Adult Low-Hypodiploid Acute Lymphoblastic Leukemia Emerges from Preleukemic TP53-Mutant Clonal Hematopoiesis

UNLABELLED Low hypodiploidy defines a rare subtype of B-cell acute lymphoblastic leukemia (B-ALL) with a dismal outcome. To investigate the genomic basis of low-hypodiploid ALL (LH-ALL) in adults, we analyzed copy-number aberrations, loss of heterozygosity, mutations, and cytogenetics data in a prospective cohort of Philadelphia (Ph)-negative B-ALL patients (n = 591, ages 18-84 years), allowing us to identify 80 LH-ALL cases (14%). Genomic analysis was critical for evidencing low hypodiploidy in many cases missed by cytogenetics. The proportion of LH-ALL within Ph-negative B-ALL dramatically increased with age, from 3% in the youngest patients (under 40 years old) to 32% in the oldest (over 55 years old). Somatic TP53 biallelic inactivation was the hallmark of adult LH-ALL, present in virtually all cases (98%). Strikingly, we detected TP53 mutations in posttreatment remission samples in 34% of patients. Single-cell proteogenomics of diagnosis and remission bone marrow samples evidenced a preleukemic, multilineage, TP53-mutant clone, reminiscent of age-related clonal hematopoiesis. SIGNIFICANCE We show that low-hypodiploid ALL is a frequent entity within B-ALL in older adults, relying on somatic TP53 biallelic alteration. Our study unveils a link between aging and low-hypodiploid ALL, with TP53-mutant clonal hematopoiesis representing a preleukemic reservoir that can give rise to aneuploidy and B-ALL. See related commentary by Saiki and Ogawa, p. 102. This article is highlighted in the In This Issue feature, p. 101

RelB-Dependent Stromal Cells Promote T-Cell Leukemogenesis

BACKGROUND: The Rel/NF-kappaB transcription factors are often activated in solid or hematological malignancies. In most cases, NF-kappaB activation is found in malignant cells and results from activation of the canonical NF-kappaB pathway, leading to RelA and/or c-Rel activation. Recently, NF-kappaB activity in inflammatory cells infiltrating solid tumors has been shown to contribute to solid tumor initiation and progression. Noncanonical NF-kappaB activation, which leads to RelB activation, has also been reported in breast carcinoma, prostate cancer, and lymphoid leukemia. METHODOLOGY/PRINCIPAL FINDINGS: Here we report a novel role for RelB in stromal cells that promote T-cell leukemogenesis. RelB deficiency delayed leukemia onset in the TEL-JAK2 transgenic mouse model of human T acute lymphoblastic leukemia. Bone marrow chimeric mouse experiments showed that RelB is not required in the hematopoietic compartment. In contrast, RelB plays a role in radio-resistant stromal cells to accelerate leukemia onset and increase disease severity. CONCLUSIONS/SIGNIFICANCE: The present results are the first to uncover a role for RelB in the crosstalk between non-hematopoietic stromal cells and leukemic cells. Thus, besides its previously reported role intrinsic to specific cancer cells, the noncanonical NF-kappaB pathway may also play a pro-oncogenic role in cancer microenvironmental cells

Analyse de survie et évolution sur le plan respiratoire dans une cohorte d'enfants avec un poids de naissance extrêmement bas: expérience sur 13 ans (1996-2008)

Nous avons identifié de manière rétrospective tous les enfants nés avant 29 semaines gestationnelles (SG) et admis aux soins intensifs de néonatologie de Genève, entre 1996 et 2008, présentant un syndrome de détresse respiratoire à la naissance. Les taux de mortalité et de dysplasie broncho-pulmonaire (DBP) ont été analysés avec mise en évidence de facteurs de risque. Pour chaque enfant, la stratégie ventilatoire utilisée a été détaillée. La DBP était classifiée comme légère, modérée et sévère, selon la définition de Jobe et Bancalari. 356 enfants ont été inclus dans l'étude. La mortalité globale était de 24.7%. Chez les survivants, à 36 SG, 17.2% ont développé une DBP modérée ou sévère. Les facteurs de risque pour la DBP modérée et sévère étaient l'âge gestationnel, le faible poids de naissance, les barotraumatismes et l'hypertension artérielle pulmonaire. La variable support ventilatoire à la naissance (CPAP seule, échec de CPAP ou intubation) ne ressortait pas comme un facteur de risque

Diagnostic Accuracy of the French Version of the Adult Attention Deficit / Hyperactivity Disorder Self-Report Screening Scale for DSM-5 (ASRS-5)

Attention Deficit/Hyperactivity Disorder (ADHD) often persists into adulthood. However, few screening tools have been adapted to assess adult ADHD using the DSM-5 criteria. This study assessed the diagnostic accuracy of a French version of the ADHD Self-Report Screening for DSM-5 (ASRS-5). This multicentric cross-sectional study included 557 participants: 309 adult ADHD outpatients without bipolar disorder (BD)/borderline personality disorder (BPD) (n = 236) or with BD/BPD (n = 36) and 285 adults without ADHD who were either healthy volunteers (n = 248) or outpatients with BD or BPD (n = 37). Measures included ADHD diagnosis and the ASRS-5. The ASRS-5 was a good predictor of ADHD diagnosis (cut-off score ≥ 13/24: sensitivity = 84.3%, specificity = 91.9%) in the sample of adult outpatients without comorbid disorders/healthy controls. Performances were lower with this cut-off score in some subgroups, notably low-severity ADHD symptomatology (sensitivity = 63.5%) and participants with BD or BPD (sensitivity = 91.7%, specificity = 54.1%). The French ASRS-5 had acceptable screening properties, even if its performance varied according to clinical variables. Further evidence is needed for patients with comorbid disorders having overlapping symptoms

Combined deficiency of RAB32 and RAB38 in the mouse mimics Hermansky-Pudlak syndrome and critically impairs thrombosis

International audienceContrary to rat platelets, mouse platelets express both RAB32 and RAB38 that play fully redundant roles for dense granule biogenesis. • Combined RAB32 and RAB38 deficiency mimics severe Hermansky-Pudlak syndrome with albinism and profound defects in hemostasis. The biogenesis of lysosome related organelles is defective in Hermansky-Pudlak syndrome (HPS), a disorder characterized by oculocutaneous albinism and platelet dense granule (DG) defects. The first animal model of HPS was the fawn-hooded rat, harboring a spontaneous mutation inactivating the small guanosine triphosphatase Rab38. This leads to coat color dilution associated with the absence of DGs and lung morphological defects. Another RAB38 mutant, the cht mouse, has normal DGs, which has raised controversy about the role of RAB38 in DG biogenesis. We show here that murine and human, but not rat, platelets also express the closely related RAB32. To elucidate the parts played by RAB32 and RAB38 in the biogenesis of DGs in vivo and their effects on platelet functions, we generated mice inactivated for Rab32, Rab38, and both genes. Single Rab38 inactivation mimicked cht mice, whereas single Rab32 inactivation had no effect in DGs, coat color, or lung morphology. By contrast, Rab32/38 double inactivation mimicked severe HPS, with strong coat and eye pigment dilution, some enlarged lung multilamellar bodies associated with a decrease in the number of DGs. These organelles were morphologically abnormal, decreased in number, and devoid of 5-hydroxytryptamine content. In line with the storage pool defect, platelet activation was affected, resulting in severely impaired thrombus growth and prolongation of the bleeding time. Overall, our study demonstrates the absence of impact of RAB38 or RAB32 single deficiency in platelet biogenesis and function resulting from full redundancy, and characterized a new mouse model mimicking HPS devoid of DG content