, cytogenetic, and molecular levels. Female predominance, a survival prognosis similar to other MDS, a low monocyte count, and dysmegakaryopoiesis were the specific clinical and cytological features of del(11q) MDS. In most cases, del(11q) was isolated, primary and interstitial encompassing the 11q22-23 region containing ATM, KMT2A, and CBL genes. The common deleted region at 11q23.2 is centered on an intergenic region between CADM1 (also known as Tumor Suppressor in Lung Cancer 1) and NXPE2. CADM1 was expressed in all myeloid cells analyzed in contrast to NXPE2. At the functional level, the deletion of Cadm1 in murine Lineage-Sca1+Kit+ cells modifies the lymphoid-to-myeloid ratio in bone marrow, although not altering their multilineage hematopoietic reconstitution potential after syngenic transplantation. Together with the frequent simultaneous deletions of KMT2A, ATM, and CBL and mutations of ASXL1, SF3B1, and CBL, we show that CADM1 may be important in the physiopathology of the del(11q) MDS, extending its role as tumor-suppressor gene from solid tumors to hematopoietic malignancies.
Subject(s)
Cell Adhesion Molecule-1/metabolism , Leukemia, Myeloid, Acute , Myelodysplastic Syndromes , Animals , Cell Adhesion Molecule-1/genetics , Chromosome Deletion , Chromosomes, Human, Pair 11 , Female , Genes, Tumor Suppressor , Humans , Leukemia, Myeloid, Acute/genetics , Mice , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/pathologyABSTRACT
A 3-year-old girl of nonconsanguineous healthy parents presented with cervical and mediastinal lymphadenopathy due to Mycobacterium fortuitum infection. Routine blood analysis showed normal hemoglobin, neutrophils, and platelets but profound mononuclear cell deficiency (monocytes < 0.1 × 109/L; B cells 78/µL; NK cells 48/µL). A 548 902-bp region containing GATA2 was sequenced by targeted capture and deep sequencing. This revealed a de novo 187-kb duplication of the entire GATA2 locus, containing a maternally inherited copy number variation deletion of 25 kb (GRCh37: esv2725896 and nsv513733). Many GATA2-associated phenotypes have been attributed to amino acid substitution, frameshift/deletion, loss of intronic enhancer function, or aberrant splicing. Gene deletion has been described, but other structural variation has not been reported in the germline configuration. In this case, duplication of the GATA2 locus was paradoxically associated with skewed diminished expression of GATA2 messenger RNA and loss of GATA2 protein. Chimeric RNA fusion transcripts were not detected. A possible mechanism involves increased transcription of the anti-sense long noncoding RNA GATA2-AS1 (RP11-472.220), which was increased several fold. This case further highlights that evaluation of the allele count is essential in any case of suspected GATA2-related syndrome.
Subject(s)
GATA2 Deficiency , Alleles , Child, Preschool , DNA Copy Number Variations , Female , GATA2 Deficiency/genetics , GATA2 Transcription Factor/genetics , Humans , Monocytes , PhenotypeABSTRACT
We previously reported the benefit of lomustine addition to conventional chemotherapy in older acute myeloid leukemias with nonadverse chromosomal aberrations in the LAM-SA 2007 randomized clinical trial (NCT00590837). A molecular analysis of 52 genes performed in 330 patients included in this trial, 163 patients being treated with lomustine in combination with idarubicin and cytarabine and 167 without lomustine, identified 1088 mutations with an average of 3.3 mutations per patient. NPM1, FLT3, and DNMT3A were the most frequently mutated genes. A putative therapeutic target was identified in 178 patients (54%). Among five molecular classifications analyzed, the ELN2017 risk classification has the stronger association with the clinical evolution. Patients not treated with lomustine have an expected survival prognosis in agreement with this classification regarding the overall and event-free survivals. In strong contrast, lomustine erased the ELN2017 classification prognosis. The benefit of lomustine in nonadverse chromosomal aberrations was restricted to patients with RUNX1, ASXL1, TP53, and FLT3-ITDhigh/NPM1WT mutations in contrast to the intermediate and favorable ELN2017 patients. This post-hoc analysis identified a subgroup of fit elderly AML patients with intermediate cytogenetics and molecular markers who may benefit from lomustine addition to intensive chemotherapy.
Subject(s)
Antineoplastic Agents, Alkylating/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Lomustine/therapeutic use , Biomarkers, Tumor/genetics , Chromosome Aberrations/drug effects , Cytarabine/therapeutic use , Cytogenetics/methods , Female , Humans , Idarubicin/therapeutic use , Karyotype , Karyotyping/methods , Leukemia, Myeloid, Acute/genetics , Male , Middle Aged , Mutation/drug effects , Nucleophosmin , PrognosisABSTRACT
Hypomethylating agents are a classical frontline low-intensity therapy for older patients with acute myeloid leukemia. Recently, TP53 gene mutations have been described as a potential predictive biomarker of better outcome in patients treated with a ten-day decitabine regimen., However, functional characteristics of TP53 mutant are heterogeneous, as reflected in multiple functional TP53 classifications and their impact in patients treated with azacitidine is less clear. We analyzed the therapeutic course and outcome of 279 patients treated with azacitidine between 2007 and 2016, prospectively enrolled in our regional healthcare network. By screening 224 of them, we detected TP53 mutations in 55 patients (24.6%), including 53 patients (96.4%) harboring high-risk cytogenetics. The identification of any TP53 mutation was associated with worse overall survival but not with response to azacitidine in the whole cohort and in the subgroup of patients with adverse karyotype. Stratification of patients according to three recent validated functional classifications did not allow the identification of TP53 mutated patients who could benefit from azacitidine. Systematic TP53 mutant classification will deserve further exploration in the setting of patients treated with conventional therapy and in the emerging field of therapies targeting TP53 pathway.
Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Azacitidine/therapeutic use , Genes, p53 , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Mutation , Tumor Suppressor Protein p53/genetics , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Female , France/epidemiology , Humans , Kaplan-Meier Estimate , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Prognosis , Prospective Studies , RegistriesABSTRACT
PURPOSE: Children with Down syndrome (constitutive trisomy 21) that develop acute lymphoblastic leukemia (DS-ALL) have a 3-fold increased likelihood of treatment-related mortality coupled with a higher cumulative incidence of relapse, compared with other children with B-cell acute lymphoblastic leukemia (B-ALL). This highlights the lack of suitable treatment for Down syndrome children with B-ALL. EXPERIMENTAL DESIGN: To facilitate the translation of new therapeutic agents into clinical trials, we built the first preclinical cohort of patient-derived xenograft (PDX) models of DS-ALL, comprehensively characterized at the genetic and transcriptomic levels, and have proven its suitability for preclinical studies by assessing the efficacy of drug combination between the MEK inhibitor trametinib and conventional chemotherapy agents. RESULTS: Whole-exome and RNA-sequencing experiments revealed a high incidence of somatic alterations leading to RAS/MAPK pathway activation in our cohort of DS-ALL, as well as in other pediatric B-ALL presenting somatic gain of the chromosome 21 (B-ALL+21). In murine and human B-cell precursors, activated KRASG12D functionally cooperates with trisomy 21 to deregulate transcriptional networks that promote increased proliferation and self renewal, as well as B-cell differentiation blockade. Moreover, we revealed that inhibition of RAS/MAPK pathway activation using the MEK1/2 inhibitor trametinib decreased leukemia burden in several PDX models of B-ALL+21, and enhanced survival of DS-ALL PDX in combination with conventional chemotherapy agents such as vincristine. CONCLUSIONS: Altogether, using novel and suitable PDX models, this study indicates that RAS/MAPK pathway inhibition represents a promising strategy to improve the outcome of Down syndrome children with B-cell precursor leukemia.
Subject(s)
Down Syndrome/complications , Down Syndrome/genetics , Down Syndrome/metabolism , Leukemia, B-Cell/diagnosis , Leukemia, B-Cell/etiology , Mitogen-Activated Protein Kinases/metabolism , Signal Transduction , ras Proteins/metabolism , Animals , Computational Biology/methods , Disease Models, Animal , Disease Susceptibility , Gene Expression Profiling , Humans , Immunophenotyping , Leukemia, B-Cell/therapy , Mice , Mice, Transgenic , Oncogenes , Protein Kinase Inhibitors/pharmacology , Pyridones/pharmacology , Pyrimidinones/pharmacology , Signal Transduction/drug effectsABSTRACT
Describing the prognosis of sub-groups of acute myeloid leukemia (AML) patients treated in real world with current therapies is becoming increasingly relevant to estimate the benefit that new targeted drugs will bring in the field. This is particularly the case when novel drugs are registered on the basis of non-randomized studies. IDH2 inhibitors have recently emerged as promising drugs in patients with IDH2R140 or IDH2R172 mutations. Enasidenib, a first-in-class IDH2 inhibitor, has been approved following promising results of a phase 1-2 clinical trial in relapsed or refractory AML patients with IDH2 mutations. In this study, we described the characteristics, treatments and outcome of 75 IDH2 mutated patients both at diagnosis and relapse or refractory disease. Among the 33 relapsed/refractory AML patients with either IDH2R140 or IDH2R172, 28 (84.8%) patients received salvage therapy and 14 achieved a complete response (50%). Median duration of response was 15.2 months. Median, 1-y, 3-y and 5-y OS were 15.1 months (IQR, 4.6-37.7), 53.1% (95% CI, 33.2-69.5), 29.2% (95% CI, 12.6-48.1) and 24.4% (95% CI, 9.3-43.1), respectively. In responding patients, median OS was 37.7 months and 1-y, 3-y and 5-y OS was 85.7%, 57.1% and 47.6%, respectively. In non-responding patients, median OS was 5.0 months (IQR, 4.5-8.6) and 1-y and 3-y OS was 17.9% and 0%, respectively. Thus, a substantial number of R/R AML patients with IDH2 mutations can be salvaged by current treatments and benefit from prolonged survival. It is expected that novel targeted agents such as enasidenib will further improve efficacy and safety in the next future.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Drug Resistance, Neoplasm/drug effects , Isocitrate Dehydrogenase/genetics , Leukemia, Myeloid, Acute/mortality , Mutation , Neoplasm Recurrence, Local/mortality , Adult , Aged , Female , Follow-Up Studies , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Male , Middle Aged , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Prognosis , Retrospective Studies , Survival RateABSTRACT
Pax5 is the guardian of the B cell identity since it primes or enhances the expression of B cell specific genes and concomitantly represses the expression of B cell inappropriate genes. The tight regulation of Pax5 is therefore required for an efficient B cell differentiation. A defect in its dosage can translate into immunodeficiency or malignant disorders such as leukemia or lymphoma. Pax5 is expressed from two different promoters encoding two isoforms that only differ in the sequence of their first alternative exon. Very little is known regarding the role of the two isoforms during B cell differentiation and the regulation of their expression. Our work aims to characterize the mechanisms of regulation of the expression balance of these two isoforms and their implication in the B cell differentiation process using murine ex vivo analyses. We show that these two isoforms are differentially regulated but have equivalent function during early B cell differentiation and may have functional differences after B cell activation. The tight control of their expression may thus reflect a way to finely tune Pax5 dosage during B cell differentiation process.