A Senescence-Like Cell-Cycle Arrest Occurs During Megakaryocytic Maturation: Implications for Physiological and Pathological Megakaryocytic Proliferation

During normal megakaryocyte development, in response to thrombopoetin, mature cells enter a senescence-like state in which they shed platelets; this state, characterized by cell cycle arrest, is defective in malignant megakaryocytes

HAEMATOLOGY Smear microscopy revision Smear microscopy revision: propositions by the GFHC

Abstract Despite the development of automated haematology analysers for reliable blood counts, examining blood smears under the microscope is still indispensable for confirming results when the data the analyser obtains are qualitatively or quantitatively abnormal. Although most criteria that lead to blood smear examination are widely recognised and used in laboratories, a multicentre survey indicates that they are still highly heterogeneous. To contribute to the harmonisation and standardisation of essential cellular haematology practice within the context of laboratory accreditation, the GFHC reviewed in detail the criteria used within the CBC to generate blood smears and has decided on a number of minimum recommendations. The conclusions presented in this article are based on a 'strong professional consensus', defining threshold values and various situations in which the blood smear review is desirable. They are presented as minimum recommendations for technical verification and biological validation. All laboratories are free to use more restrictive thresholds based on their patient populations

Multicentric study underlining the interest of adding CD5, CD7 and CD56 expression assessment to the flow cytometric Ogata score in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms

Although numerous recent publications have demonstrated interest in multiparameter flow cytometry in the investigation of myelodysplastic disorders, it is perceived by many laboratory hematologists as difficult and expensive, requiring a high level of expertise. We report a multicentric open real-life study aimed at evaluating the added value of the technically simple flow cytometry score described by the Ogata group for the diagnosis of myelodysplastic syndromes. A total of 652 patients were recruited prospectively in four different centers: 346 myelodysplastic syndromes, 53 myelodysplastic/myeloproliferative neoplasms, and 253 controls. The Ogata score was assessed using CD45 and CD34 staining, with the addition of CD10 and CD19. Moreover, labeling of CD5, CD7 and CD56 for the evaluation of myeloid progenitors and monocytes was tested on a subset of 294 patients. On the whole series, the specificity of Ogata score reached 89%. Respective sensitivities were 54% for low-risk myelodysplastic syndromes, 68% and 84% for type 1 and type 2 refractory anemia with excess of blasts, and 72% for myelodysplastic/myeloproliferative neoplasms. CD5 expression was poorly informative. When adding CD56 or CD7 labeling to the Ogata score, sensitivity rose to 66% for low-risk myelodysplastic syndromes, to 89% for myelodysplastic/myeloproliferative neoplasms and to 97% for refractory anemia with excess of blasts. This large multicenter study confirms the feasibility of Ogata scoring in routine flow cytometry diagnosis but highlights its poor sensitivity in low-risk myelodysplastic syndromes. The addition of CD7 and CD56 in flow cytometry panels improves the sensitivity but more sophisticated panels would be more informative

Macrophage migration inhibitory factor is overproduced through EGR1 in TET2^low resting monocytes.

Somatic mutation in TET2 gene is one of the most common clonal genetic events detected in age-related clonal hematopoiesis as well as in chronic myelomonocytic leukemia (CMML). In addition to being a pre-malignant state, TET2 mutated clones are associated with an increased risk of death from cardiovascular disease, which could involve cytokine/chemokine overproduction by monocytic cells. Here, we show in mice and in human cells that, in the absence of any inflammatory challenge, TET2 downregulation promotes the production of MIF (macrophage migration inhibitory factor), a pivotal mediator of atherosclerotic lesion formation. In healthy monocytes, TET2 is recruited to MIF promoter and interacts with the transcription factor EGR1 and histone deacetylases. Disruption of these interactions as a consequence of TET2-decreased expression favors EGR1-driven transcription of MIF gene and its secretion. MIF favors monocytic differentiation of myeloid progenitors. These results designate MIF as a chronically overproduced chemokine and a potential therapeutic target in patients with clonal TET2 downregulation in myeloid cells

The level of blast CD33 expression positively impacts the effect of gemtuzumab ozogamicin in patients with acute myeloid leukemia

International audienceGemtuzumab ozogamicin (GO) is an immunoconjugate, combining an anti-CD33 monoclonal antibody to calicheamicin, a highly cytotoxic antibiotic. First developed as single agent in adults with relapsed acute myeloid leukemia (AML), it was then evaluated in combination with chemotherapy in newly diagnosed patients. In the randomized Acute Leukemia French Association (ALFA)–0701 study, we reported that sequential administration of a lower dose of GO allowed the safe delivery of a high cumulative dose associated with a substantial improvement in patient outcome. A recent meta-analysis has confirmed that adding GO to chemotherapy may provide a survival advantage in patients without adverse cytogenetic characteristics. However, these results were obtained regardless of the level of blast CD33 expression. In vitro, a clear relationship between CD33 expression and GO efficacy has nevertheless been shown. In vivo, contradictory results have been reported so far. No impact was found when CD33 expression was evaluated as a continuous covariable or using a 20% cutoff. Higher response rates were nevertheless reported for patients with CD33+ expression ≥98% in 1 phase 2 study or when showing CD33 expression as mean fluorescence intensity (MFI) using an isotype antibody as control. To further evaluate the impact of CD33 expression on GO treatment effect, we retrospectively analyzed the results of the ALFA-0701 study