Oncogenic alterations underlying B-cell acute lymphoblastic leukemia (B-ALL) in adults remain incompletely elucidated. To uncover novel oncogenic drivers, we performed RNA sequencing and whole-genome ...analyses in a large cohort of unresolved B-ALL. We identified a novel subtype characterized by a distinct gene expression signature and the unique association of 2 genomic microdeletions. The 17q21.31 microdeletion resulted in a UBTF::ATXN7L3 fusion transcript encoding a chimeric protein. The 13q12.2 deletion resulted in monoallelic ectopic expression of the homeobox transcription factor CDX2, located 138 kb in cis from the deletion. Using 4C-sequencing and CRISPR interference experiments, we elucidated the mechanism of CDX2 cis-deregulation, involving PAN3 enhancer hijacking. CDX2/UBTF ALL (n = 26) harbored a distinct pattern of additional alterations including 1q gain and CXCR4 activating mutations. Within adult patients with Ph− B-ALL enrolled in GRAALL trials, patients with CDX2/UBTF ALL (n = 17/723, 2.4%) were young (median age, 31 years) and dramatically enriched in females (male/female ratio, 0.2, P = .002). They commonly presented with a pro-B phenotype ALL and moderate blast cell infiltration. They had poor response to treatment including a higher risk of failure to first induction course (19% vs 3%, P = .017) and higher post-induction minimal residual disease (MRD) levels (MRD ≥ 10−4, 93% vs 46%, P < .001). This early resistance to treatment translated into a significantly higher cumulative incidence of relapse (75.0% vs 32.4%, P = .004) in univariate and multivariate analyses. In conclusion, we discovered a novel B-ALL entity defined by the unique combination of CDX2 cis-deregulation and UBTF::ATXN7L3 fusion, representing a high-risk disease in young adults.
•CDX2 cis-deregulation and UBTF::ATXN7L3 fusion driven by focal deletions define a novel subtype of B-ALL.•CDX2/UBTF::ATXN7L3 is a high-risk B-ALL subtype in young adults, which warrants improved therapeutic strategies.
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Genomic studies in human acute lymphoblastic leukemia (ALL) have revealed clonal heterogeneity at diagnosis and clonal evolution at relapse. In this study, we used genome-wide profiling to compare ...human T cell ALL samples at the time of diagnosis and after engraftment (xenograft) into immunodeficient recipient mice. Compared with paired diagnosis samples, the xenograft leukemia often contained additional genomic lesions in established human oncogenes and/or tumor suppressor genes. Mimicking such genomic lesions by short hairpin RNA-mediated knockdown in diagnosis samples conferred a selective advantage in competitive engraftment experiments, demonstrating that additional lesions can be drivers of increased leukemia-initiating activity. In addition, the xenograft leukemias appeared to arise from minor subclones existing in the patient at diagnosis. Comparison of paired diagnosis and relapse samples showed that, with regard to genetic lesions, xenograft leukemias more frequently more closely resembled relapse samples than bulk diagnosis samples. Moreover, a cell cycle- and mitosis-associated gene expression signature was present in xenograft and relapse samples, and xenograft leukemia exhibited diminished sensitivity to drugs. Thus, the establishment of human leukemia in immunodeficient mice selects and expands a more aggressive malignancy, recapitulating the process of relapse in patients. These findings may contribute to the design of novel strategies to prevent or treat relapse.
Using a combination of molecular cytogenetic and large-scale expression analysis in human T-cell acute lymphoblastic leukemias (T-ALLs), we identified and characterized a new recurrent chromosomal ...translocation, targeting the major homeobox gene cluster HOXA and the TCRB locus. Real-time quantitative polymerase chain reaction (RQ-PCR) analysis showed that the expression of the whole HOXA gene cluster was dramatically dysregulated in the HOXA-rearranged cases, and also in MLL and CALM-AF10-related T-ALL cases, strongly suggesting that HOXA genes are oncogenic in these leukemias. Inclusion of HOXA-translocated cases in a general molecular portrait of 92 T-ALLs based on large-scale expression analysis shows that this rearrangement defines a new homogeneous subgroup, which shares common biologic networks with the TLX1- and TLX3-related cases. Because T-ALLs derive from T-cell progenitors, expression profiles of the distinct T-ALL subgroups were analyzed with respect to those of normal human thymic subpopulations. Inappropriate use or perturbation of specific molecular networks involved in thymic differentiation was detected. Moreover, we found a significant association between T-ALL oncogenic subgroups and ectopic expression of a limited set of genes, including several developmental genes, namely HOXA, TLX1, TLX3, NKX3-1, SIX6, and TFAP2C. These data strongly support the view that the abnormal expression of developmental genes, including the prototypical homeobox genes HOXA, is critical in T-ALL oncogenesis.
Previously, several individuals with X-linked SCID (SCID-X1) were treated by gene therapy to restore the missing IL-2 receptor gamma (IL2RG) gene to CD34+ BM precursor cells using gammaretroviral ...vectors. While 9 of 10 patients were successfully treated, 4 of the 9 developed T cell leukemia 31-68 months after gene therapy. In 2 of these cases, blast cells contained activating vector insertions near the LIM domain-only 2 (LMO2) proto-oncogene. Here, we report data on the 2 most recent adverse events, which occurred in patients 7 and 10. In patient 10, blast cells contained an integrated vector near LMO2 and a second integrated vector near the proto-oncogene BMI1. In patient 7, blast cells contained an integrated vector near a third proto-oncogene,CCND2. Additional genetic abnormalities in the patients' blast cells included chromosomal translocations, gain-of-function mutations activating NOTCH1, and copy number changes, including deletion of tumor suppressor gene CDKN2A, 6q interstitial losses, and SIL-TAL1 rearrangement. These findings functionally specify a genetic network that controls growth in T cell progenitors. Chemotherapy led to sustained remission in 3 of the 4 cases of T cell leukemia, but failed in the fourth. Successful chemotherapy was associated with restoration of polyclonal transduced T cell populations. As a result, the treated patients continued to benefit from therapeutic gene transfer.
Fanconi anemia (FA) patients experience chromosome instability, yielding hematopoietic stem/progenitor cell (HSPC) exhaustion and predisposition to poor-prognosis myeloid leukemia. Based on a ...longitudinal cohort of 335 patients, we performed clinical, genomic, and functional studies in 62 patients with clonal evolution. We found a unique pattern of somatic structural variants and mutations that shares features of BRCA-related cancers, the FA-hallmark being unbalanced, microhomology-mediated translocations driving copy-number alterations. Half the patients developed chromosome 1q gain, driving clonal hematopoiesis through MDM4 trisomy downmodulating p53 signaling later followed by secondary acute myeloid lukemia genomic alterations. Functionally, MDM4 triplication conferred greater fitness to murine and human primary FA HSPCs, rescued inflammation-mediated bone marrow failure, and drove clonal dominance in FA mouse models, while targeting MDM4 impaired leukemia cells in vitro and in vivo. Our results identify a linear route toward secondary leukemogenesis whereby early MDM4-driven downregulation of basal p53 activation plays a pivotal role, opening monitoring and therapeutic prospects.
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•Copy-number alterations rather than point mutations drive Fanconi anemia leukemia•Early trisomy 1q/MDM4 downregulates p53 signaling, conferring clonal advantage to FA HSPCs•Clonal hematopoiesis preceding MDS/AML can be monitored for timely intervention
Sebert, Gachet et al. analyzed longitudinal data from patients with Fanconi anemia, a rare inherited DNA-repair disease. They provided genomic and functional insights into MDM4-driven p53 response modulation yielding clonal hematopoiesis and preceding transformation to myeloid leukemia in the background of chromosomal instability and HSC attrition.
Acute myeloid leukemia (AML) is a heterogeneous group of malignancies that may be sensitive to the NK cell antitumor response. However, NK cells are frequently defective in AML. In this study, we ...found in an exploratory cohort (n = 46) that NK cell status at diagnosis of AML separated patients in two groups with a different clinical outcome. Patients with a deficient NK cell profile, including reduced expression of some activating NK receptors (e.g., DNAX accessory molecule-1, NKp46, and NKG2D) and decreased IFN-γ production, had a significantly higher risk of relapse (p = 0.03) independently of cytogenetic classification in multivariate analysis. Patients with defective NK cells showed a profound gene expression decrease in AML blasts for cytokine and chemokine signaling (e.g., IL15, IFNGR1, IFNGR2, and CXCR4), Ag processing (e.g., HLA-DRA, HLA-DRB1, and CD74) and adhesion molecule pathways (e.g., PVR and ICAM1). A set of 388 leukemic classifier genes defined in the exploratory cohort was independently validated in a multicentric cohort of 194 AML patients. In total, these data evidenced the interplay between NK cells and AML blasts at diagnosis allowing an immune-based stratification of AML patients independently of clinical classifications.
PTPN2 (protein tyrosine phosphatase non-receptor type 2, also known as TC-PTP) is a cytosolic tyrosine phosphatase that functions as a negative regulator of a variety of tyrosine kinases and other ...signaling proteins. In agreement with its role in the regulation of the immune system, PTPN2 was identified as a susceptibility locus for autoimmune diseases. In this work, we describe the identification of focal deletions of PTPN2 in human T-cell acute lymphoblastic leukemia (T-ALL). Deletion of PTPN2 was specifically found in T-ALLs with aberrant expression of the TLX1 transcription factor oncogene, including four cases also expressing the NUP214-ABL1 tyrosine kinase. Knockdown of PTPN2 increased the proliferation and cytokine sensitivity of T-ALL cells. In addition, PTPN2 was identified as a negative regulator of NUP214-ABL1 kinase activity. Our study provides genetic and functional evidence for a tumor suppressor role of PTPN2 and suggests that expression of PTPN2 may modulate response to treatment.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Fanconi anemia (FA) is a genetic condition associated with bone marrow (BM) failure, myelodysplasia (MDS), and acute myeloid leukemia (AML). We studied 57 FA patients with hypoplastic or aplastic ...anemia (n = 20), MDS (n = 18), AML (n = 11), or no BM abnormality (n = 8). BM samples were analyzed by karyotype, high-density DNA arrays with respect to paired fibroblasts, and by selected oncogene sequencing. A specific pattern of chromosomal abnormalities was found in MDS/AML, which included 1q+ (44.8%), 3q+ (41.4%), −7/7q (17.2%), and 11q− (13.8%). Moreover, cryptic RUNX1/AML1 lesions (translocations, deletions, or mutations) were observed for the first time in FA (20.7%). Rare mutations of NRAS, FLT3-ITD, MLL-PTD, ERG amplification, and ZFP36L2-PRDM16 translocation, but no TP53, TET2, CBL, NPM1, and CEBPα mutations were found. Frequent homozygosity regions were related not to somatic copy-neutral loss of heterozygosity but to consanguinity, suggesting that homologous recombination is not a common progression mechanism in FA. Importantly, the RUNX1 and other chromosomal/genomic lesions were found at the MDS/AML stages, except for 1q+, which was found at all stages. These data have implications for staging and therapeutic managing in FA patients, and also to analyze the mechanisms of clonal evolution and oncogenesis in a background of genomic instability and BM failure.
The C-Myb transcription factor is essential for hematopoiesis, including in the T-cell lineage. The C-Myb locus is a common site of retroviral insertional mutagenesis, however no recurrent genomic ...involvement has been reported in human malignancies. Here, we identified 2 types of genomic alterations involving the C-MYB locus at 6q23 in human T-cell acute leukemia (T-ALL). First, we found a reciprocal translocation, t(6;7)(q23;q34), that juxtaposed the TCRB and C-MYB loci (n = 6 cases). Second, a genome-wide copy-number analysis by array-based comparative genomic hybridization (array-CGH) identified short somatic duplications that include C-MYB (MYBdup, n = 13 cases of 84 T-ALL, 15%). Expression analysis, including allele-specific approaches, showed stronger C-MYB expression in the MYB-rearranged cases compared with other T-ALLs, and a dramatically skewed C-MYB allele expression in the TCRB-MYB cases, which suggests that a translocation-driven deregulated expression may overcome a cellular attempt to down-regulate C-MYB. Strikingly, profiling of the T-ALLs by clinical, genomic, and large-scale gene expression analyses shows that the TCRB-MYB translocation defines a new T-ALL subtype associated with a very young age for T-cell leukemia (median, 2.2 years) and with a proliferation/mitosis expression signature. By contrast, the MYBdup alteration was associated with the previously defined T-ALL subtypes.
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