Non-donor specific anti-human leukocyte antigen (HLA) antibodies are not associated with poor outcome in hematopoietic stem cell transplant recipients.

Testing for anti-human leukocyte antigen (HLA) antibodies has now become standard practice in allogeneic hematopoietic stem cell transplantation (HSCT), and anti-HLA antibodies (both donor specific and non-donor specific) are being identified and have many potential consequences. Most studies suggest that donor-specific HLA antibodies lead to adverse outcomes, though little is reported on non-donor specific anti-HLA antibodies. We present the results of a retrospective cohort analysis of 157 patients who received HSCT at the University of Rochester over a period of four years. We identified 45 patients (28.7%) who had detectable anti-HLA antibodies, while only one patient (0.6%) had donor-specific anti-HLA antibodies. Patients with prior pregnancies and multiple transfusions were at increased risk to develop antibodies. In our cohort, the presence of non-donor specific anti-HLA antibodies did not significantly impact overall survival, progression free survival, graft failure, or transplant-related mortality.

Alternatively spliced, truncated GCSF receptor promotes leukemogenic properties and sensitivity to JAK inhibition.

Granulocyte colony-stimulating factor (GCSF) drives the production of myeloid progenitor and precursor cells toward neutrophils via the GCSF receptor (GCSFR, gene name CSF3R). Children with severe congenital neutropenia chronically receive pharmacologic doses of GCSF, and ∼30% will develop myelodysplasia/acute myeloid leukemia (AML) associated with GCSFR truncation mutations. In addition to mutations, multiple isoforms of CSF3R have also been reported. We found elevated expression of the alternatively spliced isoform, class IV CSF3R in adult myelodysplastic syndrome/AML patients. Aside from its association with monosomy 7 and higher rates of relapse in pediatric AML patients, little is known about the biology of the class IV isoform. We found developmental regulation of CSF3R isoforms with the class IV expression more representative of a progenitor cell stage. Striking differences were found in phosphoprotein signaling involving Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and cell cycle gene expression. Enhanced proliferation by class IV GCSFR was associated with diminished STAT3 and STAT5 activation, yet showed sensitivity to JAK2 inhibitors. Alterations in the C-terminal domain of the GCSFR result in leukemic properties of enhanced growth, impaired differentiation and resistance to apoptosis, suggesting that they can behave as oncogenic drivers, sensitive to JAK2 inhibition.