bims-tremyl 2024-11-24 papers

on Therapy resistance biology in myeloid leukemia

Issue of 2024–11–24
forty-four papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Ven-Aza outcomes in AML by genetic risk.
Outcomes of patients with acute myeloid leukemia and bone marrow fibrosis.
The role of allogeneic stem cell transplantation in acute myeloid leukemia with translocation t(8;16)(p11;p13).
Clonal hematopoiesis in large granular lymphocytic leukemia.
DNMT3AR882H Is Not Required for Disease Maintenance in Primary Human AML, but Is Associated With Increased Leukemia Stem Cell Frequency.
T-cell immune cluster analysis using CyTOF identifies unique subgroups of patients with acute myeloid leukemia.
The co-receptor Neuropilin-1 enhances proliferation in inv(16) acute myeloid leukemia via VEGF signaling.
A phase II trial of ipilimumab, nivolumab, or ipilimumab and nivolumab with or without azacitidine in relapsed or refractory myelodysplastic neoplasms.
Dynamics of measurable residual disease for risk stratification and guiding allogeneic transplant in acute myeloid leukaemia patients with myelodysplasia-related mutations in first remission.
Mitochondrial heteroplasmy improves risk prediction for myeloid neoplasms.
Preclinical efficacy of CDK7 inhibitor-based combinations against myeloproliferative neoplasms transformed to AML.
Acute Leukemias of Ambiguous Lineage With MDS-Associated Mutations Show Similar Prognosis Compared to Acute Myeloid Leukemia With MDS-Associated Mutations: A Study From the Bone Marrow Pathology Group.
Acute myeloid leukemia drug tolerant persister cells survive chemotherapy by transiently increasing plasma membrane rigidity, that also increases their sensitivity to immune cell killing.
Human Plasma Proteomic Profile of Clonal Hematopoiesis.
A single-chain variable fragment-based bispecific T-cell activating antibody against CD117 enables T-cell mediated lysis of acute myeloid leukemia and hematopoietic stem and progenitor cells.
Venetoclax-Based Combination Regimens in Acute Myeloid Leukemia.
DNA methylation stochasticity is linked to transcriptional variability and identifies convergent epigenetic disruption across genetically-defined subtypes of AML.
What have we learned about TP53-mutated acute myeloid leukemia?
Treatment Intensification With Either Fludarabine, AraC, G-CSF and Idarubicin, or Cladribine Plus Daunorubicin and AraC on the Basis of Residual Disease Status in Older Patients With AML: Results From the NCRI AML18 Trial.
Somatic co-alteration signatures are prognostic in high-grade TP53-mutated myeloid neoplasms.
Methylation sequencing enhances interpretation of clonal hematopoiesis dynamics.
Role of molecular alterations in transplantation decisions for patients with primary myelofibrosis.
CD70 CAR T cells secreting an anti-CD33/anti-CD3 dual targeting antibody overcome antigen heterogeneity in AML.
Polycomb group protein Mel18 inhibits hematopoietic stem cell self-renewal through repressing the transcription of self-renewal and proliferation genes.
Itacitinib for Prevention of Graft-Versus-Host Disease and Cytokine Release Syndrome in Haploidentical Transplantation.
Proteogenomic profiling of acute myeloid leukemia to identify therapeutic targets.
Targeting heterochromatin eliminates chronic myelomonocytic leukemia malignant stem cells through reactivation of retroelements and immune pathways.
The glycosyltransferase ST3GAL4 drives immune evasion in acute myeloid leukemia by synthesizing ligands for the glyco-immune checkpoint receptor Siglec-9.
G-CSF resistance of ELANE mutant neutropenia depends on SERF1 containing truncated neutrophil elastase aggregates.
Real-world experience of paediatric acute promyelocytic leukaemia in the United Kingdom and Ireland.
Glucose uptake capacity of leukaemia cells in vitro correlates with response to induction therapy in acute myeloid leukaemia.
Discovery of IRAK1/4/pan-FLT3 Kinase Inhibitors as Treatments for Acute Myeloid Leukemia.
Cost-effectiveness of Enasidenib versus conventional care for older patients with IDH2-mutant refractory/relapsed AML.
Olverembatinib After Failure of Tyrosine Kinase Inhibitors, Including Ponatinib or Asciminib: A Phase 1b Randomized Clinical Trial.
Chronic Inflammation Deters Natural Killer Cell Fitness and Cytotoxicity in Myeloid Leukemia.
Arginine methylation of the p30 C/EBPα oncoprotein regulates progenitor proliferation and myeloid differentiation.
The Aza/Ven reshuffle.
Diagnosis and Treatment of Polycythemia Vera: A Review.
Impaired branched chain amino acid (BCAA) catabolism during adipocyte differentiation decreases glycolytic flux.
FLT3 ligand kinetic profile predicts response to treatment in patients with high-risk myelodysplastic syndrome / chronic myelomonocytic leukemia receiving CPX-351: a study from the Groupe Francophone des Myélodysplasies.
Clinical and Immune Effects of Peri-Transplantation JAK Inhibition for Myelofibrosis.
Human HDAC6 senses valine abundancy to regulate DNA damage.
CHIP away at the marrow-clot connection: inflammation, clonal hematopoiesis, and thromboembolic disease.
Prognostic significance of mutation type and chromosome fragility in Fanconi anemia.

Blood. 2024 Nov 21. 144(21): 2271

Ven-Aza outcomes in AML by genetic risk.

DOI: https://doi.org/10.1182/blood.2024027149
J Hematol Oncol. 2024 Nov 15. 17(1): 112

Outcomes of patients with acute myeloid leukemia and bone marrow fibrosis.

Samuel Urrutia, Hagop M Kantarjian, Farhad Ravandi-Kashani, Carlos Bueso-Ramos, Rashmi Kanagal-Shamanna, Elias Jabbour, Guillermo Montalban-Bravo, Nicholas J Short, Naval Daver, Gautam Borthakur, Courtney D Dinardo, Tapan M Kadia, Lucia Masarova, Prithviraj Bose, Naveen Pemmaraju, Guillermo Garcia-Manero, Koji Sasaki.

  The outcomes of patients with acute myeloid leukemia (AML) and bone marrow fibrosis (MF) are not well defined. The study objectives were to evaluate the degrees of MF in AML, and corresponding response rates and outcomes. We performed a retrospective review of 2302 patients with AML. We annotated the clinical and molecular characteristics, response to therapy, and survival outcomes of patients with bone marrow fibrosis. Overall, 492 patients (21.4%) had a reported microscopic evaluation of MF: 344 (69.9%) had MF grade 0-1 and 148 (30.1%) had MF grade 2-3. Patients with MF 2-3 had a higher proportion of complex cytogenetics (39.2% vs. 24.7%, p = 0.002) JAK2 mutations (25.7% vs. 18%, p = 0.07) and lower proportion of IDH2 (16.9% vs. 25.9%, p = 0.03) and CEBPA (15.5% vs. 27.6%, p = 0.006) mutations. 64% were treated with low-intensity chemotherapy (LIT) and 36.1% with intensive chemotherapy (IT). The complete remission (CR)/CR with incomplete count recovery (CRi) rates were 63.5% with IC versus 37.9% with LIT (p = 0.007). In patients aged 60 or older 4-week mortality was 12.5% with IC vs. 9.3% with LIT (p = 0.8). The median overall survival (OS) was 14.2 with MF 0-1 versus 7.5 months with MF 2-3 (p < 0.005). In patients aged 60 or older with MF 2-3 median OS was 6.5 months with IT versus 7.0 months with LIT (p = 0.19). In a multivariate analysis, grade 2-3 MF (HR 2.0, 95%CI 1.59-2.51) was the strongest prognostic factor for survival. In summary, grade 2-3 MF in AML is associated with worse outcomes.

Keywords:  Acute myeloid leukemia; Bone marrow fibrosis; Prognostication

DOI:  https://doi.org/10.1186/s13045-024-01630-w
Am J Hematol. 2024 Nov 18.

The role of allogeneic stem cell transplantation in acute myeloid leukemia with translocation t(8;16)(p11;p13).

Ann-Kristin Schmälter, Myriam Labopin, Jurjen Versluis, Maria Pilar Gallego Hernanz, Matthias Eder, Peter von dem Borne, Gerard Socié, Patrice Chevallier, Edouard Forcade, Andreas Neubauer, Frédéric Baron, Ali Bazarbachi, Gesine Bug, Arnon Nagler, Christoph Schmid, Jordi Esteve, Mohamad Mohty, Fabio Ciceri.

Acute myeloid leukemia (AML) with translocation t(8;16)(p11;p13) represents a rare entity that has been categorized as a disease-defining recurring cytogenetic abnormality with adverse risk in the 2022 European LeukemiaNet classification. This rating was mainly based on a retrospective analysis comprising patients from several large clinical trials, which, however, included only 21 patients treated with allogeneic stem cell transplantation (alloSCT). Therefore, the European Society for Blood and Marrow Transplantation performed a registry study on a larger cohort to evaluate the role of alloSCT in t(8;16) AML. Sixty transplant recipients with t(8;16) AML were identified. Two-year overall and leukemia-free survival (OS/LFS) was 43/39%. Patients transplanted in first complete remission (CR1, n = 44) achieved a 2-year OS/LFS of 48%/48%. Following alloSCT in CR1, the multivariable analysis identified a complex karyotype (CK) as a major risk factor for relapse (HR 4.17, p = .016), lower LFS (HR 3.38, p = .01), and lower OS (HR 3.08, p = .017). Two-year OS/LFS of patients with CK was 19%/19%, in contrast to 67%/67% in patients with t(8;16) outside a CK. Other factors for inferior outcomes were older age and secondary AML. In summary, alloSCT could mitigate the adverse risk of patients with t(8;16) AML not harboring a CK, particularly when performed in CR1.

DOI: https://doi.org/10.1002/ajh.27496
Leukemia. 2024 Nov 21.

Clonal hematopoiesis in large granular lymphocytic leukemia.

Naomi Kawashima, Carmelo Gurnari, Carlos Bravo-Perez, Yasuo Kubota, Simona Pagliuca, Luca Guarnera, Nakisha D Williams, Arda Durmaz, Arooj Ahmed, Danai Dima, Fauzia Ullah, Hetty E Carraway, Abhay Singh, Valeria Visconte, Jaroslaw P Maciejewski.

Past studies described occasional patients with myeloid neoplasms (MN) and coexistent large granular lymphocytic leukemia (LGLL) or T-cell clonopathy of unknown significance (TCUS), which may represent expansion of myeloid clonal hematopoiesis (CH) as triggers or targets of clonal cytotoxic T cell reactions. We retrospectively analyzed 349 LGLL/TCUS patients, 672 MN patients, and 1443 CH individuals to establish the incidence, genetic landscape, and clinical phenotypes of CH in LGLL. We identified 8% of cases overlapping with MN, while CH was found in an additional 19% of cases (CH + /LGLL) of which TET2 (23%) and DNMT3A (14%) were the most common. In MN cohort, 3% of cases showed coexistent LGLL. The incidence of CH in LGLL was exceedingly higher than age-matched CH controls (P < 0.0001). By multivariate analysis, the presence of CH in LGLL (P = 0.026) was an independent risk factor for cytopenia in addition to older age (P = 0.003), splenomegaly (P = 0.015) and STAT3/5B mutations (P = 0.001). CH + /LGLL cases also showed a higher progression rate to MN than CH-/LGLL (10% vs. 2% at 5 years; P = 0.02). A close relationship between CH and LGLL suggests that cytopenia in LGLL may be not only related to LGLL but be also secondary to coexisting clonal cytopenia of unclear significance.

DOI: https://doi.org/10.1038/s41375-024-02460-y
bioRxiv. 2024 Oct 29. pii: 2024.10.26.620318. [Epub ahead of print]

DNMT3AR882H Is Not Required for Disease Maintenance in Primary Human AML, but Is Associated With Increased Leukemia Stem Cell Frequency.

Thomas Koehnke, Daiki Karigane, Eleanor Hilgart, Amy C Fan, Kensuke Kayamori, Masashi Miyauchi, Cailin T Collins, Fabian P Suchy, Athreya Rangavajhula, Yang Feng, Yusuke Nakauchi, Eduardo Martinez-Montes, Jonas Fowler, Kyle M Loh, Hiromitsu Nakauchi, Michael A Koldobskiy, Andrew P Feinberg, Ravindra Majeti.

Genetic mutations are being thoroughly mapped in human cancers, yet a fundamental question in cancer biology is whether such mutations are functionally required for cancer initiation, maintenance of established cancer, or both. Here, we study this question in the context of human acute myeloid leukemia (AML), where DNMT3AR882 missense mutations often arise early, in pre-leukemic clonal hematopoiesis, and corrupt the DNA methylation landscape to initiate leukemia. We developed CRISPR-based methods to directly correct DNMT3AR882 mutations in leukemic cells obtained from patients. Surprisingly, DNMT3AR882 mutations were largely dispensable for disease maintenance. Replacing DNMT3AR882 mutants with wild-type DNMT3A did not impair the ability of AML cells to engraft in vivo, and minimally altered DNA methylation. Taken together, DNMT3AR882 mutations are initially necessary for AML initiation, but are largely dispensable for disease maintenance. The notion that initiating oncogenes differ from those that maintain cancer has important implications for cancer evolution and therapy.

DOI: https://doi.org/10.1101/2024.10.26.620318
Blood Adv. 2024 Nov 21. pii: bloodadvances.2024014553. [Epub ahead of print]

T-cell immune cluster analysis using CyTOF identifies unique subgroups of patients with acute myeloid leukemia.

Talha Badar, Keith Knutson, James M Foran, Naseema Gangat, Kevin D Pavelko, Scott H Kaufmann, Mark R Litzow, Hemant S Murthy, Davitte Cogen, Margaret Ushman, Arini Arsana, Aref Al-Kali, Hassan B Alkhateeb, Ayalew Tefferi, Mrinal M Patnaik, Mithun Vinod Shah.

DOI: https://doi.org/10.1182/bloodadvances.2024014553
Leukemia. 2024 Nov 21.

The co-receptor Neuropilin-1 enhances proliferation in inv(16) acute myeloid leukemia via VEGF signaling.

Mahesh Hegde, Mohd H Ahmad, Roger Mulet Lazaro, Mayumi Sugita, Rui Li, Kai Hu, Claudia Gebhard, Monica L Guzman, John H Bushweller, Lihua J Zhu, Michael Brehm, Scot A Wolfe, Ruud Delwel, Lucio H Castilla.

Oncogenic programs regulate the proliferation and maintenance of cancer stem cells, and can define pharmacologic dependencies. In acute myeloid leukemia (AML) with the chromosome inversion 16 (inv(16)), the fusion oncoprotein CBFβ::MYH11 regulates pathways associated with leukemia stem cell activity. Here we demonstrate that expression of Neuropilin-1 (NRP1) is regulated by the fusion oncoprotein, and promotes AML expansion. Mechanistically, we show that the NRP1 locus has open chromatin in inv(16) AML, and that CBFβ::MYH11 modulates the local function of the transcription factors ERG, GATA2 and RUNX1 to sustain NRP1 levels. We found that ERG activates NRP1 expression, and that CBFβ::MYH11 knockdown represses ERG expression, thereby allowing the repressive activity of GATA2/RUNX1 at three NRP1 enhancers. Functionally, we demonstrate that NRP1 enhances the expansion of leukemic cells in vitro and in mice, and that this activity is dependent on its VEGFR-associated FV/FVIII domain. Finally, we show that treatment with VEGF inhibitor axitinib reduces AML cell growth and delays median leukemia latency in vivo. Our findings reveal that the NRP1/VEGF axis mediates proliferation in inv(16) AML blasts, and suggest that targeting NRP1 function could be promising in combination AML therapy.

DOI: https://doi.org/10.1038/s41375-024-02471-9
Leukemia. 2024 Nov 17.

A phase II trial of ipilimumab, nivolumab, or ipilimumab and nivolumab with or without azacitidine in relapsed or refractory myelodysplastic neoplasms.

Ian M Bouligny, Guillermo Montalban-Bravo, Koji Sasaki, Naval Daver, Elias Jabbour, Yesid Alvarado, Courtney D DiNardo, Farhad Ravandi, Gautam Borthakur, Naveen Pemmaraju, Tapan Kadia, Lucia Masarova, Koichi Takahashi, Michael Andreeff, Alexandre Bazinet, Hui Yang, Rashmi Kanagal, Sherry Pierce, Meghan Meyer, Xuelin Huang, Guillermo Garcia-Manero.

DOI: https://doi.org/10.1038/s41375-024-02457-7
Br J Haematol. 2024 Nov 22.

Dynamics of measurable residual disease for risk stratification and guiding allogeneic transplant in acute myeloid leukaemia patients with myelodysplasia-related mutations in first remission.

Ling Jiang, Jiaying Cheng, Junya Sun, Yujiao Zhang, Quan Wu, Yun Huang, Zhiquan Long, Ping Yan, Xuejie Jiang.

  Accurate classification and risk prediction are critical for therapeutic decision-making in patients with acute myeloid leukaemia (AML). Myelodysplasia-related (MR) gene mutations are classified as adverse genetic factors by the European LeukaemiaNet-2022 guidelines. However, their prognostic value in de novo AML remains controversial. This study retrospectively analysed 188 patients with de novo AML-MR, stratifying them into four subgroups based on dynamic measurable residual disease (MRD) after induction, one or two courses of consolidation chemotherapy. The median follow-up was 36.8 months (4.6-73.7). Patients with persistent or recurrent MRD positivity after the second consolidation had the poorest 3-year relapse-free survival (RFS), overall survival (OS) and cumulative incidence of relapse compared to the other groups (p < 0.001). Multivariable analysis identified this high-risk group as an independent risk factor for both RFS and OS. We observed significant heterogeneity of OS benefit from allogeneic stem cell transplantation (allo-SCT) by MRD-risk groups, with substantial OS advantage for patients in subgroup D (3-year OS: allo-SCT 70.0% vs. 18.2% without, p < 0.001) but no benefit for others (p = 0.047 for interaction). This study underscores the importance of dynamic MRD in refining risk stratification and identifying de novo AML patients with MR mutations who would benefit from allo-SCT during the first complete remission.

Keywords:  acute myeloid leukaemia; measurable residual disease; myelodysplasia‐related mutations; risk stratification; stem cell transplantation

DOI:  https://doi.org/10.1111/bjh.19917
Nat Commun. 2024 Nov 22. 15(1): 10133

Mitochondrial heteroplasmy improves risk prediction for myeloid neoplasms.

Yun Soo Hong, Sergiu Pasca, Wen Shi, Daniela Puiu, Nicole J Lake, Monkol Lek, Meng Ru, Megan L Grove, Anna Prizment, Corinne E Joshu, Elizabeth A Platz, Eliseo Guallar, Dan E Arking, Lukasz P Gondek.

Clonal hematopoiesis of indeterminate potential is the primary pathogenic risk factor for myeloid neoplasms, while heteroplasmy (mutations in a subset of cellular mitochondrial DNA) is another marker of clonal expansion associated with hematological malignancies. We explore how these two markers relate and influence myeloid neoplasms incidence, and their role in risk stratification. We find that heteroplasmy is more common in individuals with clonal hematopoiesis of indeterminate potential, particularly those with higher variant allele fractions, multiple mutations, or spliceosome machinery mutations. Individuals with both markers have a higher risk of myeloid neoplasms than those with either alone. Furthermore, heteroplasmic variants with higher predicted deleteriousness increase the risk of myeloid neoplasms. Incorporating heteroplasmy in an existing risk score model for individuals with clonal hematopoiesis of indeterminate potential significantly improves sensitivity and better identifies high-risk groups. This suggests heteroplasmy as a clonal expansion marker and potentially as a biomarker for myeloid neoplasms development.

DOI: https://doi.org/10.1038/s41467-024-54443-3
Blood. 2024 Nov 19. pii: blood.2024026388. [Epub ahead of print]

Preclinical efficacy of CDK7 inhibitor-based combinations against myeloproliferative neoplasms transformed to AML.

Warren Fiskus, Christopher P Mill, Prithviraj Bose, Lucia Masarova, Naveen Pemmaraju, Andrew Dunbar, Christine Birdwell, John A Davis, Kaberi Das, Hanxi Hou, Taghi Manshouri, Antrix Jain, Anna Malovannaya, Kevin Philip, Noor Alhamadani, Alicia Matthews, Katie Lin, Lauren Flores, Sanam Loghavi, Courtney D DiNardo, Xiaoping Su, Raajit K Rampal, Kapil N Bhalla.

Rising blast-percentage or secondary (s) AML transformation (sAML) in MPNs leads to JAK inhibitor (JAKi) therapy-resistance and poor survival. Here, we demonstrate that the CDK7 inhibitor (CDK7i) SY-5609 treatment depletes phenotypically-characterized post-MPN-sAML stem/progenitor cells. In the cultured post-MPN sAML SET2 and HEL as well as patient-derived (PD) post-MPN-sAML cells, SY-5609 treatment inhibited growth and induced lethality, while sparing normal cells. RNA-Seq analysis following SY-5609 treatment demonstrated reduced mRNA expressions of MYC, MYB, CDK4/6, PIM1, and CCND1, but increased mRNA levels of CDKN1A and BCL2L1. Mass spectrometry of SY-5609-treated MPN-sAML cells also demonstrated reduced c-Myc, c-Myb, PIM1, and CDK4/6 but increased p21, caspase 9 and BAD protein levels. CRISPR-mediated CDK7 depletion also reduced viability of HEL cells. CyTOF analysis of SY-5609-treated PD, post-MPN-sAML stem/progenitor cells showed reduced c-Myc, CDK6 and PU.1, but increased protein levels of CD11b, p21 and cleaved Caspase 3. Co-treatment with SY-5609 and ruxolitinib was synergistically lethal in HEL, SET2 and PD post-MPN-sAML cells.  A CRISPR screen in SET2 and HEL cells revealed BRD4, CBP and p300 as co-dependencies with SY-5609 treatment. Accordingly, co-treatment with SY-5609 and the BETi OTX015 or pelabresib or with the CBP/p300 inhibitor GNE-049 was synergistically lethal in MPN-sAML cells (including those exhibiting TP53 loss). Finally, in the HEL-Luc/GFP xenograft model, compared to each agent alone, co-treatment with SY-5609 and OTX015 reduced post-MPN-sAML burden and improved survival without inducing host toxicity. These findings demonstrate promising preclinical activity of the CDK7i-based combinations with BETi or HATi against advanced-MPNs, including post-MPN-sAML.

DOI: https://doi.org/10.1182/blood.2024026388
Am J Hematol. 2024 Nov 23.

Acute Leukemias of Ambiguous Lineage With MDS-Associated Mutations Show Similar Prognosis Compared to Acute Myeloid Leukemia With MDS-Associated Mutations: A Study From the Bone Marrow Pathology Group.

Timothy J Kirtek, Weina Chen, Jaryse C Harris, Adam Bagg, Kathryn Foucar, Wayne Tam, Attilio Orazi, Eric D Hsi, Robert P Hasserjian, Sa A Wang, David P Ng, Tracy I George, Min Shi, Kaaren K Reichard, Emily Symes, Xinmin Zhang, Daniel A Arber, Olga K Weinberg.



Keywords:  AML; leukemia; molecular genetics; myelodysplastic syndrome; outcomes research

DOI:  https://doi.org/10.1002/ajh.27537
Haematologica. 2024 Nov 21.

Acute myeloid leukemia drug tolerant persister cells survive chemotherapy by transiently increasing plasma membrane rigidity, that also increases their sensitivity to immune cell killing.

Yael Morgenstern, JongBok Lee, Yoosu Na, Brandon Y Lieng, Nicholas S Ly, William D Gwynne, Rose Hurren, Li Ma, Dakai Ling, Marcela Gronda, Andrea Arruda, Avraham Frisch, Tsila Zuckerman, Yishai Ofran, Mark D Minden, Li Zhang, Catherine O'Brien, Andrew T Quaile, J Rafael Montenegro-Burke, Aaron D Schimmer.

Resistance to chemotherapy remains a major hurdle to the cure of Acute Myeloid Leukemia (AML) patients. Recent studies indicate a minority of malignant cells, termed drug-tolerant persisters (DTPs), stochastically upregulate stress pathways to evade cell death upon acute exposure to chemotherapy without acquiring new genetic mutations. This chemoresistant state is transient and the cells return to baseline after removal of chemotherapy. Yet, the mechanisms employed by DTPs to resist chemotherapy are not well understood and it is largely unknown whether these mechanisms are also seen in patients receiving chemotherapy. Here, we used leukemia cell lines, primary AML patient samples and samples from patients with AML receiving systemic chemotherapy to study the DTP state. We demonstrated that a subset of AML cells transiently increases membrane rigidity to resist killing due to acute exposure to Daunorubicin and Ara-C. Upon removal of the chemotherapy, membrane rigidity returned to baseline and the cells regained chemosensitivity. Although resistant to chemotherapy, the increased membrane rigidity, rendered AML cells more susceptible to T-cell mediated killing. Thus, we identified a novel mechanism by which DTP leukemic cells evade chemotherapy and a strategy to eradicate these persistent cells.

DOI: https://doi.org/10.3324/haematol.2024.286018
bioRxiv. 2024 Oct 31. pii: 2023.07.25.550557. [Epub ahead of print]

Human Plasma Proteomic Profile of Clonal Hematopoiesis.

NHLBI Trans-Omics for Precision Medicine

Plasma proteomic profiles associated with subclinical somatic mutations in blood cells may offer novel insights into downstream clinical consequences. Here, we explore such patterns in clonal hematopoiesis of indeterminate potential (CHIP), which is linked to several cancer and non-cancer outcomes, including coronary artery disease (CAD). Among 61,833 ancestrally diverse participants (3,881 with CHIP) from NHLBI TOPMed and UK Biobank with blood-based DNA sequencing and proteomic measurements (1,148 proteins by SomaScan in TOPMed and 2,917 proteins by Olink in UK Biobank), we identified 32 and 345 unique proteins from TOPMed and UK Biobank, respectively, associated with the most prevalent driver genes (DNMT3A, TET2, and ASXL1). These associations showed substantial heterogeneity by driver genes, sex, and race, and were enriched for immune response and inflammation pathways. Mendelian randomization in humans, coupled with ELISA in hematopoietic Tet2-/- vs wild-type mice validation, disentangled causal proteomic perturbations from TET2 CHIP. Lastly, we identified plasma proteins shared between CHIP and CAD.

DOI: https://doi.org/10.1101/2023.07.25.550557
Hemasphere. 2024 Nov;8(11): e70055

A single-chain variable fragment-based bispecific T-cell activating antibody against CD117 enables T-cell mediated lysis of acute myeloid leukemia and hematopoietic stem and progenitor cells.

Laura Volta, Renier Myburgh, Mara Hofstetter, Christian Koch, Jonathan D Kiefer, Celeste Gobbi, Francesco Manfredi, Kathrin Zimmermann, Philipp Kaufmann, Serena Fazio, Christian Pellegrino, Norman F Russkamp, Danielle Villars, Mattia Matasci, Monique Maurer, Jan Mueller, Florin Schneiter, Paul Büschl, Niclas Harrer, Jacqueline Mock, Stefan Balabanov, César Nombela-Arrieta, Timm Schroeder, Dario Neri, Markus G Manz.

Acute myeloid leukemia (AML) derives from hematopoietic stem and progenitor cells (HSPCs). To date, no AML-exclusive, non-HSPC-expressed cell-surface target molecules for AML selective immunotherapy have been identified. Therefore, to still apply surface-directed immunotherapy in this disease setting, time-limited combined immune-targeting of AML cells and healthy HSPCs, followed by hematopoietic stem cell transplantation (HSCT), might be a viable therapeutic approach. To explore this, we generated a recombinant single-chain variable fragment-based bispecific T-cell engaging and activating antibody directed against CD3 on T-cells and CD117, the surface receptor for stem cell factor, expressed by both AML cells and healthy HSPCs. Bispecific CD117xCD3 targeting induced lysis of CD117-positive healthy human HSPCs, AML cell lines and patient-derived AML blasts in the presence of T-cells at subnanomolar concentrations in vitro. Furthermore, in immunocompromised mice, engrafted with human CD117-expressing leukemia cells and human T-cells, the bispecific molecule efficiently prevented leukemia growth in vivo. Additionally, in immunodeficient mice transplanted with healthy human HSPCs, the molecule decreased the number of CD117-positive cells in vivo. Therefore, bispecific CD117xCD3 targeting might be developed clinically in order to reduce CD117-expressing leukemia cells and HSPCs prior to HSCT.

DOI: https://doi.org/10.1002/hem3.70055
Blood Cancer Discov. 2024 Nov 20. OF1-OF15

Venetoclax-Based Combination Regimens in Acute Myeloid Leukemia.

Hannah Goulart, Hagop Kantarjian, Naveen Pemmaraju, Naval Daver, Courtney D DiNardo, Caitlin R Rausch, Farhad Ravandi, Tapan M Kadia.

SIGNIFICANCE: In recent years, there has been tremendous interest surrounding the integration of venetoclax into both non-intensive and intensive chemotherapy regimens for AML. However, with this increasing utilization of venetoclax, considerable questions surrounding key issues such as dosing strategies and the practicality of venetoclax administration have arisen. This review highlights the evolution of venetoclax-based regimens in AML and provides a commentary on notable practical considerations when utilizing this agent.

DOI: https://doi.org/10.1158/2643-3230.BCD-24-0171
bioRxiv. 2024 Oct 29. pii: 2024.10.26.620422. [Epub ahead of print]

DNA methylation stochasticity is linked to transcriptional variability and identifies convergent epigenetic disruption across genetically-defined subtypes of AML.

Eleanor Hilgart, Weiqiang Zhou, Eduardo Martinez-Montes, Adrian Idrizi, Rakel Tryggvadottir, Lukasz P Gondek, Ravindra Majeti, Hongkai Ji, Michael A Koldobskiy, Andrew P Feinberg.

Disruption of the epigenetic landscape is of particular interest in acute myeloid leukemia (AML) due to its relatively low mutational burden and frequent occurrence of mutations in epigenetic regulators. Here, we applied an information-theoretic analysis of methylation potential energy landscapes, capturing changes in mean methylation level and methylation entropy, to comprehensively analyze DNA methylation stochasticity in subtypes of AML defined by mutually exclusive genetic mutations. We identified AML subtypes with CEBPA double mutation and those with IDH mutations as distinctly high-entropy subtypes, marked by methylation disruption over a convergent set of genes. We found a core program of epigenetic landscape disruption across all AML subtypes, with discordant methylation stochasticity and transcriptional dysregulation converging on functionally important leukemic signatures, suggesting a genotype-independent role of stochastic disruption of the epigenetic landscape in mediating leukemogenesis. We further established a relationship between methylation entropy and gene expression variability, connecting the disruption of the epigenetic landscape to transcription in AML. This approach identified a convergent program of epigenetic dysregulation in leukemia, clarifying the contribution of specific genetic mutations to stochastic disruption of the epigenetic and transcriptional landscapes of AML.

DOI: https://doi.org/10.1101/2024.10.26.620422
Blood Cancer J. 2024 Nov 19. 14(1): 202

What have we learned about TP53-mutated acute myeloid leukemia?

Moazzam Shahzad, Muhammad Kashif Amin, Naval G Daver, Mithun Vinod Shah, Devendra Hiwase, Daniel A Arber, Mohamed A Kharfan-Dabaja, Talha Badar.

TP53 is a tumor suppressor gene frequently mutated in human cancers and is generally associated with poor outcomes. TP53 mutations are found in approximately 5% to 10% of patients with de novo acute myeloid leukemia (AML), more frequently observed in elderly patients and those with therapy-related AML. Despite recent advances in molecular profiling and the emergence of targeted therapies, TP53-mutated AML remains a challenge to treat. Current treatment strategies, including conventional chemotherapy, hypomethylating agents, and venetoclax-based therapies, have shown limited efficacy in TP53-mutated AML, with low response rates and poor overall survival. Allogeneic hematopoietic stem cell transplantation is a potentially curative option; however, its efficacy in TP53-mutated AML depends on comorbid conditions and disease status at transplantation. Novel therapeutic modalities, including immune-based therapies, did show promise in early-phase studies but did not translate into effective therapies in randomized controlled trials. This review provides a comprehensive overview of TP53 mutations in AML, outcomes based on allelic burden, clinical implications, and therapeutic challenges.

DOI: https://doi.org/10.1038/s41408-024-01186-5
J Clin Oncol. 2024 Nov 18. JCO2400259

Treatment Intensification With Either Fludarabine, AraC, G-CSF and Idarubicin, or Cladribine Plus Daunorubicin and AraC on the Basis of Residual Disease Status in Older Patients With AML: Results From the NCRI AML18 Trial.

Nigel H Russell, Abin Thomas, Robert K Hills, Ian Thomas, Amanda Gilkes, Nuria Marquez Almuina, Sarah Burns, Lucy Marsh, Paresh Vyas, Marlen Metzner, Nicholas McCarthy, Georgia Andrew, Jennifer Byrne, Rob S Sellar, Richard Kelly, Paul Cahalin, Ulrik Malthe Overgaard, Priyanka Mehta, Mike Dennis, Steven Knapper, Sylvie D Freeman.

PURPOSE: To evaluate the survival benefit of chemotherapy intensification in older patients with AML who have not achieved a measurable residual disease (MRD)-negative remission.
METHODS: Five hundred twenty-three patients with AML (median age, 67 years; range, 51-79) without a flow cytometric MRD-negative remission response after a first course of daunorubicin and AraC (DA; including 165 not in remission) were randomly assigned between up to two further courses of DA or intensified chemotherapy-either fludarabine, cytarabine, granulocyte colony-stimulating factor and idarubicin (FLAG-Ida) or DA with cladribine (DAC).
RESULTS: Overall survival (OS) was not improved in the intensification arms (DAC v DA: hazard ratio [HR], 0.74 [95% CI, 0.55 to 1.01]; P = .054; FLAG-Ida v DA: HR, 0.86 [95% CI, 0.66 to 1.12]; P = .270); OS at 3 years was 34%, 46%, and 42% for DA, DAC, and FLAG-Ida, respectively. Early deaths and other adverse events were more frequent with FLAG-Ida (9% day 60 deaths v 4% after DA or DAC; P = .032). Of patients entering random assignment, 131 had MRD unknown status. In this subgroup of patients lacking evidence of residual leukemia by flow cytometry, there was no detectable survival advantage from intensification. A planned sensitivity analysis excluding these patients demonstrated a survival benefit for both DAC (HR, 0.66 [95% CI, 0.46 to 0.93]; P = .018) and FLAG-Ida (HR, 0.72 [95% CI, 0.53 to 0.98]; P = .035); OS at 3 years was 30%, 46%, and 46% for DA, DAC, and FLAG-Ida, respectively. There was a concordant reduction in relapse (DAC v DA: HR, 0.66 [95% CI, 0.45 to 0.98]; P = .039; FLAG-Ida v DA: HR, 0.70 [95% CI, 0.49 to 0.99]; P = .042). DAC benefit was maintained when survival was censored for transplant (P = .042).
CONCLUSION: In this study of older patients with AML considered fit and with evidence of residual disease after first induction, chemotherapy intensification improved survival. DAC intensification was better tolerated than FLAG-Ida.

DOI: https://doi.org/10.1200/JCO.24.00259
Br J Haematol. 2024 Nov 17.

Somatic co-alteration signatures are prognostic in high-grade TP53-mutated myeloid neoplasms.

Emily O Symes, Peng Wang, Payal Sojitra, Madhu P Menon, Anand A Patel, Faheema Hasan, Sharmila Ghosh, Gregory W Roloff, Qianghua Zhou, Anthony Findley, Talha Badar, Jingjing Zhang, Hamza Tariq, Hong Chang, Robert C Bell, Anamarija M Perry, Girish Venkataraman.

  To assess the relevance of co-occurring somatic mutations in TP53-mutated myeloid neoplasms with ≥10% blasts, we pooled 325 individuals from 10 centres. We focused on comparing three published somatic co-alteration signatures comprising (1) nine MDS-related genes ('ICC-MDSR'), (2) ICC-MDSR + additional secondary mutations-related genes ('Tazi signature') and (3) EPI6 (comprising six genes). Outcomes examined were 24-month overall survival (OS24) and front-line complete response (CR1). The median age was 69 years with 77% receiving front-line hypomethylating agents (HMA). All three signatures ICC-MDSR (p = 0.009), Tazi signature (p = 0.001) and EPI6 (p = 0.025) predicted inferior CR1. In the low-intensity (HMA) subgroup, only Tazi signature (p = 0.026) predicted inferior CR1. In OS24 analysis of the HMA-treated subgroup (N = 200), only Tazi signature was adverse (hazard ratio, HR = 1.6 [1.1-2.2]; p = 0.011). However, a forward stepwise multivariable age-adjusted Cox model including all three signatures picked EPI6 as the sole significant adverse predictor in the entire cohort (p = 0.0001) as well as within the HMA-treated subgroup (p = 0.0071). These data confirm the value of testing co-occurring somatic alterations even within a high-grade TP53-mutated myeloid neoplasm cohort.

Keywords:   TP53 ; co‐mutations; outcomes; pathology; response

DOI:  https://doi.org/10.1111/bjh.19895
Blood. 2024 Nov 20. pii: blood.2024026555. [Epub ahead of print]

Methylation sequencing enhances interpretation of clonal hematopoiesis dynamics.

Alyssa C Parker, Joseph Van Amburg, J Brett Heimlich, Yash Pershad, Nicole Angelina Mickels, Taralynn Mack, Paul Brent Ferrell, Michael R Savona, Angela Jones, Alexander G Bick.

We have developed a cost-effective DNA methylation sequencing assay to improve monitoring of clonal hematopoiesis. By inferring cell-type proportions, this method enhances interpretation of clonal trajectories compared to interpretation based on variant allele fraction only.

DOI: https://doi.org/10.1182/blood.2024026555
Blood Adv. 2024 Nov 19. pii: bloodadvances.2024014368. [Epub ahead of print]

Role of molecular alterations in transplantation decisions for patients with primary myelofibrosis.

Damien Luque Paz, Nico Gagelmann, Lina Benajiba, Jérémie Riou, Rachel B Salit, Corentin Orvain, Thomas Schroeder, Claire Bories, Carmelo Gurnari, Anita Badbaran, Francoise Boyer-Perrard, Simona Pagliuca, Christina Rautenberg, Suzanne Tavitian, Victoria Panagiota, Jean-Christophe Ianotto, Felicitas R Thol, Emilie Cayssials, Michael Heuser, Marie-Therese Rubio, Bruno Cassinat, Rafael Daltro de Oliveira, Craig S Sauter, Jaroslaw P Maciejewski, Hans Christian Reinhardt, Bart L Scott, Valérie Ugo, Nicolaus Kröger, Jean-Jacques Kiladjian, Marie Robin.

The aim of our study was to analyze the potential survival benefit associated with HSCT according to clinico-biological scores which incorporate molecular data (MIPSS70 and MIPSS70+V2) to facilitate decision-making in this context. One transplant (n=241) and one non-transplant cohorts (n=239) were used to test the hypothesis that PMF patients with higher risk molecular score benefit from HSCT. A weighted propensity score was applied to balance confounding factors with the transplanted cohort as reference. Weighted Cox proportional hazard models and logistic regression analyses were performed. 105 non-transplanted patients could be matched to the 239 transplanted patients. Mean age in transplanted and non-transplanted matched patients was 55.5 and 57.9 years. Blood cell count and DIPSS score distribution were similar in both groups. HSCT was associated with a higher 6-year OS rate in intermediate-2 (60.1% versus 41.5%) and high-risk DIPSS patients (44.4% versus 6.55%), high-risk MIPSS70 (46.5 versus 23.9%), high-risk (73.2% versus 39.7%) or very high-risk MIPSS70V2 (51.8% versus 24%). Intermediate MIPSS70 patients have an advantage of survival with HSCT only when their MTSS were low or intermediate. Transplanted patients had an increased mortality risk the first year but a significant benefit with HSCT after the one-year landmark was observed in higher risk patients. This study confirms that similar to DIPSS, MIPSS70 and MIPSS70+V2 risk score in addition to MTSS can be used to determine which patients with primary myelofibrosis have survival benefit from HSCT over non-HSCT strategies.

DOI: https://doi.org/10.1182/bloodadvances.2024014368
Blood. 2024 Nov 21. pii: blood.2023023210. [Epub ahead of print]

CD70 CAR T cells secreting an anti-CD33/anti-CD3 dual targeting antibody overcome antigen heterogeneity in AML.

Harrison Silva, Grace Martin, Filippo Birocchi, Marc Wehrli, Michael C Kann, Valentina M Supper, Aiyana Parker, Charlotte E Graham, Alexandra Grace Bratt, Amanda A Bouffard, Hannah Donner, Giulia Escobar, Hana N Takei, Alexander Armstrong, Sadie Goncalves, Trisha R Berger, Bryan D Choi, Marcela V Maus, Mark B Leick.

CD70 has emerged as a promising target in acute myeloid leukemia (AML), and we have previously demonstrated the potency of an optimized CD70-targeted ligand-based CAR. However, here, we identify in vivo CD70 antigen escape as a limitation of single antigen targeting. Combination targeting of CD70 and CD33 may overcome AML antigen heterogeneity. We hypothesized that modifying our CD70 CAR platform to secrete a bispecific T cell engaging antibody molecule ("TEAM") targeting CD33 (7033) would create a therapeutic window whereby AML heterogeneity could be addressed without increasing tissue toxicity. We found that CD33 TEAMs mediated specific cytotoxicity across AML cell lines, including CD33 or CD70 single-antigen knockout tumors. 7033 CAR-T cells eradicated tumor in an in vivo mixed tumor model of CD70 antigen escape and outperformed the previously optimized CD70 CAR in a patient-derived xenograft. In vivo gene expression profiling of CAR-T cells revealed enhanced 7033 CAR-T cell pathway scoring for persistence, activation, and TCR signaling. Additionally, CD33 TEAMs successfully redirected T cells isolated from AML patients to activate, secrete cytokines, and kill tumor targets despite exposure to substantial prior cytotoxic therapies. In summary, our findings demonstrate the feasibility of our 7033 CAR to overcome AML heterogeneity and leverage the bystander T cells of patients; this approach warrants further study in patients with this dire clinical need.

DOI: https://doi.org/10.1182/blood.2023023210
Leukemia. 2024 Nov 19.

Polycomb group protein Mel18 inhibits hematopoietic stem cell self-renewal through repressing the transcription of self-renewal and proliferation genes.

Wenjie Cai, Xicheng Liu, Sergio Barajas, Shiyu Xiao, Sasidhar Vemula, Hongxia Chen, Yuxia Yang, Christopher Bochers, Danielle Henley, Sheng Liu, Yuzhi Jia, Michelle Hong, Tiffany M Mays, Maegan L Capitano, Huiping Liu, Peng Ji, Zhonghua Gao, Diego Pasini, Jun Wan, Feng Yue, Leonidas C Platanias, Rongwen Xi, Sisi Chen, Yan Liu.

Polycomb group (PcG) proteins play important roles in hematopoietic stem cell (HSC) self-renewal. Mel18 and Bmi1 are homologs of the PCGF subunit within the Polycomb repressive complex 1 (PRC1). Bmi1 (PCGF4) enhances HSC self-renewal and promotes terminal differentiation. However, the role of Mel18 (PCGF2) in hematopoiesis is not fully understood and how Mel18 regulates gene transcription in HSCs remains elusive. We found that acute deletion of Mel18 in the hematopoietic compartment significantly increased the frequency of functional HSCs in the bone marrow. Furthermore, we demonstrate that Mel18 inhibits HSC self-renewal and proliferation. RNA-seq studies revealed that HSC self-renewal and proliferation gene signatures are enriched in Mel18-/- hematopoietic stem and progenitors (HSPCs) compared to Mel18+/+ HSPCs. Notably, ATAC-seq revealed increased chromatin accessibility at genes important for HSC self-renewal, whereas CUT&RUN showed decreased enrichment of H2AK119ub1 at genes important for proliferation, leading to increased expression of both Hoxb4 and Cdk4 in Mel18-/- HSPCs. Thus, we demonstrate that Mel18 inhibits hematopoietic stem cell self-renewal through repressing the transcription of genes important for HSC self-renewal and proliferation.

DOI: https://doi.org/10.1038/s41375-024-02462-w
Blood. 2024 Nov 22. pii: blood.2024026497. [Epub ahead of print]

Itacitinib for Prevention of Graft-Versus-Host Disease and Cytokine Release Syndrome in Haploidentical Transplantation.

Ramzi Abboud, Mark A Schroeder, Michael P Rettig, Reyka G Jayasinghe, Feng Gao, Jeremy Eisele, Leah Gehrs, Julie K Ritchey, Jaebok Choi, Camille N Abboud, Iskra Pusic, Meagan A Jacoby, Peter Westervelt, Matthew Christopher, Amanda F Cashen, Armin Ghobadi, Keith Stockerl-Goldstein, Geoffrey L Uy, John F DiPersio.

Haploidentical hematopoietic cell transplantation (haplo-HCT) is an increasingly used treatment for hematologic malignancies. Although post-transplant cyclophosphamide (PtCy) has improved graft vs. host disease (GvHD) prophylaxis in haplo-HCT, patients continue to experience life-threatening complications. IFN-γ and IL-6 are central in the pathophysiology of GvHD and cytokine release syndrome (CRS), and both cytokines signal through Janus kinase (JAK)-1. We tested the effect of adding the JAK-1 selective inhibitor, itacitinib, to PtCy-haplo-HCT to mitigate these complications and improve overall survival. This open-label, single-arm study evaluated the safety and efficacy of itacitinib combined with standard GvHD prophylaxis after haplo-HCT. A total of 42 patients were treated with itacitinib 200 mg daily from day -3 through +100 or +180, followed by a taper. Itacitinib resulted in low CRS grades, all patients had grade 0 (22%) or grade 1 (78%) CRS and there were no cases of grade 2-5 CRS. There were no cases of primary graft failure. No patients developed grade 3-4 aGvHD through day +180. The cumulative incidence of grade 2 aGvHD at day +100 was 21.9%. The 1-year cumulative incidence of moderate or severe chronic GvHD was 5%. The cumulative incidence of relapse at 2 years was 14%. Overall survival (OS) at 1 year was 80%. The cumulative incidence of nonrelapse mortality at day 180 was 8%. Itacitinib, when added to standard GvHD prophylaxis, was well tolerated and resulted in low rates of CRS, acute and chronic GvHD, NRM and encouraging rates of GvHD-free relapse-free survival (GRFS) and OS after haplo-HCT. NCT03755414.

DOI: https://doi.org/10.1182/blood.2024026497
Expert Rev Proteomics. 2024 Nov 22. 1-14

Proteogenomic profiling of acute myeloid leukemia to identify therapeutic targets.

Heather C Murray, Jonathan Sillar, Maddison Chambers, Nicole M Verrills.

   INTRODUCTION: Acute myeloid leukemia (AML) is an aggressive and poor-prognosis blood cancer. Despite a low mutation burden compared to other cancers, AML is heterogenous and identifying robust therapeutic targets has been difficult. Genomic profiling has greatly advanced our understanding of AML, and has revealed targets for AML therapy. However, only 50% of AML patients have gene mutations that are currently druggable, and relapse rates remain high. The addition of proteomic profiling is emerging to address these challenges.
AREAS COVERED: Using references collected through Pubmed, we review recent studies that have combined genomic and proteomic profiling (i.e. proteogenomic profiling), as well as studies that have additionally integrated other omics approaches, such as phosphoproteomics. We highlight how proteogenomic profiling promises to deconvolve the cellular pathways driving leukemogenesis, uncover novel therapeutic targets, and identify biomarkers of response to novel and existing therapies.
EXPERT OPINION: Proteogenomic profiling is providing unparalleled insight into AML, and is beginning to identify robust biomarkers. Standardization of workflows will be required before mass spectrometry-based proteomic assays can be integrated into routine clinical use. However, the demonstrated ability to adapt signatures into biomarker panels that can be assayed by existing clinical workflows is enabling current clinical translation.

Keywords:  Acute myeloid leukemia; biomarkers; phosphoproteomics; precision therapy; proteogenomics; proteomics

DOI:  https://doi.org/10.1080/14789450.2024.2431272
Commun Biol. 2024 Nov 22. 7(1): 1555

Targeting heterochromatin eliminates chronic myelomonocytic leukemia malignant stem cells through reactivation of retroelements and immune pathways.

Donia Hidaoui, Audrey Porquet, Rabie Chelbi, Mathieu Bohm, Aikaterini Polyzou, Vincent Alcazer, Stéphane Depil, Aygun Imanci, Margot Morabito, Aline Renneville, Dorothée Selimoglu-Buet, Sylvain Thépot, Raphael Itzykson, Lucie Laplane, Nathalie Droin, Eirini Trompouki, Emilie Elvira-Matelot, Eric Solary, Françoise Porteu.

Chronic myelomonocytic leukemia (CMML) is a severe myeloid malignancy affecting the elderly, for which therapeutic options are limited. DNA hypomethylating agents (HMAs) provide transient responses, failing to eradicate the malignant clone. Hematopoietic stem cell (HSC) aging involves heterochromatin reorganization, evidenced by alterations in histone marks H3K9me2 and H3K9me3. These repressive marks together with DNA methylation are essential for suppressing transposable elements (TEs). In solid cancers, the antitumor efficacy of HMAs involves the derepression of TEs, mimicking a state of viral infection. In this study, we demonstrate a significant disorganization of heterochromatin in CMML HSCs and progenitors (HSPCs) characterized by an increase in the repressive mark H3K9me2, mainly at the level of TEs, and a repression of immune and age-associated transcripts. Combining HMAs with G9A/GLP H3K9me2 methyltransferase inhibitors reactivates these pathways, selectively targeting mutated cells while preserving wild-type HSCs, thus offering new therapeutic avenues for this severe myeloid malignancy.

DOI: https://doi.org/10.1038/s42003-024-07214-1
Leukemia. 2024 Nov 17.

The glycosyltransferase ST3GAL4 drives immune evasion in acute myeloid leukemia by synthesizing ligands for the glyco-immune checkpoint receptor Siglec-9.

Vignesh Krishnamoorthy, John Daly, Jimmy Kim, Lidia Piatnitca, Katie A Yuen, Bhoj Kumar, Mehrnoush Taherzadeh Ghahfarrokhi, Tom Q T Bui, Parastoo Azadi, Ly P Vu, Simon Wisnovsky.

Immunotherapy has demonstrated promise as a treatment for acute myeloid leukemia (AML). However, there is still an urgent need to identify new molecules that inhibit the immune response to AML. Most prior research in this area has focused on protein-protein interaction interfaces. While carbohydrates also regulate immune recognition, the role of cell-surface glycans in driving AML immune evasion is comparatively understudied. The Siglecs, for example, are an important family of inhibitory, glycan-binding signaling receptors that have emerged as prime targets for cancer immunotherapy in recent years. In this study, we find that AML cells express ligands for the receptor Siglec-9 at high levels. Integrated CRISPR genomic screening and clinical bioinformatic analysis identified ST3GAL4 as a potential driver of Siglec-9 ligand expression in AML. Depletion of ST3GAL4 by CRISPR-Cas9 knockout (KO) dramatically reduced the expression of Siglec-9 ligands in AML cells. Mass spectrometry analysis of cell-surface glycosylation in ST3GAL4 KO cells revealed that Siglec-9 primarily binds N-linked sialoglycans on these cell types. Finally, we found that ST3GAL4 KO enhanced the sensitivity of AML cells to phagocytosis by Siglec-9-expressing macrophages. This work reveals a novel axis of immune evasion and implicates ST3GAL4 as a possible target for immunotherapy in AML.

DOI: https://doi.org/10.1038/s41375-024-02454-w
J Clin Invest. 2024 Nov 19. pii: e177342. [Epub ahead of print]

G-CSF resistance of ELANE mutant neutropenia depends on SERF1 containing truncated neutrophil elastase aggregates.

Ramesh C Nayak, Sana Emberesh, Lisa Trump, Ashley Wellendorf, Abhishek Singh, Brice Korkmaz, Marshall S Horwitz, Kasiani C Myers, Theodosia A Kalfa, Carolyn Lutzko, Jose A Cancelas.

  Severe congenital neutropenia (SCN) is frequently associated with dominant point mutations in ELANE, the gene encoding neutrophil elastase (NE). Chronic administration of granulocyte colony-stimulating factor (G-CSF) is a first-line treatment of ELANE-mutant (ELANEmut) SCN. However, some ELANEmut patients including patients with ELANE start codon mutations do not respond to G-CSF. Here, through directed granulopoiesis of gene-edited isogenic normal and patient-derived iPSCs, we demonstrate that ELANE start codon mutations suffice to induce G-CSF resistant granulocytic precursor cell death and refractory SCN. ELANE start codon mutated neutrophil precursors express predominantly nuclear N-terminal truncated alternate NE. Unlike G-CSF sensitive ELANE mutations that induce endoplasmic reticulum and unfolded protein response stress, we found that the mutation of the ELANE translation initiation codon resulted in NE aggregates and activated pro-apoptotic aggrephagy as determined by downregulated BAG1 expression, decreased BAG1/BAG3 ratio, NE co-localization with BAG3, and localized expression of autophagic LC3B. We found that SERF1, an RNA-chaperone protein, known to localize in misfolded protein aggregates in neurodegenerative diseases, was highly upregulated and interacted with cytoplasmic NE of mutant neutrophil precursors. Silencing of SERF1 enhanced survival and differentiation of iPSC-derived neutrophil precursors, restoring their responsiveness to G-CSF. These observations provide a mechanistic insight of G-CSF-resistant ELANEmut SCN, revealing targets for therapeutic intervention.

Keywords:  Hematology; Neutrophils

DOI:  https://doi.org/10.1172/JCI177342
Br J Haematol. 2024 Nov 17.

Real-world experience of paediatric acute promyelocytic leukaemia in the United Kingdom and Ireland.

Aditi Vedi, Sarah Maria Leiter, Irum Latif Memon, Arunthethy Mahendrayogam, Elsje Van Rijswijk, Urmila Uparkar, Geoff Shenton, Amelie Trinquand, Katherine Clesham, Vanessa McLelland, Helen Campbell, Katharine Patrick, Lyndsey Thompson, Susan Baird, Philip Connor, Donna Lancaster, Beki James.

  Acute promyelocytic leukaemia (APL), defined by the t(15;17)(q24;q21) translocation, accounts for 5%-10% of paediatric acute myeloid leukaemia cases. All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are key treatments, though ATO access varies. We evaluated treatment, complications and survival in 50 UK paediatric APL patients diagnosed between 2014 and 2021. All patients received ATRA and most received ATO. Event-free survival was lower in high-risk patients (85% vs. 100%, p = 0.03), and those not receiving ATO at diagnosis. All relapsed patients could be salvaged with ATO. Addressing ATO availability and consistent funding is crucial to ensure timely treatment and improve outcomes.

Keywords:  APL; Leukaemia; Paediatric; all‐trans retinoic acid; arsenic trioxide

DOI:  https://doi.org/10.1111/bjh.19843
Leukemia. 2024 Nov 18.

Glucose uptake capacity of leukaemia cells in vitro correlates with response to induction therapy in acute myeloid leukaemia.

Suqi Deng, Juan Du, Kexiu Huang, Robert Peter Gale, Danqi Pan, Lu Wang, Junjie Wei, Xue Zheng, Ying Xu, Shengqian Xie, Wei Zhou, Weihao Xiao, Bo Liu, Zhiyang Chen, Zhenyu Ju, Hui Zeng.

DOI: https://doi.org/10.1038/s41375-024-02469-3
ACS Med Chem Lett. 2024 Nov 14. 15(11): 1843-1851

Discovery of IRAK1/4/pan-FLT3 Kinase Inhibitors as Treatments for Acute Myeloid Leukemia.

Scott B Hoyt, Chris J Finocchio, Elizabeth Croll, Gregory J Tawa, Huixu Li, Li Ma, Kaikai Li, Li Liu, Ranran Li, Xiaohu Zhang, Kelli Wilson, Xin Xu, Pranav Shah, Jordan Williams, Yuhong Fang, Lyndsey C Bolanos, Gabriel Gracia-Maldonado, Amal Kolt, Christina Robinson, Jessica Free, Elijah F Edmondson, Simone Difilippantonio, LaQuita M Jones, Ashley E Culver-Cochran, Jan S Rosenbaum, Daniel T Starczynowski, Craig J Thomas.

We report the discovery of an imidazopyridine series of IRAK1/4/pan-FLT3 kinase inhibitors. Optimization of this series has produced compound 31 which displays potent and selective inhibition of IRAK1, IRAK4, FLT3, and all mutant forms of FLT3, as well as good in vitro ADME and pharmacokinetic properties. In a mouse xenograft model of AML, 31 produces survival prolongation equal to that of Gilteritinib, the leading marketed FLT3 inhibitor currently used to treat AML.

DOI: https://doi.org/10.1021/acsmedchemlett.4c00269
Leuk Lymphoma. 2024 Nov 19. 1-9

Cost-effectiveness of Enasidenib versus conventional care for older patients with IDH2-mutant refractory/relapsed AML.

Abdulrahman Alhajahjeh, Kishan K Patel, Rory M Shallis, Nikolai A Podoltsev, Tariq Kewan, Jessica M Stempel, Lourdes Mendez, Scott F Huntington, Maximilian Stahl, George Goshua, Jan Philipp Bewersdorf, Amer M Zeidan.

  In the randomized phase III IDHENTIFY trial, the IDH2 inhibitor enasidenib (ENA) showed improvement in event-free but not overall survival compared with conventional care regimens (CCR) among patients with relapsed/refractory (R/R), IDH2-mutant AML. We constructed a partitioned survival model to evaluate the cost-effectiveness of enasidenib for the treatment of older patients with R/R, and IDH2-mutant AML. In the base-case scenario, ENA exhibited an incremental effectiveness of 0.234quality-adjusted life-years (QALYs) compared to CCR, and an incremental cost of $126,800, leading to an incremental cost-effectiveness ratio of $540,300/QALY(95% CI: $197,800-$4,777,000/QALY). In probabilistic sensitivity analysis, CCR was favored in 99.8% of simulations. The cost of ENA would need to be decreased by 72% to be cost-effective at a willingness-to-pay threshold of $150,000/QALY. Our findings suggest that ENA is unlikely to be a cost-effective treatment for older patients with IDH2-mutant R/R AML under current pricing.

Keywords:  Acute myeloid leukemia; IDH2 mutation; cost-effectiveness analysis; enasidenib

DOI:  https://doi.org/10.1080/10428194.2024.2426073
JAMA Oncol. 2024 Nov 21.

Olverembatinib After Failure of Tyrosine Kinase Inhibitors, Including Ponatinib or Asciminib: A Phase 1b Randomized Clinical Trial.

Elias Jabbour, Vivian G Oehler, Paul B Koller, Omer Jamy, Elza Lomaia, Anthony M Hunter, Olga Uspenskaya, Svetlana Samarina, Sudipto Mukherjee, Jorge E Cortes, Maria R Baer, Vera Zherebtsova, Vasily Shuvaev, Anna Turkina, Igor Davydkin, Huanshan Guo, Zi Chen, Tommy Fu, Lixin Jiang, Cunlin Wang, Hengbang Wang, Dajun Yang, Yifan Zhai, Hagop Kantarjian.

Importance: Patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) resistant or intolerant to BCR-ABL1 tyrosine kinase inhibitors (TKIs) have limited treatment options. Olverembatinib, which is approved in China, has only been tested in Chinese patients.
Objective: To assess the pharmacokinetics, safety, efficacy, and recommended dose of olverembatinib in patients with CML or Philadelphia chromosome-positive ALL resistant or intolerant to at least 2 TKIs.
Design, Setting, and Participants: This multicenter phase 1b randomized clinical trial was conducted from January 28, 2020, to January 2, 2024, with a median (range) follow-up of 48 (0-166) weeks. Patients with CML or Philadelphia chromosome-positive ALL were enrolled. This bridging study was performed in part to confirm that there are no racial differences in the pharmacokinetic profile of olverembatinib.
Interventions: Patients were randomly assigned to 30, 40, or 50 mg of olverembatinib orally every other day in 28-day cycles.
Main Outcomes and Measures: Pharmacokinetic profile of olverembatinib.
Results: Of 80 included patients, 46 (58%) were male, and the median (range) age was 54.0 (21-80) years. The pharmacokinetic profile of olverembatinib was compatible with alternate-day dosing and similar to that in Chinese patients. Based on investigators' assessments, 60 patients (75%) experienced at least 1 treatment-related adverse event; 32 (40%) experienced grade 3 or higher treatment-related adverse events; and 12 (15%) experienced treatment-related serious adverse events, none of which were fatal. Frequently reported (10% or more) treatment-emergent adverse events included elevated blood creatine phosphokinase (all grades, 31 [39%]; grade 3 or higher, 10 [13%]) and thrombocytopenia (all grades, 23 [29%]; grade 3 or higher, 14 [18%]). Among evaluable patients with chronic-phase CML, complete cytogenetic response (CCyR) occurred in 31 of 51 patients (61%; 95% CI, 46.1-74.2), and major molecular response (MMR) occurred in 25 of 59 patients (42%; 95% CI, 29.6-55.9). Cytogenetic and molecular responses were similar in patients with or without T315I variants. A total of 15 of 26 patients with prior ponatinib treatment (58%; 95% CI, 36.9-76.6) achieved CCyR, and 11 of 30 (37%; 95% CI, 19.9-56.1) achieved MMR. A total of 4 of 8 patients with asciminib resistance (50%; 95% CI, 15.7-84.3) had CCyR, and 4 of 12 (33%; 95% CI, 9.9-65.1) had MMR. The recommended phase 3 dose of olverembatinib is 30 mg every other day in patients without T315I variants.
Conclusions and Relevance: In this trial, olverembatinib had a favorable pharmacokinetic profile, was generally well tolerated, and showed strong antileukemic activity in patients with heavily pretreated chronic-phase CML with or without T315I variants, including prior ponatinib and/or asciminib failure. Olverembatinib may provide a viable new treatment option for patients after failure of 2 or more TKIs.
Trial Registration: ClinicalTrials.gov Identifier: NCT04260022.

DOI: https://doi.org/10.1001/jamaoncol.2024.5157
Blood Adv. 2024 Nov 21. pii: bloodadvances.2024014592. [Epub ahead of print]

Chronic Inflammation Deters Natural Killer Cell Fitness and Cytotoxicity in Myeloid Leukemia.

Valeriya Kuznetsova, Vaidehi Krishnan, Amanda Costa, Xi Ren, Tiffany D Ricketts, Sweta B Patel, Ashley N Connelly, Paran Goel, Joshua P Knapp, Alana M Franceski, Francesca Luca, Lorena Lobo de Figueiredo-Pontes, Ravi Bhatia, Shyam Prabhakar, S Tiong Ong, Robert S Welner.

Natural killer (NK) cells play an integral role in immunosurveillance against myeloid malignancies, with their mature phenotype and abundance linked to prolonged treatment-free remission in chronic myeloid leukemia (CML). However, NK cell function is suppressed during the disease, and the orchestrators of this impairment are not fully understood. Using a chimeric BCR::ABL1+ CML mouse model, we characterized the impact of the leukemic microenvironment on NK cell function. We showed that NK cells have reduced counts, immature phenotype, poor cytotoxicity, and altered expression of activating and inhibitory receptors in CML mice, which revert to a steady state upon BCR::ABL1 inhibition. Single-cell RNA sequencing revealed an inflammatory cytokine response in CML-exposed NK cells, highlighted by the tumor necrosis factor-a (TNFa)-induced gene signature, upregulation of TNFa receptor TNFR2, and enrichment of SOCS family genes such as Cish, the critical NK cell checkpoint. Ex vivo exposure of healthy NK cells to leukemic soluble factors compromised target-specific NK cell degranulation, which was partially rescued by targeting Cish or TNFa. In alignment with these findings, NK cells from healthy donors displayed suppressed cytotoxicity when exposed to plasma from untreated CML patients, with a partial restoration upon Cish or TNFa inhibition. Furthermore, NK cells from newly diagnosed CML patients pre-destined for blast crisis showed an enrichment of the TNFa-induced pro-inflammatory gene signature identified in CML mice. These results suggest that targeting inflammatory signaling could enhance NK cell-based immunotherapies for CML.

DOI: https://doi.org/10.1182/bloodadvances.2024014592
iScience. 2024 Nov 15. 27(11): 111199

Arginine methylation of the p30 C/EBPα oncoprotein regulates progenitor proliferation and myeloid differentiation.

Linh T Nguyen, Karin Zimmermann, Elisabeth Kowenz-Leutz, Dorothea Dörr, Anja Schütz, Jörg Schönheit, Alexander Mildner, Achim Leutz.

  The transcription factor CCAAT enhancer binding protein alpha (C/EBPα) is a master regulator of myelopoiesis. CEBPA encodes a long (p42) and a truncated (p30) protein isoform from a single mRNA. Mutations that abnormally enhance expression of p30 are associated with acute myelogenous leukemia (AML). We show by mutational analysis that three highly conserved arginine residues in the p30 C/EBPα N-terminus, previously found to be methylated, are involved in myeloid lineage commitment, progenitor proliferation, and differentiation. The conservative amino acid substitution with lysine that retains the amino acid side chain charge enhanced progenitor proliferation, while a non-conservative substitution with uncharged side chains (alanine, leucine) impaired proliferation and enhanced granulopoiesis. Analysis of protein interactions suggested that arginine methylation of p30 C/EBPα differentially determines interactions with SWI/SNF and MLL complexes. Pharmacological targeting of p30 C/EBPα arginine methylation may have clinical relevance in myeloproliferative and inflammatory diseases, in neutropenia, and in leukemic stem cells.

Keywords:  biochemistry; cell biology; transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2024.111199
Blood. 2024 Nov 21. 144(21): 2159-2160

The Aza/Ven reshuffle.

Mark Levis.

DOI: https://doi.org/10.1182/blood.2024026429
JAMA. 2024 Nov 18.

Diagnosis and Treatment of Polycythemia Vera: A Review.

Douglas Tremblay, Marina Kremyanskaya, John Mascarenhas, Ronald Hoffman.

Importance: Polycythemia vera (PV), a myeloproliferative neoplasm characterized by an increased red blood cell mass and increased risk of thrombosis, affects approximately 65 000 people in the US, with an annual incidence of 0.5 to 4.0 cases per 100 000 persons.
Observations: Erythrocytosis (hemoglobin >16.5 mg/dL in men or >16.0 mg/dL in women) is a required diagnostic criterion, although thrombocytosis (53%) and leukocytosis (49%) are common. Patients may have pruritus (33%), erythromelalgia (5.3%), transient visual changes (14%), and splenomegaly (36%) with abdominal discomfort. More than 95% of patients have a JAK2 gene variant, which helps distinguish PV from secondary causes of erythrocytosis, such as tobacco smoking or sleep apnea. Among 7 cohorts (1545 individuals), the median survival from diagnosis was 14.1 to 27.6 years. Prior to or at the time of PV diagnosis, arterial thrombosis occurred in 16% of patients and 7% had venous thrombotic events, which could involve unusual sites, such as splanchnic veins. PV is also associated with an increased bleeding risk, especially in patients with acquired von Willebrand disease, which can occur with extreme thrombocytosis (platelet count, ≥1000 × 109/L). All patients with PV should receive therapeutic phlebotomy (goal hematocrit, <45%) and low-dose aspirin (if no contraindications). Patients who are at higher risk of thrombosis include those aged 60 years or older or with a prior thrombosis. These patients and those with persistent PV symptoms may benefit from cytoreductive therapy with hydroxyurea or interferon to lower thrombosis risk and decrease symptoms. Ruxolitinib is a Janus kinase inhibitor that can alleviate pruritus and decrease splenomegaly in patients who are intolerant of or resistant to hydroxyurea. About 12.7% of patients with PV develop myelofibrosis and 6.8% develop acute myeloid leukemia.
Conclusions and Relevance: PV is a myeloproliferative neoplasm characterized by erythrocytosis and is almost universally associated with a JAK2 gene variant. PV is associated with an increased risk of arterial and venous thrombosis, hemorrhage, myelofibrosis, and acute myeloid leukemia. To decrease the risk of thrombosis, all patients with PV should be treated with aspirin and therapeutic phlebotomy to maintain a hematocrit of less than 45%. Cytoreductive therapies, such as hydroxyurea or interferon, are recommended for patients at high risk of thrombosis.

DOI: https://doi.org/10.1001/jama.2024.20377
J Biol Chem. 2024 Nov 15. pii: S0021-9258(24)02506-7. [Epub ahead of print] 108004

Impaired branched chain amino acid (BCAA) catabolism during adipocyte differentiation decreases glycolytic flux.

Courtney R Green, Lynn M Alaeddine, Karl A Wessendorf-Rodriguez, Rory Turner, Merve Elmastas, Justin D Hover, Anne N Murphy, Mikael Ryden, Niklas Mejhert, Christian M Metallo, Martina Wallace.

  Dysregulated branched chain amino acid (BCAA) metabolism has emerged as a key metabolic feature associated with the obese insulin resistant state, and adipose BCAA catabolism is decreased in this context. BCAA catabolism is upregulated early in adipogenesis, but the impact of suppressing this pathway on the broader metabolic functions of the resultant adipocyte remains unclear. Here, we use CRISPR/Cas9 to decrease BCKDHA in 3T3-L1 and human pre-adipocytes, and ACAD8 in 3T3-L1 pre-adipocytes to induce a deficiency in BCAA catabolism through differentiation. We characterize the transcriptional and metabolic phenotype of 3T1-L1 cells using RNAseq and 13C metabolic flux analysis within a network spanning glycolysis, tricarboxylic acid (TCA) metabolism, BCAA catabolism, and fatty acid synthesis. While lipid droplet accumulation is maintained in Bckdha-deficient adipocytes, they display a more fibroblast-like transcriptional signature. In contrast, Acad8 deficiency minimally impacts gene expression. Decreased glycolytic flux emerges as the most distinct metabolic feature of 3T3-L1 Bckdha-deficient cells, accompanied by a ∼40% decrease in lactate secretion, yet pyruvate oxidation and utilization for de novo lipogenesis are increased to compensate for loss of BCAA carbon. Deletion of BCKDHA in human adipocyte progenitors also led to a decrease in glucose uptake and lactate secretion, however these cells did not upregulate pyruvate utilisation and lipid droplet accumulation and expression of adipocyte differentiation markers was decreased in BCKDH knockout cells. Overall our data suggest that human adipocyte differentiation may be more sensitive to the impact of decreased BCKDH activity than 3T3-L1 cells, and that both metabolic and regulatory cross-talk exists between BCAA catabolism and glycolysis in adipocytes. Suppression of BCAA catabolism associated with metabolic syndrome may result in a metabolically compromised adipocyte.

Keywords:  adipogenesis; adipose; branched chain amino acids; glycolysis; metabolic flux

DOI:  https://doi.org/10.1016/j.jbc.2024.108004
Haematologica. 2024 Nov 21.

FLT3 ligand kinetic profile predicts response to treatment in patients with high-risk myelodysplastic syndrome / chronic myelomonocytic leukemia receiving CPX-351: a study from the Groupe Francophone des Myélodysplasies.

Pierre Peterlin, Joëlle Gaschet, Pascal Turlure, Marie-Pierre Gourin, Pierre-Yves Dumas, Sylvain Thepot, Ana Berceanu, Sophie Park, Marie-Anne Hospital, Thomas Cluzeau, Jose-Miguel Torregrosa-Diaz, Louis Drevon, Rosa Sapena, Fatiha Chermat, Lionel Ades, Sophie Dimicoli-Salazar, Maxime Jullien, Pierre Fenaux, Patrice Chevallier.

Not available.

DOI: https://doi.org/10.3324/haematol.2024.286025
Am J Hematol. 2024 Nov 16.

Clinical and Immune Effects of Peri-Transplantation JAK Inhibition for Myelofibrosis.

Kristin Rathje, Nico Gagelmann, Anita Badbaran, Claudia Langebrake, Adrin Dadkhah, Johanna Richter, Radwan Massoud, Mathias Schäfersküpper, Franziska E Marquard, Sofia Oechsler, Evgeny Klyuchnikov, Ina Rudolph, Silke Heidenreich, Christian Niederwieser, Catherina Lueck, Dietlinde Janson, Christine Wolschke, Boris Fehse, Francis Ayuk, Nicolaus Kröger.

  Despite the introduction of JAK inhibitors, allogeneic hematopoietic cell transplant remains the only potentially curative treatment for patients with myelofibrosis but has considerable treatment-related complications. Whether the incorporation of JAK inhibition into the transplant algorithm leads to improved outcomes is still unclear. Here, we analyzed different transplant platforms in myelofibrosis patients undergoing a first transplant, comparing immune profiles and outcomes of (1) 33 patients continuing JAK inhibition at start of conditioning until stable engraftment (PERI-group), (2) 38 patients receiving JAK inhibition prior to transplant until start of conditioning (PRE-group), and (3) 38 patients that had never received JAK inhibition (NON-group). Patients in the PERI-group showed significantly higher early B-cell recovery as well as significantly increased late recovery of gamma-delta T cells and NK cells. We observed excellent neutrophil and platelet engraftment (100% for both) in the PERI-group and no hematotoxic effects or increased rates of infections following peri-transplant JAK inhibition. Cumulative incidence of acute graft-versus-host disease (GvHD) grade II-IV at day 100 after transplant was 15% in the PERI-group versus 29% in the PRE-group versus 34% in the NON-group. Cumulative incidence of relapse at 1 year after transplant was 9% in the PERI-group compared with 16% in the PRE-group and 18% in the NON-group. In conclusion, peri-transplant JAK inhibition was feasible with promising engraftment and acute GvHD rates, though deserves further investigation.

Keywords:  JAK inhibition; allogeneic hematopoietic cell transplant; myelofibrosis

DOI:  https://doi.org/10.1002/ajh.27529
Nature. 2024 Nov 20.

Human HDAC6 senses valine abundancy to regulate DNA damage.

Jiali Jin, Tong Meng, Yuanyuan Yu, Shuheng Wu, Chen-Chen Jiao, Sihui Song, Ya-Xu Li, Yu Zhang, Yuan-Yuan Zhao, Xinran Li, Zixin Wang, Yu-Fan Liu, Runzhi Huang, Jieling Qin, Yihua Chen, Hao Cao, Xiao Tan, Xin Ge, Cong Jiang, Jianhuang Xue, Jian Yuan, Dianqing Wu, Wei Wu, Ci-Zhong Jiang, Ping Wang.

As an essential branched amino acid, valine is pivotal for protein synthesis, neurological behaviour, haematopoiesis and leukaemia progression1-3. However, the mechanism by which cellular valine abundancy is sensed for subsequent cellular functions remains undefined. Here we identify that human histone deacetylase 6 (HDAC6) serves as a valine sensor by directly binding valine through a primate-specific SE14 repeat domain. The nucleus and cytoplasm shuttling of human, but not mouse, HDAC6 is tightly controlled by the intracellular levels of valine. Valine deprivation leads to HDAC6 retention in the nucleus and induces DNA damage. Mechanistically, nuclear-localized HDAC6 binds and deacetylates ten-eleven translocation 2 (TET2) to initiate active DNA demethylation, which promotes DNA damage through thymine DNA glycosylase-driven excision. Dietary valine restriction inhibits tumour growth in xenograft and patient-derived xenograft models, and enhances the therapeutic efficacy of PARP inhibitors. Collectively, our study identifies human HDAC6 as a valine sensor that mediates active DNA demethylation and DNA damage in response to valine deprivation, and highlights the potential of dietary valine restriction for cancer treatment.

DOI: https://doi.org/10.1038/s41586-024-08248-5
Blood Adv. 2024 Nov 19. pii: bloodadvances.2024014430. [Epub ahead of print]

CHIP away at the marrow-clot connection: inflammation, clonal hematopoiesis, and thromboembolic disease.

Angela Todorovski, Tzu-Fei Wang, Marc Carrier, Yan Xu.

Both the incidence and prognosis of arterial atherothrombosis and venous thromboembolism are strongly correlated with increasing age. Over the past decade, clonal hematopoiesis of indeterminate potential (CHIP) has been identified as a novel biomarker for cardiovascular disease. Driven by somatic mutations in the hematopoietic system, the epidemiology of CHIP is highly age-dependent: among individuals aged ≥70 years in the general population, estimated prevalence of CHIP exceeds 10%. Several additional risk factors for CHIP have emerged in recent years, including smoking, receipt of anti-cancer therapy, and germline predispositions. CHIP carriers consistently have higher risk of incident arterial atherothrombosis, even after accounting for traditional cardiovascular risk factors. However, the magnitude of this association varies across studies. In addition, individuals with established cardiovascular disease and CHIP have higher risks of recurrence and all-cause mortality compared to their non-CHIP counterparts. An association between CHIP carriership and incident venous thromboembolism has recently been made, though additional studies are needed to confirm this finding. No approved therapy exists to modify the cardiovascular risk among CHIP carriers. However, canakinumab showed promise in a post-hoc analyses of patients with TET2-mutated CHIP, and other anti-inflammasome agents are actively under development or evaluation. In this review, we provide an overview of CHIP as a mediator of thromboembolic diseases and discuss emerging therapeutics aimed at intervening on this thrombo-inflammatory nexus.

DOI: https://doi.org/10.1182/bloodadvances.2024014430
Am J Hematol. 2024 Nov 19.

Prognostic significance of mutation type and chromosome fragility in Fanconi anemia.

María José Ramírez, Roser Pujol, Jordi Minguillón, Massimo Bogliolo, Ilaria Persico, Debora Cavero, Aurora de la Cal, Paula Río, Susana Navarro, José Antonio Casado, Almudena Bailador, Antonio Sanchez de la Fuente, Miguel López de Heredia, Francisco Almazán, M Luisa Antelo, Bienvenida Argilés, Isabel Badell, Marta Baragaño, Cristina Beléndez, Mar Bermúdez, Marta Bernués, María Isabel Buedo, Estela Carrasco, Albert Català, Dolors Costa, Isabel Cuesta, Rafael Fernandez-Delgado, Ana Fernández-Teijeiro, Ángela Figuera, Marta García, Ainhoa Gondra, Macarena González, Soledad González Muñiz, Ines Hernández-Rodríguez, Fátima Ibañez, Nicholas John Kelleher, Francisco Lendínez, Mónica López, Ricardo López-Almaraz, Inmaculada Marchante, Carmen Mendoza, José Nieto, Emilio Ojeda, Salvador Payán-Pernía, Irene Peláez, Inmaculada Pérez de Soto, Raquel Portugal, María A Ramos-Arroyo, Alexandra Regueiro, Ana Rodríguez, Jordi Rosell, Raquel Saez, José Sánchez, Martha Sánchez, MªLeonor Senent, María Tapia, Juan Pablo Trujillo-Quintero, José Manuel Vagace, Jaime Verdú-Amorós, Victória Verdugo, Isabel Vidales, Jasson Villarreal, Cristina Díaz-de-Heredia, Julián Sevilla, Juan Antonio Bueren, Jordi Surrallés.

Fanconi anemia (FA) is a rare genetic disease characterized by high phenotypic and genotypic heterogeneity, and extreme chromosome fragility. To better understand the natural history of FA, identify genetic risk and prognostic factors, and develop novel therapeutic strategies, the Spanish Registry of Patients with FA collects data on clinical features, chromosome fragility, genetic subtypes, and DNA sequencing with informed consent of participating individuals. In this article, we describe the clinical evolution of 227 patients followed up for up to 30 years, for whom our data indicate a cumulative cancer incidence of 86% by age 50. We found that patients with lower chromosome fragility had a milder malformation spectrum and better outcomes in terms of later-onset hematologic impairment, less severe bone marrow failure, and lower cancer risk. We also found that outcomes were better for patients with mutations leading to mutant FANCA protein expression (genetic hypomorphism) than for patients lacking this protein. Likewise, prognosis was consistently better for patients with biallelic mutations in FANCD2 (mainly hypomorphic mutations) than for patients with biallelic mutations in FANCA and FANCG, with the lack of the mutant protein in patients with biallelic mutations in FANCG contributing to their poorer outcomes. Our results regarding the clinical impact of chromosome fragility and genetic hypomorphism suggest that mutant FA proteins retain residual activity. This finding should encourage the development of novel therapeutic strategies aimed at partially or fully enhancing mutant FA function, thereby preventing or delaying bone marrow failure and cancer in patients with FA. Clinical Trial Registration number: NCT06490510.

DOI: https://doi.org/10.1002/ajh.27520