Delivery of every aspect of care by all clinical and non-clinical departments in the UK's NHS is being reassessed and fundamentally reorganised in the expectation of an imminent surge of patients with covid-19. 1 Modelling of the outbreak assumes an infection fatality ratio of 0.9% and a hospital admission rate of 4.4%, with 30% of those admitted requiring critical care or extracorporeal membrane oxygenation. 2 3 The increased demand on healthcare services will be compounded by the apparent increased risk of infection among healthcare workers, 4 and staff absences because of illness or self-isolation may be as high as 20%. 11 The government has made recommendations for case isolation, social distancing, and household quarantine intended to reduce the peak of the epidemic and the resulting pressure on NHS hospitals. 5 6

Eighty-four patients with typical chronic lymphocytic leukemia 27% of patients with B-CLL. [11][12][13] Fegan et al 13 studied 45 (CLL) (by morphological and immunophenotypic criteria) on patients with typical CLL over 5 years and performed cytowhom karyotypes were available were studied. Binet stage at genetic analysis every 6-12 months or more frequently if there diagnosis and follow-up were defined. Survival was calculated was evidence of disease progression. Abnormalities were from diagnosis. Fifty-one percent of patients had a karyotypic detected in 62% at some point during the study with 38% abnormality, the commonest being abnormalities at 13q14 (16%); these patients did not have significantly different surshowing clonal evolution. 11q deletions were found most frevival from patients with normal karyotype. The second comquently in the patients with progressive disease. This original monest abnormality was del(11q) (13%); these patients had sigstudy was extended to an adjacent centre and here we present nificantly worse survival when compared both with patients our updated long-term results. The patients' records were examined and the Binet stage was with CLL have chromosomal abnormalities as detected by noted at diagnosis and any change was documented. Treatcytogenetic analysis 1,2 but few centres perform routine cytogments for CLL were also recorded as were the causes of death. enetic analysis because of the perception that limited prognos-A patient was considered to have had a CLL-related death if tic information can be gained over and above that of the he/she died as a result of cytopenias, high-grade lymphoma Binet/Rai staging. The presence of a clonal abnormality, howor infection; also if CLL was quoted as the cause of death on ever, may be an aid in the diagnosis and assessment of progthe death certificate. Otherwise death was considered nonnosis. Deletions at 13q14 are the most frequent abnormality CLL related. In all cases survival was assessed from diagnosis. in CLL and occur in up to 30% of patients. 2-4 Such patients have been shown to have a similar survival pattern to those with a normal karyotype. 2 Trisomy 12 is another common abnormality, affecting about 20% of patients as determined Diagnosis of CLL by conventional techniques 2 but as many as 30-40% when analysed by FISH, detecting abnormalities in previously norThis required a peripheral lymphocytosis (Ͼ4 × 10 9 /l) of small mal karyotypes. 5,6 Trisomy 12 is thought to be an adverse mature lymphocytes, Ͻ10% prolymphocytes or large lymphoprognostic feature and correlation with atypical morphology cytes and Ͻ15% cleaved or lymphoplasmacytic cells. and poor survival has been shown. 2,6,7 Multiple karyotypic Immunophenotype of typical CLL was needed ie CD5, CD19 abnormalities, a high percentage of abnormal metaphases and and CD23 positive with weak immunoglobulin expression abnormalities of chromosome 14 are also associated with demonstrating or restriction. FMC7 was weak and/or poorer outlook; 2,8-10 at least a proportion of the latter wi...

Key Points• Germline JAK2V617I mutation as a sole genetic event does not suppress hematopoietic stem cells.• JAK2V617I induces weaker constitutive activation than JAK2V617F but considerable cytokine hyperresponsiveness.The association between somatic JAK2 mutation and myeloproliferative neoplasms (MPNs) is now well established. However, because JAK2 mutations are associated with heterogeneous clinical phenotypes and often occur as secondary genetic events, some aspects of JAK2 mutation biology remain to be understood. We recently described a germline JAK2V617I mutation in a family with hereditary thrombocytosis and herein characterize the hematopoietic and signaling impact of JAK2V617I. Through targeted sequencing of MPN-associated mutations, exome sequencing, and clonality analysis, we demonstrate that JAK2V617I is likely to be the sole driver mutation in JAK2V617I-positive individuals with thrombocytosis. Phenotypic hematopoietic stem cells (HSCs) were increased in the blood and bone marrow of JAK2V617I-positive individuals and were sustained at higher levels than controls after xenotransplantation. In signaling and transcriptional assays, JAK2V617I demonstrated more activity than wild-type JAK2 but substantially less than JAK2V617F. After cytokine stimulation, JAK2V617I resulted in markedly increased downstream signaling compared with wild-type JAK2 and comparable with JAK2V617F. These findings demonstrate that JAK2V617I induces sufficient cytokine hyperresponsiveness in the absence of other molecular events to induce a homogeneous MPN-like phenotype. We also provide evidence that the JAK2V617I mutation may expand the HSC pool, providing insights into both JAK2 mutation biology and MPN disease pathogenesis. (Blood. 2013;121(20):4156-4165)