Danicopan add-on therapy in PNH, neural networks to identify bone marrow cells, and RNA editome and hematopoiesis
In this week’s episode, we’ll review results of a phase 2 study showing the beneficial effects of a first-in-class factor D inhibitor as add-on therapy in PNH patients who remain anemic and are transfusion-dependent despite C5 inhibition. Next, we’ll review the work of researchers who have developed a neural network that they say is highly accurate in differentiating between bone marrow cell morphologies. We’ll close with a report demonstrating that RNA editing of antizyme inhibitor 1, or Azin1, is a novel regulator of hematopoietic cell fate that can influence self-renewal and differentiation.
Highly accurate differentiation of bone marrow cell morphologies using deep neural networks on a large image data set
Artificial intelligence (AI) and machine learning algorithms are changing many facets of our lives and have great potential for disease diagnosis. In this Plenary Paper, Matek et al describe training a convolutional neural network model using 171 374 bone marrow cytology images from 945 patients with various hematological diseases before validating its accuracy in classifying single cells in an independent set of 627 images. The system can automatically classify 22 classes of bone marrow leukocytes, and with further improvements, it may bring AI-aided diagnosis of bone marrow biopsy specimens closer to fruition.
Phase 2 study of danicopan in patients with paroxysmal nocturnal hemoglobinuria with an inadequate response to eculizumab
Some patients with paroxysmal nocturnal hemoglobinuria (PNH) remain persistently anemic despite treatment with eculizumab and may have significant extravascular hemolysis. Kulasekararaj and colleagues report a phase 2 trial of danicopan, a first-inclass oral complement factor D inhibitor, added to ongoing eculizumab therapy in PNH patients who still needed transfusions. This small study of 12 patients reveals that the combination has acceptable safety while substantially increasing the hemoglobin concentration, reducing extravascular hemolysis, and improving the fatigue score.
A comprehensive RNA editome reveals that edited Azin1 partners with DDX1 to enable hematopoietic stem cell differentiation
Wang et al provide insight into how epigenetic regulation of the transcriptome can rewire cell fate decisions by mapping the RNA-editing landscape during hematopoiesis. They report that adenosine-to-inosine RNA editing of antizyme inhibitor 1 (Azin1) is a novel regulator of hematopoietic cell fate, capable of influencing self-renewal and differentiation of hematopoietic stem cells. This work sets the scene for developing RNA editing–targeted therapeutics for stem cell expansion and modulating AZIN1-induced cancer stem cell generation.
MicroRNA-497/195 is tumor suppressive and cooperates with CDKN2A/B in pediatric acute lymphoblastic leukemia
Current improvements in treatment for children with acute lymphoblastic leukemia (ALL) are based on detailed molecular classification that influences prognosis and can guide therapy. Boldrin et al identified a novel biomarker of poor outcome in ALL, and, using cell and in vivo models, they delineated the biological link between microRNA-497/195 repression and more aggressive disease. Their research also points to exploring pharmacological cell cycle inhibition as a potential method for treating these high-risk leukemias.
IgM-MM is predominantly a pre–germinal center disorder and has a distinct genomic and transcriptomic signature from WM
In this month’s CME article, Bazarbachi et al describe the genomic characterization of immunoglobulin M (IgM) multiple myeloma (MM) and contrast this rare entity with the far more common non-IgM MM and Waldenström macroglobulinemia. Their results help explain why IgM-MM is a distinct clinical and biological entity and highlight specific genetic abnormalities and transcriptomic features. These findings provide a rational basis for the future exploration of additional targeted therapies beyond those typically prescribed for MM in general.
