Somatic mutations in TET2 occur in about 15% of patients with various myeloid cancers.

Objective. Because it has no unique clinical, biologic, or histologic features, reactive hemophagocytic syndrome may be difficult to distinguish from other diseases such as severe sepsis or hematologic malignancies. This study was undertaken to develop and validate a diagnostic score for reactive hemophagocytic syndrome.Methods. A multicenter retrospective cohort of 312 patients who were judged by experts to have reactive hemophagocytic syndrome (n ‫؍‬ 162), were judged by experts to not have reactive hemophagocytic syndrome (n ‫؍‬ 104), or in whom the diagnosis of reactive hemophagocytic syndrome was undetermined (n ‫؍‬ 46) was used to construct and validate the reactive hemophagocytic syndrome diagnostic score, called the HScore. Ten explanatory variables were evaluated for their association with the diagnosis of hemophagocytic syndrome, and logistic regression was used to calculate the weight of each criterion included in the score. Performance of the score was assessed using developmental and validation data sets.

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Reactive haemophagocytic syndrome is a life-threatening disease for which factors influencing the outcome remain unclear. We sought to identify determinants of early mortality in patients with reactive haemophagocytic syndrome by conducting a non-interventional retrospective multicentre study in three tertiary care teaching hospitals over a 6-year period. The medical files of 162 patients fulfilling our diagnostic criteria of haemophagocytic syndrome were reviewed. Patients were classified according to 30-d outcome following diagnosis. Thirty-three patients (20·4%) died within 30 d. Clinical features at diagnosis associated with 30-d death in univariate analysis were older age (P = 0·004), underlying lymphoma (P = 0·04), lower platelet count (P = 0·001) and elevated aspartate aminotransferase and lactate dehydrogenase (P = 0·04 both). The use of etoposide as a first-line treatment tended to be associated with a better outcome (P = 0·079). In multivariate analyses, increasing age, decreasing platelet count, underlying lymphoma and no etoposide in the management were associated with a poorer prognosis (P = 0·03, 0·01, 0·003 and 0·04, respectively). These prognostic factors could help to identify those patients more severely affected by reactive haemophagocytic syndrome, who should benefit from aggressive supportive care, combined with specific treatment of the precipitating factor.

Key Points• Enrichment of atypical MPL mutations in essential thrombocythemia.• MPLS204P and MPLY591N mutants are weak gain-offunction mutants.Mutations in signaling molecules of the cytokine receptor axis play a central role in myeloproliferative neoplasm (MPN) pathogenesis. Polycythemia vera is mainly related to JAK2 mutations, whereas a wider mutational spectrum is detected in essential thrombocythemia (ET) with mutations in JAK2, the thrombopoietin (TPO) receptor (MPL), and the calreticulin (CALR) genes. Here, we studied the mutational profile of 17 ET patients negative for JAK2V617F, MPLW515K/L, and CALR mutations, using whole-exome sequencing and next-generation sequencing (NGS) targeted on JAK2 and MPL. We found several signaling mutations including JAK2V617F at very low allele frequency, 1 homozygous SH2B3 mutation, 1 MPLS505N, 1 MPLW515R, and 2 MPLS204P mutations. In the remaining patients, 4 presented a clonal and 7 a polyclonal hematopoiesis, suggesting that certain triple-negative ETs are not MPNs. NGS on 26 additional triple-negative ETs detected only 1 MPLY591N mutation. Functional studies on MPLS204P and MPLY591N revealed that they are weak gain-of-function mutants increasing MPL signaling and conferring either TPO hypersensitivity or independence to expressing cells, but with a low efficiency. Further studies should be performed to precisely determine the frequency of MPLS204 and MPLY591 mutants in a bigger cohort of MPN. (Blood. 2016;127(3):333-342)

In acute myeloid leukaemia (AML) initiating pre-leukaemic lesions can be identified through three major hallmarks: their early occurrence in the clone, their persistence at relapse and their ability to initiate multilineage haematopoietic repopulation and leukaemia in vivo. Here we analyse the clonal composition of a series of AML through these characteristics. We find that not only DNMT3A mutations, but also TET2, ASXL1 mutations, core-binding factor and MLL translocations, as well as del(20q) mostly fulfil these criteria. When not eradicated by AML treatments, pre-leukaemic cells with these lesions can re-initiate the leukaemic process at various stages until relapse, with a time-dependent increase in clonal variegation. Based on the nature, order and association of lesions, we delineate recurrent genetic hierarchies of AML. Our data indicate that first lesions, variegation and treatment selection pressure govern the expansion and adaptive behaviour of the malignant clone, shaping AML in a time-dependent manner.

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