Altered microenvironmental regulation of CML stem cells
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Uncovering two neutrophil-committed progenitors that immediately precede promyelocytes during human neutropoiesis
Technological advances have greatly improved our knowledge of myelopoiesis, for example, with the discovery of granulocyte‒monocyte‒dendritic cell (DC) progenitors (GMDPs), monocyte‒DC progenitors (MDPs), common DC progenitors (CDPs) and common monocyte progenitors (cMoPs) on the basis of flow cytometry approaches. Concomitantly, some progress has been made in characterizing the very early phases of human neutropoiesis with the description of novel CD66b+ progenitors, including eNePs, PMs w/o eNePs, ProNeus, and PreNeus. More recently, we identified four SSCloLin–CD66b–CD45dimCD34+/CD34dim/-CD64dimCD115– cells as the earliest precursors specifically committed to the neutrophil lineage present in human bone marrow (BM), which we called neutrophil-committed progenitors (NCPs, from NCP1s to NCP4s). In this study, we report the isolation and characterization of two new SSChiCD66b–CD64dimCD115–NCPs that, by phenotypic, transcriptomic, maturation and immunohistochemistry properties, as well as by flow cytometric side-scattered light (SSC), stand after NCP4s but precede promyelocytes during the neutropoiesis cascade. Similar to SSCloCD45RA+NCP2s/NCP3s and SSCloCD45RA–NCP1s/NCP4s, these cells exhibit phenotypic differences in CD45RA expression levels and, therefore, were named SSChiCD45RA+NCP5s and SSChiCD45RA–NCP6s. Moreover, NCP5s were more immature than NCP6s, as determined by cell differentiation and proliferative potential, as well as by transcriptomic and phenotypical features. Finally, by examining whether NCPs and all other CD66b+ neutrophil precursors are altered in representative hematological malignancies, we found that, in patients with chronic-phase chronic myeloid leukemia (CP-CML), but not with systemic mastocytosis (SM), there is an increased frequency of BM NCP4s, NCP6s, and all downstream CD45RA-negative neutrophil progenitors, suggesting their expansion in CML pathogenesis. Taken together, our data advance our knowledge of human neutropoiesis.
CDK8/19 inhibition attenuates G1 arrest induced by BCR-ABL antagonists and accelerates death of chronic myelogenous leukemia cells
Imatinib mesylate (IM) and other BCR-ABL tyrosine kinase inhibitors (BCR-ABLi) are the mainstay of chronic myelogenous leukemia (CML) treatment. However, activation of circumventing signaling pathways and quiescence may limit BCR-ABLi efficacy. CDK8/19 Mediator kinases have been implicated in the emergence of non-genetic drug resistance. Dissecting the effects of pharmacological CDK8/19 inhibition on CML survival in response to BCR-ABLi, we found that a selective, non-toxic CDK8/19 inhibitor (CDK8/19i) Senexin B (SenB) and other CDK8/19i sensitized K562 cells to different BCR-ABLi via attenuation of cell cycle arrest. In particular, SenB prevented IM-induced upregulation of genes that negatively regulate cell cycle progression. SenB also antagonized IM-activated p27Kip1 elevation thereby diminishing the population of G1-arrested cells. After transient G1 arrest, cells treated with IM + SenB re-entered the S phase, where they were halted and underwent replicative stress. Consequently, the combination of IM and SenB intensified apoptotic cell death, measured by activation of caspase 9 and 3, subsequent cleavage of poly(ADPriboso)polymerase 1, positive Annexin V staining and increase of subG1 fraction. In contrast, IM-treated BCR-ABL-positive KU812 CML cells, which did not induce p27Kip1, readily died regardless of SenB treatment. Thus, CDK8/19i prevent the quiescence-mediated escape from BCR-ABLi-induced apoptosis, suggesting a strategy for avoiding the CML relapse.
Challenges determining the best target duration of deep molecular response after which to attempt achieving therapy-free remission in chronic myeloid leukaemia
Eradication of leukaemia stem and progenitor cells Mathematical models of CML and TFR are often built on assumptions about haematopoiesis that may or may not…
The 2023 EBMT report on hematopoietic cell transplantation and cellular therapies. Increased use of allogeneic HCT for myeloid malignancies and of CAR-T at the expense of autologous HCT
In 2023, 47,731 HCT (20,485 (42.9%) allogeneic and 27,246 (57.1%) autologous) in 43,902 patients were reported by 696 European centers. 6042 patients received advanced cellular therapies, 4888 of which were CAR-T. Compared to the previous year there was an increase in CAR-T (+52.5%), in allogeneic HCT (+7.8%) but none in autologous HCT (+0.4%). Main indications for allogeneic HCT were myeloid (11,748; 60.7%), lymphoid malignancies (4,850; 25.0%), and non-malignant disorders (2558; 13.2%). Use of allogeneic HCT increased for AML (+12.1%) and for NHL (+11.0%), particularly in T-NHL (+25.6%). Main indications for autologous HCT were lymphomas (7890; 32.2%), PCD (14,271; 58.2%), and solid tumors (1608; 6.6%) with recovering numbers for autoimmune diseases. In patients with allogeneic HCT, the use of sibling donors increased by +1.0%, haploidentical donors by +11.7%, and unrelated donors by +11.1%. Cord blood HCT decreased again by −5.4%. Pediatric HCT activity increased slightly (5455; +0.1%) with differences between allogeneic (4111; −0.5%) and autologous HCT (1344: +1.7%). Use of CAR-T increased to a cumulative total of 13,927 patients including patients treated for autoimmune diseases. Overall, numbers show a complete recovery from the pandemic dip with increased cellular therapy at the expense of autologous HCT. Allogeneic HCT activity focuses on myeloid malignancies.
Immunotherapy targeting a leader sequence cathepsin G-derived peptide
Myeloid azurophil granules provide a rich source of intracellular leukemia antigens. Cathepsin G (CG) is a serine protease that has higher expression in acute myeloid leukemia (AML) blasts in comparison to normal myeloid progenitors. Based on the unique biology of HLA-A*0201 (HLA-A2), in which presentation of leader sequence (LS)-derived peptides is favored, we focused on the LS-CG-derived peptide CG1 (FLLPTGAEA). We previously detected CG1/HLA-A2 complexes on the surface of primary HLA-A2+ AML blasts and cell lines, and immunity targeting CG1/HLA-A2 in leukemia patients. T cell receptor (TCR)-mimic (m) antibodies are immunotherapeutic antibodies that target peptide-HLA (pHLA) complexes. Here we report on the engineering, preclinical efficacy, and safety evaluation of a novel CG1/HLA-A2-targeting, T cell-engager, bispecific antibody (CG1/A2xCD3). CG1/A2xCD3 showed high binding affinity to CG1/HLA-A2 monomers, CD3-Fc fusion protein, and to AML and T cells, with potent killing of HLA-A2+ primary AML and cell lines in vitro and in vivo. This correlated with both tumor- and CG1/A2xCD3-dependent T cell activation and cytokine secretion. Lastly, CG1/A2xCD3 had no activity against normal bone marrow. Together, these results support the targeting of LS-derived peptides and the continued clinical development of CG1/A2xCD3 in the setting of AML.
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