Ithamar Ganmore

Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down's syndrome

BACKGROUND Children with Downs syndrome have a greatly increased risk of acute megakaryoblastic and acute lymphoblastic leukaemias. Acute megakaryoblastic leukaemia in Downs syndrome is characterised by a somatic mutation in GATA1. Constitutive activation of the JAK/STAT (Janus kinase and signal transducer and activator of transcription) pathway occurs in several haematopoietic malignant diseases. We tested the hypothesis that mutations in JAK2 might be a common molecular event in acute lymphoblastic leukaemia associated with Downs syndrome. METHODS JAK2 DNA mutational analysis was done on diagnostic bone marrow samples obtained from 88 patients with Downs syndrome-associated acute lymphoblastic leukaemia; and 216 patients with sporadic acute lymphoblastic leukaemia, Downs syndrome-associated acute megakaryoblastic leukaemia, and essential thrombocythaemia. Functional consequences of identified mutations were studied in mouse haematopoietic progenitor cells. FINDINGS Somatically acquired JAK2 mutations were identified in 16 (18%) patients with Downs syndrome-associated acute lymphoblastic leukaemia. The only patient with non-Downs syndrome-associated leukaemia but with a JAK2 mutation had an isochromosome 21q. Children with a JAK2 mutation were younger (mean [SE] age 4.5 years [0.86] vs 8.6 years [0.59], p<0.0001) at diagnosis. Five mutant alleles were identified, each affecting a highly conserved arginine residue (R683). These mutations immortalised primary mouse haematopoietic progenitor cells in vitro, and caused constitutive Jak/Stat activation and cytokine-independent growth of BaF3 cells, which was sensitive to pharmacological inhibition with JAK inhibitor I. In modelling studies of the JAK2 pseudokinase domain, R683 was situated in an exposed conserved region separated from the one implicated in myeloproliferative disorders. INTERPRETATION A specific genotype-phenotype association exists between the type of somatic mutation within the JAK2 pseudokinase domain and the development of B-lymphoid or myeloid neoplasms. Somatically acquired R683 JAK2 mutations define a distinct acute lymphoblastic leukaemia subgroup that is uniquely associated with trisomy 21. JAK2 inhibitors could be useful for treatment of this leukaemia. FUNDING Israel Trade Ministry, Israel Science Ministry, Jewish National Fund UK, Sam Waxman Cancer Research Foundation, Israel Science Foundation, Israel Cancer Association, Curtis Katz, Constantiner Institute for Molecular Genetics, German-Israel Foundation, and European Commission FP6 Integrated Project EUROHEAR.

Down syndrome acute lymphoblastic leukemia, a highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: a report from the International BFM Study Group.

We report gene expression and other analyses to elucidate the molecular characteristics of acute lymphoblastic leukemia (ALL) in children with Down syndrome (DS). We find that by gene expression DS-ALL is a highly heterogeneous disease not definable as a unique entity. Nevertheless, 62% (33/53) of the DS-ALL samples analyzed were characterized by high expression of the type I cytokine receptor CRLF2 caused by either immunoglobulin heavy locus (IgH@) translocations or by interstitial deletions creating chimeric transcripts P2RY8-CRLF2. In 3 of these 33 patients, a novel activating somatic mutation, F232C in CRLF2, was identified. Consistent with our previous research, mutations in R683 of JAK2 were identified in 10 specimens (19% of the patients) and, interestingly, all 10 had high CRLF2 expression. Cytokine receptor-like factor 2 (CRLF2) and mutated Janus kinase 2 (Jak2) cooperated in conferring cytokine-independent growth to BaF3 pro-B cells. Intriguingly, the gene expression signature of DS-ALL is enriched with DNA damage and BCL6 responsive genes, suggesting the possibility of B-cell lymphocytic genomic instability. Thus, DS confers increased risk for genetically highly diverse ALLs with frequent overexpression of CRLF2, associated with activating mutations in the receptor itself or in JAK2. Our data also suggest that the majority of DS children with ALL may benefit from therapy blocking the CRLF2/JAK2 pathways.

Constitutional aneuploidy and cancer predisposition

Constitutional aneuploidies are rare syndromes associated with multiple developmental abnormalities and the alterations in the risk for specific cancers. Acquired somatic chromosomal aneuploidies are the most common genetic aberrations in sporadic cancers. Thus studies of these rare constitutional aneuploidy syndromes are important not only for patient counseling and clinical management, but also for deciphering the mechanisms by which chromosomal aneuploidy affect cancer initiation and progression. Here we review the major constitutional aneuploidy syndromes and suggest some general mechanisms for the associated cancer predisposition.

Magnitude and Trajectories of Cognitive Dysfunction in Type 2 Diabetes Mellitus

Abstract This chapter presents the characterization of cognitive dysfunction in type 2 diabetes mellitus (T2D). Compared with non-T2D people, important findings based on 119 studies, combined with our interpretation in cases of mixed results, are that (1) the earliest evidence for cognitive dysfunction in T2D is in the reasoning subdomain, which is found in midlife; (2) elderly patients with T2D perform worse in all cognitive subdomains except for semantic memory. All other T2D subgroups (prediabetes, newly diagnosed T2D, midlife prevalent T2D, and prevalent T2D in very old age) have normal cognitive function in most subdomains based on standard neuropsychological testing; (3) accelerated cognitive decline starts at the prediabetes phase and is seen most strongly in midlife in most cognitive subdomains; and (4) the effect size of the worst cognitive performance or most accelerated decline is small to medium in all subdomains. These results suggest that individuals with prediabetes may require additional attention with respect to monitoring future cognitive abilities.

COGNITIVE FUNCTIONING AND DECLINE IN TYPE 2 DIABETES: EVIDENCE SUPPORTING A BROAD COGNITIVE ASSESSMENT AT THE EARLIER STAGES OF T2D

Never abusers had significantly higher NPI-Q scores and more items endorsed than remote abusers for each CDR stage, except CDR1⁄43 which had a small N(Never Abusers N1⁄41040 vs. Any Abuse N1⁄474). CDR-SB did not differ significantly between Never Abusers and those with history of abuse. Conclusions: Our results associate alcohol abuse with increased and more severe NPI-Q behavioral symptoms. Remote abusers exhibit more symptoms than never-abusers, supporting the hypothesis that alcohol abuse is associated with long-lasting behavioral symptoms. However, Alcohol abuse history does not appear to change functional socres based on CDR-SB. The NACC database is funded by NIA/NIH Grant U01 AG016976.

DIETARY REDUCTION OF ADVANCED GLYCATION END PRODUCTS TO PREVENT COGNITIVE DECLINE IN HIGH-RISK DIABETICS: A PILOT RANDOMIZED TRIAL

40–70, % women 46). No trend across measurement occasions was detected and the data were interpreted to represent usual intake levels. Paired sample t-tests showed that group-based reaction time scores significantly increased from baseline to re-assessment only in the lower intake group (p<0.001), while they remained stable in the higher intake group (p1⁄40.264). These findings indicate a protective effect of higher B vitamin intake. Conclusions: Multi-trajectory analysis has been used to interpret repeated measurement lifestyle data; here, identifying groups representing usual exposure rather than change in exposure over time. In a general population sample, it was found that a higher usual dietary B vitamins intake is associated with a slower decline in mean reaction time over 4 years. Although further (multivariable) analysis is required to provide evidence of causality, multi-trajectory analysis is a useful tool for empirically characterising lifestyle, enabling more detailed investigation of the impact of lifestyle on dementia related outcomes.