Point mutations in the seed sequence of miR-142-3p are present in a subset of acute myelogenous leukemia (AML) and in several subtypes of B-cell lymphoma. Here, we show that mutations associated with AML result both in loss of miR-142-3p function and in decreased miR-142-5p expression. loss altered the hematopoietic differentiation of multipotent hematopoietic progenitors, enhancing their myeloid potential while suppressing their lymphoid potential. During hematopoietic maturation, loss of increased ASH1L protein expression and consequently resulted in the aberrant maintenance of gene expression in myeloid-committed hematopoietic progenitors. loss also enhanced the disease-initiating activity of -mutant hematopoietic cells in mice. Together these data suggest a novel model in which miR-142, through repression of ASH1L activity, plays a key role in suppressing expression during normal myeloid differentiation. AML-associated loss-of-function mutations of disrupt this negative signaling pathway, resulting in sustained expression in myeloid progenitors/myeloblasts and ultimately contributing to leukemic transformation. These findings provide mechanistic insights into the role of miRNAs in leukemogenesis and hematopoietic stem cell function. .

Diseases with clonal hematopoiesis such as myelodysplastic syndrome and acute myeloid leukemia have high rates of relapse. Only a small subset of acute myeloid leukemia patients are cured with chemotherapy alone. Relapse in these diseases occurs at least in part due to the failure to eradicate leukemic stem cells or hematopoietic stem cells in myelodysplastic syndrome. CD123, the alpha chain of the interleukin-3 receptor heterodimer, is expressed on the majority of leukemic stem cells and myelodysplastic syndrome hematopoietic stem cells and in 80% of acute myeloid leukemia. Here, we report indiscriminate killing of CD123+ normal and acute myeloid leukemia / myelodysplastic syndrome cells by SL-401, a diphtheria toxin interleukin-3 fusion protein. SL-401 induced cytotoxicity of CD123+ primary cells/blasts from acute myeloid leukemia and myelodysplastic syndrome patients but not CD123− lymphoid cells. Importantly, SL-401 was highly active even in cells expressing low levels of CD123, with minimal effect on modulation of the CD123 target in acute myeloid leukemia. SL-401 significantly prolonged survival of leukemic mice in acute myeloid leukemia patient-derived xenograft mouse models. In addition to primary samples, studies on normal cord blood and healthy marrow show that SL-401 has activity against normal hematopoietic progenitors. These findings indicate potential use of SL-401 as a “bridge-to-transplant” before allogeneic hematopoietic cell transplantation in acute myeloid leukemia / myelodysplastic syndrome patients.

No abstract

Effective treatment of opioid use disorder (OUD) must target both the medical and psychosocial aspects of a patient's condition. This, in turn, requires a collaboration between medical providers and social supports. We would like to illustrate a key difficulty in this collaboration for some patients in our country: many post-discharge recovery houses continue to refuse to allow patients to remain on medication treatment for OUD (M-OUD). This barrier to M-OUD access in recovery houses is a significant obstacle to effective OUD treatment.