This week we will explore the impact of calreticulin (CALR) haploinsufficiency on hematopoietic stem cell activity in the context of myeloproliferative neoplasms, explore mechanisms of leukemogenesis related to the E2A-PBX1 fusion protein in childhood B-cell acute lymphoblastic leukemia, and learn about the connection between intestinal microbiota, their metabolite short chain fatty acids and chronic graft versus host disease after allogeneic stem cell transplantation.
In a study reported in this Plenary Paper, Pi and colleagues used unbiased genomic profiling approaches and mechanistic studies to identify the direct and indirect target sites of the oncogenic fusion protein E2A-PBX1 in t(1,19)-positive pre-B acute lymphoblastic leukemia cells. They revealed how E2A-PBX1 acts in concert with RUNX1 to enforce transcriptome alterations underpinning the development of leukemia.
Recognition that germline mutations can predispose individuals to blood cancers, often presenting as secondary leukemias, has largely been driven in the last 20 years by studies of families with inherited mutations in the myeloid transcription factors (TFs) RUNX1, GATA2, and CEBPA.
Clinical and biological implications of target occupancy in CLL treated with the BTK inhibitor acalabrutinib
In a randomized phase 2 trial of acalabrutinib in patients with chronic lymphocytic leukemia (CLL), Sun et al documented that twice-daily dosing achieves higher Bruton tyrosine kinase (BTK) occupancy and pathway inhibition in lymph nodes than once-daily dosing and established the rate of BTK resynthesis in CLL cells. Both findings support the rationale for twice-daily dosing with this drug.
Secondary acute myeloid leukemias (AMLs) evolving from an antecedent myeloproliferative neoplasm (MPN) are characterized by a unique set of cytogenetic and molecular features distinct from de novo AML. Given the high frequency of poor-risk cytogenetic and molecular features, malignant clones are frequently insensitive to traditional AML chemotherapeutic agents.
The microbe-derived short-chain fatty acids butyrate and propionate are associated with protection from chronic GVHD
Markey and colleagues investigated the relationship between the gastrointestinal microbiome and chronic graft-versus-host disease (cGVHD), revealing that lower systemic concentrations of microbe-derived butyrate and propionate are associated with a higher chance of developing cGVHD in allogeneic hematopoietic stem cell transplant patients.