The April issue of Experimental Hematology is here!

Explore the latest findings, innovative studies and thought-provoking insights that continue to shape the field! Read the April Issue on ExpHem. 

Explore this Issue's Lineup:

Taking the direct route: menin inhibitors go straight to the frontline in KMT2A-rearranged acute leukemia

Anjum B. Khan, Brian J.P. Huntly

Menin inhibitors disrupt oncogenic transcription in KMT2A-rearranged leukemias, but responses are heterogeneous. A previous study highlighted the role of nongenetic 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. Read more>

Gene therapy acceptance in a high-consanguinity sickle cell disease population: bridging genetic literacy to therapeutic innovation in Saudi Arabia

Khaled Essawi

The Jazan region of Saudi Arabia faces high sickle cell disease (SCD) prevalence and consanguinity, yet remains underrepresented in genomic research. We surveyed 357 residents to assess genetic literacy and gene therapy (GT) attitudes. While literacy was high (84%), only 45.4% knew of GT. Graduate education (OR 3.54) and personal SCD status (OR 1.97) predicted GT awareness. Among affected families, acceptance was driven by consanguinity risk awareness (OR 3.51) and SCD status (OR 2.89). This gap between knowledge and awareness highlights a need for targeted counseling to link inheritance risks to curative advances for equitable GT delivery. Read more>

Anti-IL-18 immunotherapy decreases inflammatory and vaso-occlusive responses in mice with sickle cell disease

Érica M.F. Gotardo, Lidiane S. Torres, Irmgard Förster,...John Millholland, Fernando F. Costa, Nicola Conran

Interleukin-18 (IL-18) is elevated in sickle cell disease (SCD) and contributes to inflammatory and vaso-occlusive pathways. Using two SCD mouse models, we show that acute IL-18 blockade improves microvascular responses and preserves skin perfusion after tumor necrosis factor-alpha (TNF-α) challenge. Prolonged IL-18 inhibition reduces some inflammatory markers but does not prevent liver injury. These findings support IL-18 as a target to limit vascular inflammation in SCD, while indicating that preventing organ damage may require broader or combined approaches. Read more>

Evaluation of dual BCL-2/BCL-XL inhibition in acute myeloid leukemia preclinical models with and without prior venetoclax therapy

Reecha Shah, Nathan Kingston, Giulia Fabbri, Jamal Saeh, Courtney Andersen, Patricia Cheung

Despite advances with venetoclax-based regimens, resistance remains a major clinical challenge in acute myeloid leukemia (AML) due to compensatory BCL-XL upregulation. This study shows that dual BCL-2/BCL-XL inhibition with AZD0466 delivers robust antileukemic activity as monotherapy and in combination with AML standard agents; cytarabine and hypomethylating agents across diverse preclinical models. AZD0466 shows pronounced efficacy in relapsed or refractory AML samples previously exposed to venetoclax and hypomethylated agents (HMAs), surpassing responses with conventional therapy. Superior blast reduction and survival benefit of AZD0466-based combinations in patient-derived xenografts support its clinical evaluation for overcoming venetoclax resistance. Read more>

Pyrimethamine overcomes resistance to hypomethylating agents by reducing de novo pyrimidine synthesis

Bianca Rivera-Peña, Samarpana Chakraborty, Yang Shi,...David A. Frank, Yogen Saunthararajah, Aditi Shastri

Open Access

A Food and Drug Administration–approved antiparasitic, pyrimethamine, re-sensitizes myelodysplastic and acute myeloid leukemia models to hypomethylating agents by blocking de novo pyrimidine synthesis, drives myeloid differentiation, and shows potent synergy with venetoclax—collectively restoring normal hematopoiesis and eradicating resistant leukemic blasts in preclinical studies. Read more>

Vitamin B6 deficiency anemia resembles iron-deficiency anemia but does not activate intestinal HIF2⍺

Adonia Alexopoulos, Rushama Nahiyan, Thaarini Swaminathan, Sushmit Roddur, Nupur K. Das, Yatrik M. Shah

Open Access

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 hypoxia-inducible factor 2⍺ (HIF2⍺) activation is well established, but it is not clear if anemias such as B6DA that occur without systemic iron depletion also engage intestinal HIF2⍺ signaling. Our study shows that although degrees of IDA and B6DA are comparable, they have significant differences that offer new mechanistic insights: (1) They have separate intervals of anemia onset following dietary intervention, (2) HIF2⍺ activity remains stagnant in B6DA, and (3) intestinal HIF2⍺ activation can be used as a tool to differentiate IDAs from IDA-like anemias. Read more>

ER-diffusion barriers exist in hematopoietic stem cell mitoses, but are not required for lysosomal asymmetric cell division

Florin Schneiter, Dirk Loeffler, Timm Schroeder

Open Access

Endoplasmic reticulum diffusion barriers (ER-DBs) control the distribution of cell fate regulators during divisions, also contributing to asymmetric cell division (ACD). Here, we demonstrated that ER-DBs are also present in a subset of hematopoietic stem cell (HSC) divisions and that their strength depends on sphingolipid metabolism. Although they are not required for HSC lysosomal asymmetric cell division, these barriers are an additional mechanism orchestrating polarization and asymmetric inheritance in HSC divisions. Read more>