Transcriptome-wide subtyping of pediatric and adult T cell acute lymphoblastic leukemia in an international study of 707 cases.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy of T cell progenitors, known to be a heterogeneous disease in pediatric and adult patients. Here we attempted to better understand the disease at the molecular level based on the transcriptomic landscape of 707 T-ALL patients (510 pediatric, 190 adult patients, and 7 with unknown age; 599 from published cohorts and 108 newly investigated). Leveraging the information of gene expression enabled us to identify 10 subtypes (G1­G10), including the previously undescribed one characterized by GATA3 mutations, with GATA3R276Q capable of affecting lymphocyte development in zebrafish. Through associating with T cell differentiation stages, we found that high expression of LYL1/LMO2/SPI1/HOXA (G1­G6) might represent the early T cell progenitor, pro/precortical/cortical stage with a relatively high age of disease onset, and lymphoblasts with TLX3/TLX1 high expression (G7­G8) could be blocked at the cortical/postcortical stage, while those with high expression of NKX2-1/TAL1/LMO1 (G9­G10) might correspond to cortical/postcortical/mature stages of T cell development. Notably, adult patients harbored more cooperative mutations among epigenetic regulators, and genes involved in JAK-STAT and RAS signaling pathways, with 44% of patients aged 40 y or above in G1 bearing DNMT3A/IDH2 mutations usually seen in acute myeloid leukemia, suggesting the nature of mixed phenotype acute leukemia.

The Portrait of a Dying Child.

The portrait of a dying child is an homage to a child's journey from initial diagnosis to the terminal stages of illness in metastatic neuroblastoma, raising the critical question of the importance of defining a beautiful death - a concept I first came across as a literature student in Henrik Ibsen's renowned tragedy Hedda Gabler. In this article, we discuss a case study of a child named Peter (real names have been changed to maintain the confidentiality of the patient) and his family, whom I met during my oncology rotation as a junior pediatric resident, and various aspects of care - ranging from symptom management, pain control, the family as an emotional and spiritual unit and complications of metastatic disease. Interlaced amidst references of current practices related to pain control and palliation of symptoms are quotes from Dr Myra BluebondLangner's books and a personal encounter with the child to construct the child as a child and not another dying patient. The enigma of the definition of a beautiful death is also discussed from the patient and the family's point of view. An ideal medical death would be one without pain and with optimal symptom control; however, a beautiful death is so much more - encompassing a peaceful passing surrounded not by machines but by happiness around and at heart. We hope this article would encourage pediatricians to continue to practice pediatric palliative care in the daily setting when dealing with critically ill patients or children in their final stages of life.