Recent trials show 5-year survival rates >95% for ETV6::RUNX1 Acute Lymphoblastic Leukemia (ALL). Since treatment has many side effects, an overview of cumulative drug doses and intensities between eight international trials is presented to characterize therapy needed for cure. A meta-analysis was performed as a comprehensive summary of survival outcomes at 5 and 10 years. For drug dose comparison in non-high risk trial arms, risk group distribution was applied to split the trials into two groups: trial group A with ~70% (range: 63.5-75%) of patients in low risk (LR) (CCLSG ALL2004, CoALL 07-03, NOPHO ALL2008, UKALL2003) and trial group B with ~45% (range: 38.7-52.7%) in LR (AIEOP-BFM ALL 2000, ALL-IC BFM ALL 2002, DCOG ALL10, JACLS ALL-02). Meta-analysis did not show evidence of heterogeneity between studies in trial group A LR and medium risk (MR) despite differences in treatment intensity. Statistical heterogeneity was present in trial group B LR and MR. Trials using higher cumulative dose and intensity of asparaginase and pulses of glucocorticoids and vincristine showed better 5-year event-free survival but similar overall survival. Based on similar outcomes between trials despite differences in therapy intensity, future trials should investigate, to what extent de-escalation is feasible for ETV6::RUNX1 ALL.

• MeSH
• Precursor Cell Lymphoblastic Leukemia-Lymphoma * genetics   drug therapy   mortality   therapy   MeSH
• Oncogene Proteins, Fusion * genetics   MeSH
• Humans MeSH
• Survival Rate MeSH
• ETS Translocation Variant 6 Protein * MeSH
• Core Binding Factor Alpha 2 Subunit * genetics   MeSH
• Antineoplastic Combined Chemotherapy Protocols therapeutic use   MeSH
• Proto-Oncogene Proteins c-ets * genetics   MeSH
• Repressor Proteins * genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH

Patients with lower-risk myelodysplastic syndromes (LR-MDS) have a generally favorable prognosis; however, a small proportion of cases progress rapidly. This study aimed to define molecular biomarkers predictive of LR-MDS progression and to uncover cellular pathways contributing to malignant transformation. The mutational landscape was analyzed in 214 LR-MDS patients, and at least one mutation was detected in 137 patients (64%). Mutated RUNX1 was identified as the main molecular predictor of rapid progression by statistics and machine learning. To study the effect of mutated RUNX1 on pathway regulation, the expression profiles of CD34 + cells from LR-MDS patients with RUNX1 mutations were compared to those from patients without RUNX1 mutations. The data suggest that RUNX1-unmutated LR-MDS cells are protected by DNA damage response (DDR) mechanisms and cellular senescence as an antitumor cellular barrier, while RUNX1 mutations may be one of the triggers of malignant transformation. Dysregulated DDR and cellular senescence were also observed at the functional level by detecting γH2AX expression and β-galactosidase activity. Notably, the expression profiles of RUNX1-mutated LR-MDS resembled those of higher-risk MDS at diagnosis. This study demonstrates that incorporating molecular data improves LR-MDS risk stratification and that mutated RUNX1 is associated with a suppressed defense against LR-MDS progression.

• MeSH
• Leukemia, Myeloid, Acute * genetics   MeSH
• Humans MeSH
• Mutation MeSH
• Myelodysplastic Syndromes * pathology   MeSH
• Cell Transformation, Neoplastic genetics   metabolism   MeSH
• Prognosis MeSH
• Core Binding Factor Alpha 2 Subunit genetics   metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Akútna myeloidná leukémia (AML) je značne heterogénny podtyp leukémie, ktorý predstavuje 25 % všetkých detských leukémií. Prítomnosťou genetických mutácií v kmeňových krvotvorných/progenitorových bunkách produkuje kostná dreň veľké množstvo abnormálnych nediferencovaných leukocytov (blastov), čo výrazne narúša správnu diferenciáciu buniek. AML je indukovaná dvomi zásahmi. Chromozomálna translokácia počas hematopoézy vnútromaternicového vývoja predstavuje prvý zásah. Tak vzniknú preleukemické fúzne gény (PFG), ktoré sa môžu neskôr transformovať druhým zásahom (bodová genetická mutácia - delécia, inzercia...) na funkčný malígny klon. Medzi charakteristické fúzne gény AML patria napríklad AML1-ETO, PML‐RARA či MLL‐AF9, ktoré následne produkujú hybridné proteíny so zmenenou funkciou. Viaceré štúdie poukazujú na to, že tieto PFG sú považované za dôležitý prognostický nástroj pri hodnotení ochorení. Zatiaľ čo výskyt PFG charakteristických pre akútnu lymfoblastickú leukémiu (ALL) je relatívne dobre preskúmaný a odhadoval sa na 1 až 5 % v pupočníkovej krvi zdravých novorodencov, PFG relevantné pre AML stále nie sú dostatočne objasnené.

Acute myeloid leukemia (AML) is a highly heterogeneous subtype of leukemia, accounting for 25 % of childhood leukemias. By the presence of genetic mutations in hematopoietic/ progenitor stem cells, the bone marrow produces a large number of abnormal undifferentiated leukocytes (blasts), which significantly impairs the proper differentiation of cells. AML is induced by two interventions. Chromosomal translocation during hematopoiesis of intrauterine development is the first intervention. This creates preleukemic fusion genes (PFG), which can later be transformed by a second intervention (point genetic mutation - deletion, insertion ...) into a functional malignant clone. Characteristic AML fusion genes include AML1-ETO, PML-RARA or MLL-AF9, which in turn produce hybrid proteins with altered function. Several studies suggest that these PFGs are considered an important prognostic tool in disease assessment. While the incidence of PFG characteristic of acute lymphoblastic leukemia (ALL) has been relatively well studied by several research groups and has been estimated at 1 to 5% in the umbilical cord blood of healthy neonates, PFG relevant to AML are still not sufficiently clarified.

• MeSH
• Leukemia, Myeloid, Acute * diagnosis   genetics   MeSH
• Retinoic Acid Receptor alpha genetics   MeSH
• Oncogene Proteins, Fusion * genetics   MeSH
• Humans MeSH
• Core Binding Factor Alpha 2 Subunit genetics   MeSH
• Promyelocytic Leukemia Protein genetics   MeSH
• Myeloid-Lymphoid Leukemia Protein genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH

In systemic mastocytosis (SM), the clinical features and survival vary greatly. Patient-related factors determining the outcome in SM are largely unknown. Methods: We examined the impact of sex on the clinical features, progression-free survival (PFS), and overall survival (OS) in 3403 patients with mastocytosis collected in the registry of the European Competence Network on Mastocytosis (ECNM). The impact of cytogenetic and molecular genetic aberrations on sex differences was analyzed in a subset of patients. Results: Of all patients enrolled, 55.3% were females. However, a male predominance was found in a subset of advanced SM (AdvSM) patients, namely SM with an associated hematologic neoplasm (SM-AHN, 70%; p < 0.001). Correspondingly, organomegaly (male: 23% vs. female: 13%, p = 0.007) was more, whereas skin involvement (male: 71% vs. female: 86%, p = 0.001) was less frequent in males. In all patients together, OS (p < 0.0001) was significantly inferior in males, and also within the WHO sub-categories indolent SM, aggressive SM (ASM) and SM-AHN. PFS was significantly (p = 0.0002) worse in males when all patients were grouped together; due to low numbers of events, this significance persisted only in the subcategory smoldering SM. Finally, prognostically relevant cytogenetic abnormalities (10% vs. 5%, p = 0.006) or molecular aberrations (SRSF2/ASXL1/RUNX1 profile; 63% vs. 40%, p = 0.003) were more frequently present in males. Conclusions: Male sex has a major impact on clinical features, disease progression, and survival in mastocytosis. Male patients have an inferior survival, which seems related to the fact that they more frequently develop a multi-mutated AdvSM associated with a high-risk molecular background.

• MeSH
• Leukemia, Myeloid, Acute complications   MeSH
• Chromosome Aberrations * MeSH
• Child MeSH
• Progression-Free Survival MeSH
• Adult MeSH
• Gastrointestinal Diseases physiopathology   MeSH
• Hematologic Neoplasms complications   MeSH
• Hepatomegaly physiopathology   MeSH
• Infant MeSH
• Skin Diseases physiopathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Leukemia, Mast-Cell physiopathology   MeSH
• Survival Rate MeSH
• Adolescent MeSH
• Young Adult MeSH
• Myelodysplastic Syndromes complications   MeSH
• Infant, Newborn MeSH
• Child, Preschool MeSH
• Prognosis MeSH
• Core Binding Factor Alpha 2 Subunit genetics   MeSH
• Proto-Oncogene Proteins c-kit genetics   MeSH
• Repressor Proteins genetics   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Serine-Arginine Splicing Factors genetics   MeSH
• Sex Factors * MeSH
• Splenomegaly physiopathology   MeSH
• Mastocytosis, Systemic complications   genetics   mortality   physiopathology   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Infant, Newborn MeSH
• Child, Preschool MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

To study the prognostic relevance of rare genetic aberrations in acute myeloid leukemia (AML), such as t(16;21), international collaboration is required. Two different types of t(16;21) translocations can be distinguished: t(16;21)(p11;q22), resulting in the FUS-ERG fusion gene; and t(16;21)(q24;q22), resulting in RUNX1-core binding factor (CBFA2T3). We collected data on clinical and biological characteristics of 54 pediatric AML cases with t(16;21) rearrangements from 14 international collaborative study groups participating in the international Berlin-Frankfurt-Münster (I-BFM) AML study group. The AML-BFM cohort diagnosed between 1997 and 2013 was used as a reference cohort. RUNX1-CBFA2T3 (n = 23) had significantly lower median white blood cell count (12.5 × 109/L, P = .03) compared with the reference cohort. FUS-ERG rearranged AML (n = 31) had no predominant French-American-British (FAB) type, whereas 76% of RUNX1-CBFA2T3 had an M1/M2 FAB type (M1, M2), significantly different from the reference cohort (P = .004). Four-year event-free survival (EFS) of patients with FUS-ERG was 7% (standard error [SE] = 5%), significantly lower compared with the reference cohort (51%, SE = 1%, P < .001). Four-year EFS of RUNX1-CBFA2T3 was 77% (SE = 8%, P = .06), significantly higher compared with the reference cohort. Cumulative incidence of relapse was 74% (SE = 8%) in FUS-ERG, 0% (SE = 0%) in RUNX1-CBFA2T3, compared with 32% (SE = 1%) in the reference cohort (P < .001). Multivariate analysis identified both FUS-ERG and RUNX1-CBFA2T3 as independent risk factors with hazard ratios of 1.9 (P < .0001) and 0.3 (P = .025), respectively. These results describe 2 clinically relevant distinct subtypes of pediatric AML. Similarly to other core-binding factor AMLs, patients with RUNX1-CBFA2T3 rearranged AML may benefit from stratification in the standard risk treatment, whereas patients with FUS-ERG rearranged AML should be considered high-risk.

• MeSH
• Leukemia, Myeloid, Acute diagnosis   genetics   MeSH
• Child MeSH
• Infant MeSH
• Humans MeSH
• Chromosomes, Human, Pair 16 genetics   MeSH
• Chromosomes, Human, Pair 21 genetics   MeSH
• Adolescent MeSH
• Tumor Suppressor Proteins genetics   MeSH
• Child, Preschool MeSH
• Prognosis MeSH
• RNA-Binding Protein FUS genetics   MeSH
• Core Binding Factor Alpha 2 Subunit genetics   MeSH
• Gene Expression Regulation, Leukemic MeSH
• Repressor Proteins genetics   MeSH
• Retrospective Studies MeSH
• Transcriptional Regulator ERG genetics   MeSH
• Transcriptome MeSH
• Translocation, Genetic * MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, N.I.H., Extramural MeSH

Here we report a C-terminal RUNX1 mutation in a family with platelet disorder and predisposition to myeloid malignancies. We identified the mutation c.866delG:p.Gly289Aspfs*22 (NM_001754) (RUNX1 b-isoform NM_001001890; c.785delG:p.Gly262Aspfs*22) using exome sequencing of samples obtained from eight members of a single family. The mutation found in our pedigree is within exon eight and the transactivation domain of RUNX1. One of the affected individuals developed myelodysplastic syndrome (MDS), which progressed to acute myelogenous leukemia (AML). A search for the second hit which led to the development of MDS and later AML in this individual revealed the PHF6 gene variant (exon9:c.872G > A:p.G291E; NM_001015877), BCORL1 (exon3:c.1111A > C:p.T371P; NM_001184772) and BCOR gene variant (exon4:c.2076dupT:p.P693fs; NM_001123383), which appear to be very likely second hits participating in the progression to myeloid malignancy.

• MeSH
• Biopsy MeSH
• Chromosome Aberrations MeSH
• Genetic Predisposition to Disease * MeSH
• Polymorphism, Single Nucleotide MeSH
• Karyotype MeSH
• Humans MeSH
• Mutation * MeSH
• DNA Mutational Analysis MeSH
• Leukemia, Myeloid diagnosis   genetics   MeSH
• Platelet Count MeSH
• Child, Preschool MeSH
• Disease Progression MeSH
• Core Binding Factor Alpha 2 Subunit chemistry   genetics   MeSH
• Family MeSH
• Blood Platelet Disorders blood   genetics   pathology   MeSH
• Check Tag
• Humans MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH

RUNX1-mutated acute myeloid leukemia (AML) show a distinct pattern of genetic abnormalities and an adverse prognosis. We analyzed the impact of multiple RUNX1 mutations and RUNX1 wild-type (WT) loss in 467 AML with RUNX1 mutations (mut): (1) RUNX1 WT loss (n=53), (2) >1 RUNX1mut (n=94) and (3) 1 RUNX1mut (n=323). In 1 RUNX1mut, +8 was most frequent, whereas in WT loss +13 was the most abundant trisomy (+8: 66% vs 31%, P=0.022; +13: 15% vs 62%, P<0.001). Analyses of 28 genes in 163 selected cases revealed SRSF2 (39%), ASXL1 (36%), DNMT3A (19%), IDH2 (17%) and SF3B1 (17%) as most frequently mutated genes. RUNX1 WT loss showed a higher frequency of ASXL1mut compared with the other cases (50% vs 29%, P=0.009). Median overall survival (OS) in the total cohort was 14 months. WT loss (OS: 5 months) and >1 RUNX1mut (14 months) showed an adverse impact on prognosis compared with 1 RUNX1mut (22 months; P=0.002 and 0.048, respectively). Mutations in ASXL1 and ⩾2 additional mutations correlated with shorter OS (10 vs 18 months, P=0.028; 12 vs 20 months, P=0.017). Thus, the number of RUNX1mut, RUNX1 WT loss and the number and type of additional mutations is biologically and clinically relevant.

• MeSH
• Leukemia, Myeloid, Acute genetics   pathology   MeSH
• Alleles MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Mutation genetics   MeSH
• Prognosis MeSH
• Core Binding Factor Alpha 2 Subunit genetics   MeSH
• Repressor Proteins genetics   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Loss of Heterozygosity genetics   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

• MeSH
• Leukemia, Myeloid, Acute * drug therapy   genetics   complications   MeSH
• Azacitidine therapeutic use   MeSH
• Adult MeSH
• Epigenesis, Genetic drug effects   MeSH
• Gemtuzumab therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Survival Rate MeSH
• Disease-Free Survival MeSH
• Core Binding Factor Alpha 2 Subunit genetics   MeSH
• Antibiotics, Antineoplastic therapeutic use   MeSH
• Antineoplastic Agents therapeutic use   MeSH
• Antineoplastic Combined Chemotherapy Protocols MeSH
• Recurrence MeSH
• Neoplasm, Residual * diagnosis   drug therapy   genetics   MeSH
• Aged MeSH
• Translocation, Genetic MeSH
• Vidarabine analogs & derivatives   therapeutic use   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Publication type
• Clinical Trial MeSH

We have shown previously that ETV6/RUNX1-positive acute lymphoblastic leukemia (ALL) is distinguishable from other ALL subtypes by CD27pos /CD44low-neg immunophenotype. During diagnostic immunophenotyping of 573 childhood B-cell precursor ALL (BCP-ALL), we identified eight cases with this immunophenotype among "B-other ALL" (BCP-ALL cases negative for routinely tested chromosomal/genetic aberrations). We aimed to elucidate whether these cases belong to the recently described ETV6/RUNX1-like ALL defined by the ETV6/RUNX1-specific gene expression profile (GEP), harboring concurrent ETV6 and IKZF1 lesions. We performed comprehensive genomic analysis using single nucleotide polymorphism arrays, whole exome and transcriptome sequencing and GEP on microarrays. In unsupervised hierarchical clustering based on GEP, five out of seven analyzed CD27pos /CD44low-neg B-other cases clustered with ETV6/RUNX1-positive ALL and were thus classified as ETV6/RUNX1-like ALL. The two cases clustering outside ETV6/RUNX1-positive ALL harbored a P2RY8/CRLF2 fusion with activating JAK2 mutations and a TCF3/ZNF384 fusion, respectively, assigning them to other ALL subtypes. All five ETV6/RUNX1-like cases harbored ETV6 deletions; uniform intragenic ARPP21 deletions and various IKZF1 lesions were each found in three ETV6/RUNX1-like cases. The frequency of ETV6 and ARPP21 deletions was significantly higher in ETV6/RUNX1-like ALL compared with a reference cohort of 42 B-other ALL. In conclusion, we show that ETV6/RUNX1-like ALL is associated with CD27pos /CD44low-neg immunophenotype and identify ARPP21 deletions to contribute to its specific genomic profile enriched for ETV6 and IKZF1 lesions. In conjunction with previously published data, our study identifies the ETV6 lesion as the only common genetic aberration and thus the most likely key driver of ETV6/RUNX1-like ALL.

• MeSH
• Precursor Cell Lymphoblastic Leukemia-Lymphoma blood   genetics   immunology   MeSH
• Tumor Necrosis Factor Receptor Superfamily, Member 7 genetics   metabolism   MeSH
• Hyaluronan Receptors genetics   metabolism   MeSH
• B-Lymphocytes immunology   MeSH
• Child MeSH
• Phenotype * MeSH
• Oncogene Proteins, Fusion genetics   MeSH
• Immunophenotyping MeSH
• Polymorphism, Single Nucleotide MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Child, Preschool MeSH
• Core Binding Factor Alpha 2 Subunit genetics   MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

ETV6-related thrombocytopenia is an autosomal dominant thrombocytopenia that has been recently identified in a few families and has been suspected to predispose to hematologic malignancies. To gain further information on this disorder, we searched for ETV6 mutations in the 130 families with inherited thrombocytopenia of unknown origin from our cohort of 274 consecutive pedigrees with familial thrombocytopenia. We identified 20 patients with ETV6-related thrombocytopenia from seven pedigrees. They have five different ETV6 variants, including three novel mutations affecting the highly conserved E26 transformation-specific domain. The relative frequency of ETV6-related thrombocytopenia was 2.6% in the whole case series and 4.6% among the families with known forms of inherited thrombocytopenia. The degree of thrombocytopenia and bleeding tendency of the patients with ETV6-related thrombocytopenia were mild, but four subjects developed B-cell acute lymphoblastic leukemia during childhood, resulting in a significantly higher incidence of this condition compared to that in the general population. Clinical and laboratory findings did not identify any particular defects that could lead to the suspicion of this disorder from the routine diagnostic workup. However, at variance with most inherited thrombocytopenias, platelets were not enlarged. In vitro studies revealed that the maturation of the patients' megakaryocytes was defective and that the patients have impaired proplatelet formation. Moreover, platelets from patients with ETV6-related thrombocytopenia have reduced ability to spread on fibrinogen. Since the dominant thrombocytopenias due to mutations in RUNX1 and ANKRD26 are also characterized by normal platelet size and predispose to hematologic malignancies, we suggest that screening for ETV6, RUNX1 and ANKRD26 mutations should be performed in all subjects with autosomal dominant thrombocytopenia and normal platelet size.

• MeSH
• Precursor Cell Lymphoblastic Leukemia-Lymphoma etiology   MeSH
• Child MeSH
• Adult MeSH
• Genetic Predisposition to Disease genetics   MeSH
• Nuclear Proteins genetics   MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Mutation MeSH
• Cell Transformation, Neoplastic genetics   MeSH
• Infant, Newborn MeSH
• Child, Preschool MeSH
• Core Binding Factor Alpha 2 Subunit genetics   MeSH
• Proto-Oncogene Proteins c-ets genetics   MeSH
• Repressor Proteins genetics   MeSH
• Family MeSH
• Pedigree MeSH
• Thrombocytopenia genetics   pathology   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Infant, Newborn MeSH
• Child, Preschool MeSH
• Publication type
• Journal Article MeSH