Experimental hematology最新文献

Menin inhibitors disrupt oncogenic transcription in KMT2A-rearranged leukaemias, but responses are heterogeneous. Mahdavi et al highlight the role of non-genetic resistance driven by altered chromatin context, including loss of KMT2C/D-UTX activity, underscoring the need for broader epigenetic profiling to guide therapy timing and combination strategy selection.

Remarkable outcomes of chimeric antigen receptor (CAR)-T cell therapy in treating hematologic malignancies have inspired parallel efforts to harness the potential of other immune cell types for CAR-based immunotherapy. These efforts aim to overcome the existing limitations of CAR-T cell therapy. In recent years, CAR-macrophages (CAR-MACs) have shown astonishing efficacy in cancer treatment, leading to the approval of several CAR-MAC products for clinical trials. The lack of T-cell receptor (TCR) expression allows them to be used in allogeneic settings and as off-the-shelf products. Within the tumor microenvironment (TME), they can suppress tumor growth via multimodal mechanisms, including CAR-dependent and CAR-independent activities. They can also remodel the TME and prime other immune cells to enhance antitumor responses. Despite these merits, obtaining a sufficient number of MACs from traditional sources is challenging or is subject to regulatory hurdles. This review explores induced pluripotent stem cells (iPSCs) as an emerging source for generating iPSC-derived CAR-MACs (CAR-iMACs). In this regard, we begin with an overview of MACs and their conventional sources, and discuss the advantages of iPSCs over these traditional sources. After that, the technical procedures for generating iPSCs and differentiating them into functional CAR-iMACs are comprehensively discussed. Finally, we explore the preclinical and clinical advances in CAR-iMAC therapy.

The DNA hypomethylating agents (HMAs) 5-azacitidine and decitabine are the backbone of disease modifying therapy in myelodysplastic syndromes (MDS). Resistance to therapy often develops by upregulation of de-novo pyrimidine synthesis which competes directly with the DNMT1-depleting nucleotide Aza-dCTP by building natural cytidines and deoxycytidines from amino acid building blocks. Inhibition of de-novo pyrimidine synthesis can restore sensitivity of leukemic stem cells to therapy. Here we demonstrate that Pyrimethamine (PYR), an FDA approved antiparasitic, antifolate agent causes apoptosis in multiple leukemic cell lines, has synergy with venetoclax (Ven) and additive effect with HMA's in HMA and Ven resistant leukemic cell lines as well as murine models. It increases differentiation of stem and progenitor populations in primary MDS patient samples and is able to directly inhibit de novo pyrimidine synthesis thereby overcoming one of the primary mechanisms of HMA resistance. In combination with Ven, it also downregulates multiple enzymes implicated in pyrimidine synthesis. TEASER ABSTRACT: In myelodysplastic syndromes, one of the mechanisms of resistance to hypomethylating agents arises through activation of de novo pyrimidine synthesis, which competes with Aza-dCTP nucleotide. We show that pyrimethamine, an FDA-approved antifolate, induces apoptosis across leukemic models, synergizes with venetoclax, and restores sensitivity in HMA- and venetoclax-resistant leukemia. Pyrimethamine promotes differentiation of stem and progenitor cells in primary MDS samples and in combination with venetoclax directly inhibits pyrimidine synthesis, revealing a clinically actionable strategy to overcome a key mechanism of therapeutic resistance.

Total-body irradiation is routinely used for myeloablation prior to mouse hematopoietic cell transplant. Widespread transition from ¹³⁷Cs gamma irradiators to X-ray systems has raised questions about whether these modalities yield equivalent biological outcomes. Although prior studies compared gamma and X-ray irradiation in syngeneic transplants, their performance in reciprocal congenic models and in primary acute myeloid leukemia (AML) transplant remains unclear. Here, we systematically evaluated gamma and X-ray irradiation across dose and dose-rate conditions, and tested dose equivalents in CD45.1/CD45.2 reciprocal transplants and in AML transplant models. While each modality exhibited distinct early effects, both ultimately supported comparable long-term donor peripheral blood (PB) chimerism in congenic transplants and equivalent AML engraftment, leukemic burden, and disease progression. These findings indicate that, with proper dose calibration, X-ray irradiation is a functionally effective alternative to gamma irradiation for normal and malignant transplant studies. Teaser Abstract: Widespread transition from ¹³⁷Cs gamma irradiators to X-ray systems for myeloablation prior to mouse hematopoietic cell transplant has raised questions about whether these modalities yield equivalent biological outcomes. Here, we systematically evaluate gamma and X-ray irradiation across dose and dose-rate conditions, and test dose equivalents in CD45.1/CD45.2 reciprocal transplants and in AML transplant models. While each modality exhibited distinct early effects, both ultimately supported comparable long-term donor chimerism in congenic transplants and equivalent AML engraftment, leukemic burden, and disease progression.

The Jazan region of Saudi Arabia has a high prevalence of sickle cell disease (SCD), compounded by consanguineous marriages. The Jazan region exemplifies a population that is markedly underrepresented in genomic medicine research, distinguished by distinctive sociocultural factors, including consanguinity rates surpassing 50%. While gene therapy (GT) offers a potential cure, its implementation requires an understanding of local awareness and acceptance. A cross-sectional online survey of 357 Jazan residents, including 104 SCD-affected individuals/families, assessed genetic literacy, clinical burden, and GT attitudes. Multivariate logistic regression identified predictors of GT awareness and acceptance. Despite high genetic literacy (84.0% knew SCD inheritance; 72.5% aware of consanguinity risks), only 45.4% were aware of GT. Graduate education (OR=3.54; 95% CI=1.80-6.95) and personal SCD status (OR=1.97; 95% CI=1.15-3.37) independently predicted GT awareness. Among affected individuals, GT acceptance was independently predicted by awareness of consanguinity risk (OR=3.51; 95% CI=1.25-9.80) and personal SCD status (OR=2.89; 95% CI=1.08-7.74). This educated cohort exhibits a significant gap between genetic knowledge and GT awareness. Acceptance is strongly driven by an understanding of inheritance patterns, highlighting the need for genetic counseling that links consanguinity risks to therapeutic advances to facilitate equitable GT implementation.

Microcytic hypochromic anemias, including iron-deficiency anemia (IDA) and vitamin B6-deficiency anemia (B6DA), share similar hematologic features but differ fundamentally in etiology and therapeutic responsiveness. IDA results from insufficient dietary iron, activating adaptive intestinal iron absorption via hypoxia-inducible factor 2⍺ (HIF2⍺), whereas B6DA impairs heme biosynthesis without systemic iron depletion, rendering it refractory to iron therapy. Here, we investigated whether intestinal HIF2⍺ activation distinguishes these anemias. Using mouse models, we established that severe dietary iron restriction (<5 ppm for two weeks) robustly induced intestinal HIF2⍺ targets DMT1, Dcytb, Fpn1, and NCOA4, while suppressing hepatic hepcidin. In contrast, B6-deficient mice developed hypochromic microcytic anemia over 60 days without changes in intestinal HIF2⍺ signaling, duodenal ferritin, or hepcidin. Parenteral B6 supplementation rapidly restored hemoglobin but did not alter intestinal iron gene expression, confirming that low iron, not anemia, drives HIF2⍺-mediated intestinal adaptation. These findings reveal a mechanistic distinction: IDA engages a coordinated systemic and intestinal iron response, whereas B6DA produces anemia through heme biosynthesis defects independent of iron sensing. Importantly, assessment of intestinal HIF2⍺ activity or downstream targets provides a functional biomarker to differentiate iron-responsive from non-iron-responsive microcytic anemias. This approach could prevent misdiagnosis and guide more precise therapeutic strategies, highlighting the value of integrating molecular iron sensing into clinical evaluation of nutritional anemias. Iron-deficiency anemia (IDA) and vitamin B6-deficiency anemia (B6DA), share similar hematologic features but differ in etiology and therapeutic responsiveness. The relationship between IDA and intestinal HIF2⍺ activation is well established, but it's not clear if anemias like B6DA that occur without systemic iron depletion also engage intestinal HIF2⍺ signaling. Our study show that although degrees of IDA and B6DA are comparable, they have significant differences that offer new mechanistic insights: i) They have separate intervals of anemia onset following dietary intervention, ii) HIF2⍺ activity remains stagnant in B6DA, iii) Intestinal HIF2⍺ activation can be used as a tool to differentiate IDAs from IDA-like anemias.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy that relies heavily on the antiapoptotic protein B-cell lymphoma 2 (BCL-2) for survival. Venetoclax, a BCL-2 inhibitor, exploits this dependency and is currently approved for treatment of elderly patients with AML. BCL-XL, another prosurvival protein in the BCL-2 family, has been identified as a key driver of both intrinsic and acquired resistance to venetoclax. Patients often develop resistance to BCL-2 inhibition through upregulation of BCL-XL. This study investigates the efficacy of a dual BCL-2/BCL-XL inhibitor and its combination with standard-of-care (SOC) agents. Dual BCL-2/BCL-XL inhibitor demonstrates robust activity in AML cell lines and patient-derived models, including activity in samples from patients who relapsed following venetoclax therapy. Its combination with SOC agents deepens the antileukemic activity both in vitro and in vivo. Among the combination regimens tested, cytarabine or hypomethylating agents (HMAs) drive strong blast reduction in patient samples previously exposed to venetoclax and yield improved survival in xenograft models derived from patients with AML who underwent prior venetoclax/5-azacytidine treatment. These preclinical findings support the clinical evaluation of dual BCL-2/BCL-XL inhibition in patients with AML, particularly, those who do not respond to venetoclax.