Targeting MCL-1 and BCL-2 with polatuzumab vedotin and venetoclax overcomes treatment resistance in R/R non-Hodgkin lymphoma: Results from preclinical models and a Phase Ib study.

The treatment of patients with relapsed or refractory lymphoid neoplasms represents a significant clinical challenge. Here, we identify the pro-survival BCL-2 protein family member MCL-1 as a resistance factor for the BCL-2 inhibitor venetoclax in non-Hodgkin lymphoma (NHL) cell lines and primary NHL samples. Mechanistically, we show that the antibody-drug conjugate polatuzumab vedotin promotes MCL-1 degradation via the ubiquitin/proteasome system.

Dramatic response to cyclin D-dependent kinase 4/6 inhibitor in refractory poorly differentiated neuroendocrine carcinoma of the breast.

Neuroendocrine tumors are a rare subset of breast carcinomas. Commonly, platinum-based doublet is used as a systemic treatment option for high-grade neuroendocrine carcinomas from lung, gastrointestinal, and genitourinary origins. In comparison to other breast cancers, neuroendocrine carcinomas have unique genomic features and different treatment strategies.

Successful treatment of pegaspargase-induced acute hepatotoxicity with vitamin B complex and L-carnitine.

Pegaspargase is a chemotherapy drug used in the treatment of acute lymphoblastic leukemia (ALL). One of the adverse effects of pegaspargase is hepatotoxicity, which can rapidly lead to liver failure and death. We report a patient with ALL who developed pegaspargase-induced severe hepatotoxicity that was rescued by treatment with vitamin B complex and L-carnitine.

A KIT juxtamembrane PY567 -directed pathway provides nonredundant signals for erythroid progenitor cell development and stress erythropoiesis.

Objective: KITL/KIT can elicit diverse sets of signals within lymphoid, myeloid, mast, and erythroid lineages, and exert distinct effects on growth, survival, migration, adhesion, and secretory responses. Presently, we have applied a PY-mutant allele knockin approach to specifically assess possible roles for KIT-PY567 and KIT-PY719 sites, and coupled pathways, during erythropoiesis.

Materials And Methods: Mouse models used to investigate this problem include those harboring knocked-in KIT(Y567F/Y567F), KIT(Y569F/Y569F), KIT(Y719F,Y719F), and KIT(Y567F/Y567F:Y569F/Y569F) alleles.

DYRK3 dual-specificity kinase attenuates erythropoiesis during anemia.

During anemia erythropoiesis is bolstered by several factors including KIT ligand, oncostatin-M, glucocorticoids, and erythropoietin. Less is understood concerning factors that limit this process. Experiments performed using dual-specificity tyrosine-regulated kinase-3 (DYRK3) knock-out and transgenic mice reveal that erythropoiesis is attenuated selectively during anemia.

Lyn kinase promotes erythroblast expansion and late-stage development.

Lyn kinase is known to modulate the formation and function of B cells, monocytes, and mast cells. However, Lyn-/- mice also develop erythrosplenomegaly, and cases for both negative and positive erythropoietic actions of Lyn recently have been outlined. In phenylhydrazine-treated Lyn-/- mice, extramedullary splenic erythropoiesis was hyperactivated, but this did not lead to accelerated recovery from anemia.

Erythropoietin-dependent erythropoiesis: New insights and questions.

Committed erythroid progenitor cells require exposure to erythropoietin (Epo) for their survival and for their quantitatively regulated transition to red blood cells. With regard to Epo signal transduction mechanisms, much has been learned from analyses in cell line models, fetal liver or spleen-derived primary erythroblasts and human CD34pos progenitor cells from cord blood or mobilized bone marrow. Presently, we have developed an ex vivo system that efficiently supports the expansion and development of murine adult bone-marrow-derived erythroid progenitor cells.

Attenuated signaling by a phosphotyrosine-null Epo receptor form in primary erythroid progenitor cells.

Signals provided by the erythropoieitin receptor (EpoR) are required for erythroid development beyond the erythroid colony-forming unit (CFU-e) stage and are propagated via the EpoR-tethered Janus kinase, JAK2. JAK2 functions, in part, to phosphorylate 8 conserved EpoR phosphotyrosine (PY) sites for the binding of a diverse set of signaling factors. However, recent studies in transgenic and knock-in mice have demonstrated substantial bioactivity for PY-null EpoR forms.

DYRK3 activation, engagement of protein kinase A/cAMP response element-binding protein, and modulation of progenitor cell survival.

DYRKs are a new family of dual-specificity tyrosine-regulated kinases with emerging roles in cell growth and development. Recently, we discovered that DYRK3 is expressed primarily in erythroid progenitor cells and modulates late erythropoiesis. We now describe 1) roles for the DYRK3 YTY signature motif in kinase activation, 2) the coupling of DYRK3 to cAMP response element (CRE)-binding protein (CREB), and 3) effects of DYRK3 on hematopoietic progenitor cell survival.