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HAEMATOLOGICA

Publisher:
—
ISSN:
0390-6078
Category:
HEMATOLOGY
Impact factor:
8.2
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18 parsed articles

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Latest articles

Human cytomegalovirus control in allogeneic stem cell transplant recipients in the letermovir era – emerging humoral and cellular players

2025-11-27

Chris D. Lauruschkat, Hannah Görge, Kerstin Knies, Benedikt Weißbrich, Lars Dölken, Carolin Köchel, Nina Imhof, Magdalena Huber, Hartmut Hengel, Hermann Einsele, Sebastian Wurster, Sabrina Kraus

Allogeneic hematopoietic stem cell transplant (alloSCT) recipients frequently experience late-onset human cytomegalovirus (HCMV) reactivations following termination of letermovir prophylaxis. Letermovir prophylaxis extends the window for protective B- and T-cell reconstitution; however, our understanding of humoral responses and their contribution to HCMV immune control remains limited. Combining serological and flow cytometric analyses in 42 HCMV-seropositive alloSCT recipients, we herein provide the first comprehensive longitudinal (days 90-270 after transplant) characterization of HCMV-specific humoral responses, natural killer (NK)-cell phenotypes, and γδ T cells in the letermovir era. HCMV controllers showed predominantly HCMV-specific IgG-driven responses, higher pre-reactivation Vδ1+ γδ T-cell frequencies, and stronger expansion of “memory-like” NK cells than patients with clinically significant CMV infection. In contrast, patients with clinically significant CMV infection showed delayed HCMV-specific IgG production, IgM-skewed responses, and stronger post-reactivation expansion of memory B cells and Vδ1+ γδ T cells. Early (day 90) γδ T-cell reconstitution was associated with subsequent HCMV control. HCMV-specific IgG levels correlated only weakly with γδ T cells but showed distinct associations with “memory-like” NK-cell reconstitution in HCMV controllers, suggesting synergisms between humoral and cellular immunity. Collectively, these findings highlight a need to study anti-HCMV immune protection beyond type 1 T cells and refine risk stratification models in alloSCT patients by inclusion of novel immune markers such as γδ T-cell frequencies and phenotypes. Leveraging the extended B-cell reconstitution window created by letermovir, novel immunotherapies (e.g., therapeutic antibodies) and future vaccines might boost humoral anti-HCMV immunity and benefit from synergisms with γδ T cells and “memory-like” NK cells in improving HCMV control.

Divergent processing of FVIII light chain variants: secretory potential <i>versus</i> proteasomal retention

2025-11-27

Heike Singer, Payal Chawla, Katrin J. Czogalla-Nitsche, Pujan Engels, Francesco Forin, Marc Sylvester, Melanie Rath, Jens Müller, Tobias Feist, Behnaz Pezeshkpoor, Rawya Al-Rifai, Osman El-Maarri, Johannes Oldenburg

In 20-30% of severe hemophilia A (HA) patients, FVIII replacement therapy is hindered by inhibitory antibodies. Nonsense mutations in the FVIII light chain (A3-C1-C2) carry a higher risk of inhibitor formation than those in the heavy chain (A1-A2-B). The underlying molecular mechanism remains unclear. Using induced pluripotent stem (iPS) cells from HA patients, we developed two types of endothelial cell models, induced lymphatic endothelial cells (iLEC) and induced liver sinusoidal endothelial cells (iLSEC), that mimic native F8 mRNA expression and protein synthesis. Immunoassays detected FVIII protein in wild-type, intron 22 inversions (I22I), and two high inhibitor risk light chain variants (R1960X, R2228X). Co-staining with ER markers (PDI, BiP) revealed differential processing: R1960X exhibit enhanced proteasomal degradation with SEL1L, essential for MHC-I peptide loading, possibly contributing to higher immunogenicity. In contrast, R2228X showed a pattern more similar to wild-type, suggesting partial secretory potential. Although a mild co-localization with SEL1L was observed, it was not significant. Clinically, this patient did not develop inhibitors. In addition, exploratory in silico peptide binding predictions suggested that R1960X may generate a higher number of FVIII-derived epitopes presented via patient-specific HLA alleles compared to R2228X, further supporting differential immunogenicity. The I22I variant also showed detectable FVIII protein, which was deglycosylated and retained in the ER but did not co-localize with SEL1L; no inhibitor was observed in this case either. This cellular model shows reduced variability compared to primary cells, enabling patient-specific FVIII variant analyses, including intracellular processing, within the genetic background of the individual patient.

Loss of KDEL function from a calreticulin frameshift mutation drives expression of an immature, mutant calreticulin-dependent form of the thrombopoietin receptor MPL

2025-11-06

Nami Masubuchi, Yinjie Yang, Misa Imai, Yoshihiko Kihara, Soji Morishita, Yoko Edahiro, Norio Komatsu

Mutant calreticulin (CALR) activates the thrombopoietin (TPO) receptor MPL, thereby inducing the development of essential thrombocythemia and primary myelofibrosis. Mutant CALR, due to a frameshift mutation, loses the endoplasmic reticulum (ER) retention signal, the KDEL sequence and is released extracellularly. To examine the significance of the loss of the KDEL sequence in mutant CALR-induced MPL activation, a series of constructs were prepared, including mutant CALR plus KDEL (mutant CALR KDEL ), mutant CALR plus the Venus tag and KDEL (mutant CALR Venus-KDEL ), and wild-type (WT) CALR minus KDEL (CALR WT ΔKDEL ). UT-7/TPO cells expressing mutant CALRKDEL exhibited autonomous cell growth in the absence of TPO, accompanied by the extracellular secretion of mutant CALRKDEL and subsequent activation of MPL. In contrast, UT-7/TPO cells expressing mutant CALRVenus-KDEL did not exhibit autonomous cell growth or MPL activation without TPO as well as the reduced extracellular secretion of mutant CALR Venus-KDEL . These results suggest that the loss of KDEL function in mutant CALR is closely linked to MPL activation and the extracellular secretion of mutant CALR. While UT-7/TPO cells expressing CALR WT ΔKDEL did not exhibit autonomous cell growth, they were responsive to mutant CALR proteins added exogenously, as evidenced by STAT5 activity. Furthermore, CALR WT ΔKDEL conferred mutant CALR sensitivity to MPL by recognizing the N-glycans of MPL while maintaining it in an immature form, which may bind to mutant CALR. In conclusion, deletion of the ER retention signal KDEL from CALR is a prerequisite for the expression of the immature form of MPL, which can interact with secreted mutant CALR.

Advances in biomarkers for mantle cell lymphoma in the era of targeted therapies

2025-11-06

Zoe Loh, Paul Yeh, Colm Keane, Eliza A. Hawkes

Exciting therapeutic advances are transforming the mantle cell lymphoma (MCL) treatment landscape, with an expanding array of novel agents. Growing evidence demonstrates that MCL is a biologically heterogeneous disease ineffectively managed with historical uniform standard chemoimmunotherapy approaches. Furthermore, traditional prognosticators such as the MCL-International Prognostic index (MIPI), proliferation index Ki-67, and presence of TP53 aberrations remain valuable but are insufficient to fully capture disease complexity or guide personalized therapy. Biomarker technologies are evolving rapidly. Reflecting this technological renaissance, recent studies have identified a range of novel molecular and cytogenetic alterations that carry prognostic or therapeutic relevance in the context of both chemotherapy and novel agent delivery. Advances in measurable residual disease detection using polymerase chain reaction analysis, next-generation sequencing, and circulating tumor DNA are reshaping risk stratification and offer the potential to guide therapy intensity and duration. New information is emerging regarding the critical role of the tumor microenvironment and immune dysregulation in driving treatment resistance. Additionally, the expanding utility of fluorodeoxyglucose positron emission tomography by harnessing quantitative parameters and radiomic data offers new opportunities for multimodality risk stratification. Here, we comprehensively review the literature beyond established MCL prognosticators and provide an overview of these newer prognostic and predictive biomarkers for MCL in modern treatment paradigms, and their role in informing treatment decisions and future research directions.

TGFβ-activated kinase-1 knockdown in hematopoietic stem-progenitor cells causes PANoptosis and myelodysplastic syndrome-like disease in mice

2025-10-30

Lei Zhang, Wenyan Li, Rohit Thalla, Rongyao Ma, Ryan Mack, Ameet R. Kini, Austin Runde, Patrick A. Hagen, Kevin Barton, Jorgena Kosti-Schwartz, Peter Breslin, Hong-Long Ji, Jiwang Zhang

Mutant SF3B1 (SF3B1 mut ) in hematopoietic stem/progenitor cells (HSPC) primarily affects erythropoiesis, resulting in myelodysplastic syndromes (MDS) with refractory macrocytic anemia and ring sideroblasts. SF3B1 mut results in aberrant splicing of a large number of transcripts in HSPC due to the alternative use of cryptic splice sites. Aberrant splicing of Tmem14c and Abcb7 has been shown to be the cause of the ring sideroblasts. However, the key mis-spliced gene(s) that drive macrocytic anemia have not been well-determined. Mis-splicing and downregulation of TAK1 pre-mRNA was detected in SF3B- 1 mut -HSPC. We found that TAK1 is required for the survival of HSPC by restricting RIPK1-dependent and -independent PANoptosis. PANoptosis was increased in bone marrow samples from SF3B1 mut -MDS patients. To study whether TAK1-downregulation is the cause of anemia in SF3B1 mut -MDS, we knocked down Tak1 (Tak1KD) in mouse HSPC. We found that mice transplanted with Tak1KD-HSPC developed anemia and that Ripk1 inhibition could restore blood cell counts in such anemic mice. Tak1KD-HSPC are highly sensitive to TAK1 inhibitor- or cIAP inhibitor-induced PANoptosis. Furthermore, RIPK1 inhibition could also correct differentiation and survival defects of SF3B1 mut human erythroblasts. TAK1 inhibitor could also preferentially eliminate SF3B1 mut HSPC from MDS patient samples. Our study suggests that SF3B1 mut MDS can be treated by either inhibition of RIPK1-PANoptotic signaling to restore blood cell counts or activation of PANoptosis to eliminate the mutant HSPC.

CNS infiltration by zamtocabtagene autoleucel tandem CD20/CD19 CAR T cells leading to complete remission in a patient with primary CNS lymphoma

2025-10-16

Nancy M. Hardy, Jean A. Yared, Tim Luetkens, Haroon Ahmad, Rediet Mulatu, Daniel Yamoah, Xiaoxuan Fan, Samuel Weeks, Sophia A. Bredar, Ashley Gelin, Jillian M. Baker, Kenneth A. Dietze, Aerielle Matsangos, Ariel Fromowitz, Johanna Theruvath, Louisa Wirthlin, Remigiusz Kaleta, Anna Wijatyk, Rima Koka, Michael E. Kallen, Kim G. Hankey, Aaron P. Rapoport, Djordje Atanackovic

Long-term outcomes in <i>FLT3</i>-mutated acute myeloid leukemia after frontline hypomethylating agent, venetoclax and a FLT3 inhibitor

2025-10-02

Nicholas J. Short, Sanam Loghavi, Musa Yilmaz, Omer Karrar, Kunhwa Kim, Courtney D. Dinardo, Tapan M. Kadia, Manuel Maroun, Gautam Borthakur, Ghayas C. Issa, Joseph Jabbour, Betul Oran, Elizabeth J. Shpall, Uday Popat, Keyur P. Patel, Mark Routbort, Marina Konopleva, Farhad Ravandi, Hagop Kantarjian, Naval Daver

Triplet regimens with a hypomethylating agent, venetoclax and a FLT3 inhibitor yield high rates of response in newly diagnosed FLT3-mutated acute myeloid leukemia (AML). However, the long-term outcomes and patterns of relapse with these triplet regimens are not well-established. In this retrospective analysis, 73 patients with newly diagnosed FLT3-mutated AML received a frontline FLT3 inhibitor-containing triplet regimen. The composite complete remission and complete remission with incomplete hematologic recovery rate was 93%. According to next-generation sequencing (sensitivity: 0.005%), FLT3-ITD minimal residual disease negativity was achieved in 60% of patients after cycle 2 and 90% after cycle 4. The estimated 3-year relapse-free survival for FLT3-ITD-mutated and FLT3 TKD-mutated AML was 38% and 76%, respectively, and the 3-year overall survival (OS) was 45% and 76%, respectively. Neither age, NPM1 co-mutation, European LeukemiaNet 2022 risk category, nor allogeneic stem cell transplantation in first remission significantly impacted OS. Baseline RAS pathway mutations were associated with poor long-term survival (3-year OS 22% vs. 63% in those without a RAS pathway mutation). FLT3 wild-type relapses accounted for 65% of relapses, and new RAS pathway mutations were observed in 24% of relapses. Outcomes were poor after relapse (median OS of 6.1 months), particularly for those with persistently detectable FLT3 mutations. Triplet combinations of a hypomethylating agent, venetoclax and a FLT3 inhibitor result in durable remission and encouraging long-term OS in older adults with newly diagnosed FLT3-mutated AML. However, better strategies to prevent FLT3 wild-type relapses and to overcome RAS pathway-mediated resistance are still needed.

SLC25A1 reprograms mitochondrial and fatty acid metabolism to promote the progression of acute myeloid leukemia

2025-09-04

Miao Chen, Wenze Li, Yuan Tao, Chenglong Hu, Rui Ge, Sijing Kang, Pengjie Yue, Cheuk Him Man, Lan Wang, Xiaojing Yan

Abnormal metabolic reprogramming is a hallmark of acute myeloid leukemia (AML), contributing to leukemia initiation, progression and drug resistance. The key mitochondrial citrate transporter SLC25A1 plays an essential role in regulating cellular energy metabolism and plays an important role in the regulation of lipid metabolism. However, the role of SLC25A1 in the pathogenesis and aberrant lipid metabolism in AML remain unexplored. In this study, our analysis of public datasets and patient samples revealed that SLC25A1 expression was markedly elevated in AML and was associated with poor prognosis. Knockdown or pharmacological inhibition of SLC25A1 significantly suppressed AML cell proliferation by inducing apoptosis, without affecting cell cycle progression or differentiation. Moreover, SLC25A1 proved vital for AML tumorigenesis in vivo. Mechanistically, we demonstrated that SLC25A1 inhibition disrupted citrate homeostasis, leading to mitochondrial dysfunction and reduced fatty acid metabolism. Notably, we developed a novel SLC25A1 inhibitor, CTPI3, which effectively inhibits the progression of AML in vivo, and synergizes with venetoclax to kill AML cells by mitochondrial and fatty acid metabolism regulation. In summary, our findings highlight that SLC25A1 plays a vital role in maintaining AML cell survival and regulating its drug sensitivity. Furthermore we developed a more effective novel drug targeting SLC25A1, providing additional therapeutic options for venetoclax-resistant patients and highlighting SLC25A1 as a promising biomarker and therapeutic target for AML.