Blood最新文献

Abstract: Adoptive transfer of natural killer (NK) cells can induce complete remissions in 30% to 50% of patients with refractory acute myeloid leukemia and lymphoma. Although blood chimerism occurs, attaining functional homing to the site of tumor without exhaustion has been elusive. During chronic infections and tumorigenesis, exposure to activating stimuli weakens the effector activity of NK cells. Despite this knowledge, there is little known about the mechanisms that govern this dysregulation and whether these disparate activating stimuli use distinct pathways to downregulate effector immunity. In this study, we reveal that chronic NK cell activation receptor (NKAR) stimulation and chronic interleukin-15 exposure impart distinct modes of dysregulation, with NKAR stimulation inducing a tissue resident-like state that resembles that of tumor-infiltrating NK cells in patients with cancer. Using loss- and gain-of-function studies, we identify the transcription factor KLF2 as a master regulator of the NK cell response to chronic activation and provide evidence that KLF2 overexpression promotes NK cell cytotoxicity, cytokine production, and chemotaxis and inhibits the development of dysfunctional, tissue resident-like features. Using KLF2 reporter mice, we show that in certain tissues, tissue resident NK cells are predominantly KLF2-, whereas circulating NK cells in these tissues are overwhelmingly KLF2+. Lastly, using mixed bone marrow chimeras, we demonstrate that conditional KLF2 deficiency in NK cells leads to altered homing and the acquisition of tissue resident-like features in vivo. Together, these findings highlight the profound changes NK cells undergo during prolonged activation and advance our understanding of how some NK cell therapies fail during malignant relapse.

Abstract: Bispecific T-cell engagers (TCEs) targeting B-cell maturation antigen (BCMA) and CD3, induce deep hematologic responses in ∼60% of heavily pretreated patients with multiple myeloma (MM). We and others found that high tumor burden leads to resistance to TCE and novel strategies are urgently needed to improve responses in this setting. Ikaros degraders, including immunomodulatory drugs (IMiDs) and cereblon E3 ligase modulatory drugs (CELMoDs), represent logical partners for TCEs due to their direct anti-MM effects and additional immune-stimulatory activity; however, it is unclear how to optimally combine them with TCEs. Taking advantage of the immunocompetent IMiD-sensitive Vk∗MYChCRBN murine model of MM, we optimized strategies to overcome primary resistance to BCMA-TCEs and achieve sustained remission, while maintaining a manageable safety profile. The addition of anti-programmed cell death protein 1 (PD1) and pomalidomide reduced the T-cell exhaustion that occurs in response to TCEs in high tumor burden settings. This allowed for a higher degree of T-cell activation and significant improvement in response rates but also increased risk of lethal cytokine release syndrome (CRS). To moderate the response and prevent CRS, we evaluated Ikaros degraders and dexamethasone (DEX) with step-up-dosed TCEs. Pretreatment with iberdomide and DEX reshaped the bone marrow T-cell compartment, promoted infiltration of naïve T cells, and generated 100% response rates and the longest survival in subjects with high tumor burden. This was accompanied by more favorable T-cell profiling, with limited expansion of regulatory T cells and exhaustion. Overall, administering a TCE after DEX and iberdomide treatments provided deeper and more durable responses with a reduced risk of CRS.

Sickle cell disease (SCD) and β-thalassemia are devastating genetic disorders resulting from defects in the β-globin subunit of adult hemoglobin (HbA). Both disorders are ameliorated by the induction of γ-globin, a component of fetal hemoglobin (HbF). Therefore, the development of safe, effective, and widely available inducers of HbF is needed. Here, we discovered that slow cycling erythroid cells exhibit increased γ-globin expression. To understand the molecular basis of this, we screened all cyclin-dependent kinase inhibitors (CDKIs) for their ability to induce HbF using CRISPR activation (CRISPRa). We found that overexpression of CDKN1B, which encodes p27Kip1 (but not overexpression of other CDKIs), induces γ-globin expression at the transcriptional level. CDKN1B mutants expressing proteins unable to bind/inhibit CDKs and/or cyclins revealed that γ-globin induction by p27Kip1 depends largely on the domains involved in its cell cycle function. Pharmacological inhibition and genetic reduction of CDK4/6 also results in increased HbF. In genetic rescue experiments, we show that p27Kip1 induces HbF by inhibiting CDK4/6, through a mechanism that is likely BCL11A and ZBTB7A independent. Furthermore, palbociclib, an oral CDK4/6 inhibitor, significantly increases HbF in a murine SCD model at doses that are well tolerated. Moreover, we show that HbF induction by hydroxyurea, a drug currently in use to treat SCD, may be mediated in part by CDK4/6 inhibition. Overall, our findings establish a causal relationship between CDK4/6 activity and γ-globin production and suggest that single or dual CDK4/6 inhibitors might be therapeutically beneficial for SCD and β-thalassemia.

Abstract: Acute myeloid leukemias (AMLs) have an overall poor prognosis with many high-risk cases co-opting stem cell gene regulatory programs, but the mechanisms through which these programs are propogated remain poorly understood. The increased expression of the stem cell transcription factor, MECOM, underlies a key driver mechanism in largely incurable AMLs. However, how MECOM results in such aggressive AML phenotypes remains unknown. To address existing experimental limitations, we engineered and applied targeted protein degradation with functional genomic readouts to demonstrate that MECOM promotes malignant stem cell-like states by directly repressing prodifferentiation gene regulatory programs. Remarkably and unexpectedly, a single node in this network, a MECOM-bound cis-regulatory element located 42 kilobase (kb) downstream of the myeloid differentiation regulator CEBPA is both necessary and sufficient for maintaining MECOM-driven leukemias. Importantly, the targeted activation of this regulatory element promotes differentiation of these aggressive AMLs and reduces leukemia burden in vivo. These findings suggest a broadly applicable approach for functionally dissecting oncogenic gene regulatory networks to inform improved therapeutic strategies.