bims-tremyl 2024-07-07 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2024–07–07
33 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Combining the novel FLT3 and MERTK dual inhibitor MRX-2843 with venetoclax results in promising antileukemic activity against FLT3-ITD AML.
Tacrolimus versus cyclosporine a combined with post-transplantation cyclophosphamide for AML In first complete remission: a study from the acute leukemia working party (EBMT).
Molecular Taxonomy of Myelodysplastic Syndromes and its Clinical Implications.
Rearrangements involving 11q23.3/KMT2A in adult AML: mutational landscape and prognostic implications - a HARMONY study.
Genetic deletion of JAM-C in pre-leukemic cells rewires leukemic stem cell gene expression program in AML.
Alkynyl nicotinamides show antileukemic activity in drug-resistant acute myeloid leukemia.
FRACTION: protocol of a phase II study of Fedratinib and Nivolumab combination in patients with myelofibrosis and resistance or suboptimal response to JAK-inhibitor treatment of the German MPN study group (GSG-MPN).
High-dose cytarabine plus gemtuzumab ozogamicin as consolidation therapy in patients with favorable- or intermediate-risk acute myeloid leukemia.
Acute myeloid leukemia (AML) with chromosome 3 inversion: biology, management, and clinical outcome.
Treatment-free remission after third-line therapy with asciminib in chronic myeloid leukemia with an atypical e19a2 BCR::ABL1 transcript and T315I mutation.
SLPI overexpression in hMSCs could be implicated in the HSC gene expression profile in AML.
Conditioning with anti-CD47 and anti-CD117 plus JAK inhibition enables toxic payload-free allogeneic transplantation.
LSD1/KDM1A and GFI1B repress endothelial fate and induce hematopoietic fate in induced pluripotent stem cell-derived hemogenic endotheliums.
Less is more: An analysis of venetoclax and hypomethylating agent post-induction treatment modifications in AML.
Isolation of Human Hematopoietic Stem Cells from an Apheresis Sample.
Momelotinib for the treatment of myelofibrosis.
Detection of PNH Clones can Aid in the Distinction of Aplastic Anemia vs Inherited BM Failure Syndromes: A Single Center Experience and Review of the Literature.
Identification of clonal relationship and prognostic significance in acute myeloid leukemia patients with concomitant increase in mast cells.
Distinct pattern of genomic breakpoints in CML and BCR::ABL1-positive ALL: analysis of 971 patients.
YTHDC1 m6A-dependent and m6A-independent functions converge to preserve the DNA damage response.
Homoharringtonine Inhibits the NOTCH/MYC Pathway and Exhibits Anti-Tumor Effects in T-Cell Acute Lymphoblastic Leukemia.
Novel MAGIC composite scores using both clinical symptoms and biomarkers best predict treatment outcomes of acute GVHD.
Outcome of Hematopoietic Stem Cell Transplantation in 813 Pediatric Patients with Fanconi Anemia.
Aberrant early hematopoietic progenitor formation marks the onset of hematopoietic defects in Shwachman-Diamond syndrome.
Perspectives on drug development for the treatment of chronic myeloid leukemia in pregnant patients and patients who are breastfeeding.
Targeting exhausted cytotoxic T cells through CTLA-4 inhibition promotes elimination of neoplastic cells in human myelofibrosis xenografts.
Nilotinib vs. Dasatinib in Achieving MR4.5 for de novo Chronic Myeloid Leukemia: the Randomized JALSG CML212 Study.
DCAF15 control of cohesin dynamics sustains acute myeloid leukemia.
Myeloproliferative Neoplasms Transcriptome Reveals Pro-Inflammatory Signature and Enrichment in Peripheral Blood Monocyte-Related Genes.
Interface-guided phenotyping of coding variants in the transcription factor RUNX1.
RISK-ADAPTED MRD-DIRECTED THERAPY FOR YOUNG ACUTE MYELOID LEUKEMIA ADULTS: 6-YEAR UPDATE OF THE GIMEMA AML1310 TRIAL.
Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening.
Epigenetic-based differentiation therapy for Acute Myeloid Leukemia.

Leuk Res. 2024 Jun 24. pii: S0145-2126(24)00113-9. [Epub ahead of print]144 107547

Combining the novel FLT3 and MERTK dual inhibitor MRX-2843 with venetoclax results in promising antileukemic activity against FLT3-ITD AML.

Shuangshuang Wu, Fangbing Liu, Yuqing Gai, Jenna Carter, Holly Edwards, Maik Hüttemann, Guan Wang, Chunhuai Li, Jeffrey W Taub, Yue Wang, Yubin Ge.

  FMS-like tyrosine kinase 3 (FLT3) mutations occur in approximately one third of acute myeloid leukemia (AML) patients. FLT3-Internal tandem duplication (FLT3-ITD) mutations are the most common FLT3 mutations and are associated with a poor prognosis. Gilteritinib is a FLT3 inhibitor that is US FDA approved for treating adult patients with relapsed/refractory AML and a FLT3 mutation. While gilteritinib monotherapy has improved patient outcome, few patients achieve durable responses. Combining gilteritinib with venetoclax (VEN) appears to make further improvements, though early results suggest that patients with prior exposure to VEN fair much worse than those without prior exposure. MRX-2843 is a promising inhibitor of FLT3 and MERTK. We recently demonstrated that MRX-2843 is equally potent as gilteritinib in FLT3-ITD AML cell lines in vitro and primary patient samples ex vivo. In this study, we investigated the combination of VEN and MRX-2843 against FLT3-ITD AML cells. We found that VEN synergistically enhances cell death induced by MRX-2843 in FLT3-mutated AML cell lines and primary patient samples. Importantly, we found that VEN synergistically enhances cell death induced by MRX-2843 in FLT3-ITD AML cells with acquired resistance to cytarabine (AraC) or VEN+AraC. VEN and MRX-2843 significantly reduce colony-forming capacity of FLT3-ITD primary AML cells. Mechanistic studies show that MRX-2843 decreases Mcl-1 and c-Myc protein levels via transcriptional regulation and combined MRX-2843 and VEN significantly decreases oxidative phosphorylation in FLT3-ITD AML cells. Our findings highlight a promising combination therapy against FLT3-ITD AML, supporting further in vitro and in vivo testing.

Keywords:  Acute myeloid leukemia; Bcl-2; FLT3-ITD; MRX-2843; Venetoclax

DOI:  https://doi.org/10.1016/j.leukres.2024.107547
Bone Marrow Transplant. 2024 Jul 03.

Tacrolimus versus cyclosporine a combined with post-transplantation cyclophosphamide for AML In first complete remission: a study from the acute leukemia working party (EBMT).

Gesine Bug, Myriam Labopin, Alexander Kulagin, Didier Blaise, Anna Maria Raiola, Jan Vydra, Simona Sica, Mi Kwon, Lucía López-Corral, Stefania Bramanti, Peter von dem Borne, Maija Itälä-Remes, Massimo Martino, Yener Koc, Eolia Brissot, Sebastian Giebel, Arnon Nagler, Fabio Ciceri, Mohamad Mohty.

Choice of calcineurin inhibitor may impact the outcome of patients undergoing T-cell replete hematopoietic cell transplantation (HCT) with post-transplant cyclophosphamide (PT-Cy) and mycophenolate mofetil (MMF) for prophylaxis of graft-versus-host disease (GVHD). We retrospectively analyzed 2427 patients with acute myeloid leukemia (AML) in first remission transplanted from a haploidentical (n = 1844) or unrelated donor (UD, n = 583) using cyclosporine A (CSA, 63%) or tacrolimus (TAC, 37%) and PT-Cy/MMF. In univariate analysis, CSA and TAC groups did not differ in 2-year leukemia-free or overall survival, cumulative incidence (CI) of relapse or non-relapse mortality. CI of severe grade III-IV acute GVHD was lower with TAC (6.6% vs. 9.1%, p = 0.02), without difference in grade II-IV acute GVHD or grade III-IV acute GVHD/severe chronic GVHD, relapse-free survival (GRFS). In multivariate analysis, TAC was associated with a lower risk of severe grade III-IV acute GVHD solely with haploidentical donors (HR 0.64 [95% CI, 0.42-0.98], p = 0.04), but not UD (HR 0.49 [95% CI, 0.2-1.21], p = 0.12). There was no significant difference for chronic GVHD. In conclusion, PT-Cy/MMF-based GVHD prophylaxis resulted in favorable OS and GRFS, irrespective of the CNI added. In haploidentical HCT, TAC seemed to prevent severe acute GVHD more effectively than CSA without impact on other outcome parameters.

DOI: https://doi.org/10.1038/s41409-024-02331-1
Blood. 2024 Jul 03. pii: blood.2023023727. [Epub ahead of print]

Molecular Taxonomy of Myelodysplastic Syndromes and its Clinical Implications.

Elsa Bernard, Robert P Hasserjian, Peter L Greenberg, Juan Esteban Arango Ossa, Maria Creignou, Heinz Tuechler, Jesús Gutiérrez-Abril, Dylan Domenico, Juan Santiago Medina-Martinez, Max Fine Levine, Konstantinos Liosis, Noushin Farnoud, Maria Sirenko, Martin Jädersten, Ulrich Germing, Guillermo F Sanz, Arjan A Van de Loosdrecht, Yasuhito Nannya, Olivier Kosmider, Matilde Y Follo, Felicitas R Thol, Lurdes Zamora, Ronald Feitosa Pinheiro, Andrea Pellagatti, Harold Kunal Elias, Detlef Thomas Haase, Christina Ganster, Lionel Ades, Magnus Tobiasson, Laura Palomo, Matteo Giovanni Della Porta, Pierre Fenaux, Monika Belickova, Michael R Savona, Virginia Klimek, Fabio P S Santos, Jacqueline Boultwood, Ioannis Kotsianidis, Valeria Santini, Francesc Sole, Uwe Platzbecker, Michael Heuser, Peter Valent, Carlo Finelli, Maria Teresa Voso, Lee Yung Shih, Michaela Fontenay, Joop H Jansen, José Cervera, Norbert Gattermann, Benjamin L Ebert, Rafael Bejar, Luca Malcovati, Seishi Ogawa, Mario Cazzola, Eva S Hellstrom-Lindberg, Elli Papaemmanuil.

Myelodysplastic syndromes/neoplasms (MDS) are clonal hematologic disorders characterized by morphologic abnormalities of myeloid cells and peripheral cytopenias. While genetic abnormalities underlie the pathogenesis of these disorders and their heterogeneity, current classifications of MDS rely predominantly on morphology. We performed genomic profiling of 3,233 patients with MDS or related disorders to delineate molecular subtypes and define their clinical implications. Gene mutations, copy-number alterations (CNAs), and copy-neutral loss of heterozygosity (cnLOH) were derived from targeted sequencing of a 152-gene panel, with abnormalities identified in 91, 43, and 11% of patients, respectively. We characterized 16 molecular groups, encompassing 86% of patients, using information from 21 genes, 6 cytogenetic events, and LOH at the TP53 and TET2 loci. Two residual groups defined by negative findings (molecularly not-otherwise specified, absence of recurrent drivers) comprised 14% of patients. The groups varied in size from 0.5% to 14% of patients and were associated with distinct clinical phenotypes and outcomes. The median bone marrow blast percentage across groups ranged from 1.5 to 10%, and the median overall survival from 0.9 to 8.2 years. We validated 5 well-characterized entities, added further evidence to support 3 previously reported subsets, and described 8 novel groups. The prognostic influence of bone marrow blasts depended on the genetic subtypes. Within genetic subgroups, therapy-related MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) had comparable clinical and outcome profiles to primary MDS. In conclusion, genetically-derived subgroups of MDS are clinically relevant and may inform future classification schemas and translational therapeutic research.

DOI: https://doi.org/10.1182/blood.2023023727
Leukemia. 2024 Jul 04.

Rearrangements involving 11q23.3/KMT2A in adult AML: mutational landscape and prognostic implications - a HARMONY study.

Alberto Hernández-Sánchez, Teresa González, Marta Sobas, Eric Sträng, Gastone Castellani, María Abáigar, Peter J M Valk, Ángela Villaverde Ramiro, Axel Benner, Klaus H Metzeler, Raúl Azibeiro, Jesse M Tettero, Joaquín Martínez-López, Marta Pratcorona, Javier Martínez Elicegui, Ken I Mills, Christian Thiede, Guillermo Sanz, Konstanze Döhner, Michael Heuser, Torsten Haferlach, Amin T Turki, Dirk Reinhardt, Renate Schulze-Rath, Martje Barbus, Jesús María Hernández-Rivas, Brian Huntly, Gert Ossenkoppele, Hartmut Döhner, Lars Bullinger.

Balanced rearrangements involving the KMT2A gene (KMT2Ar) are recurrent genetic abnormalities in acute myeloid leukemia (AML), but there is lack of consensus regarding the prognostic impact of different fusion partners. Moreover, prognostic implications of gene mutations co-occurring with KMT2Ar are not established. From the HARMONY AML database 205 KMT2Ar adult patients were selected, 185 of whom had mutational information by a panel-based next-generation sequencing analysis. Overall survival (OS) was similar across the different translocations, including t(9;11)(p21.3;q23.3)/KMT2A::MLLT3 (p = 0.756). However, independent prognostic factors for OS in intensively treated patients were age >60 years (HR 2.1, p = 0.001), secondary AML (HR 2.2, p = 0.043), DNMT3A-mut (HR 2.1, p = 0.047) and KRAS-mut (HR 2.0, p = 0.005). In the subset of patients with de novo AML < 60 years, KRAS and TP53 were the prognostically most relevant mutated genes, as patients with a mutation of any of those two genes had a lower complete remission rate (50% vs 86%, p < 0.001) and inferior OS (median 7 vs 30 months, p < 0.001). Allogeneic hematopoietic stem cell transplantation in first complete remission was able to improve OS (p = 0.003). Our study highlights the importance of the mutational patterns in adult KMT2Ar AML and provides new insights into more accurate prognostic stratification of these patients.

DOI: https://doi.org/10.1038/s41375-024-02333-4
Blood Adv. 2024 Jul 02. pii: bloodadvances.2023011747. [Epub ahead of print]

Genetic deletion of JAM-C in pre-leukemic cells rewires leukemic stem cell gene expression program in AML.

Julien M P Grenier, Céline Testut, Matthieu Bal, Florence Bardin, Maria De Grandis, Véronique Gelsi-Boyer, Julien Vernerny, Marjorie C Delahaye, Samuel Granjeaud, Christophe Zemmour, Jean-François Spinella, Triantafyllos Chavakis, Stephane Jc Mancini, Jean-Marie Boher, Josée Hébert, Guy Sauvageau, Norbert Vey, Juerg Schwaller, Marie-Anne Hospital, Cyril Fauriat, Michel A Aurrand-Lions.

The leukemic stem cell (LSC) score LSC-17 based on a stemness-related gene expression signature is an indicator of poor disease outcome in acute myeloid leukemia (AML). However, our understanding of the relationships between LSC and pre-leukemic cells is still incomplete. In particular, it is not known whether "niche-anchoring" of pre-leukemic cell affects disease evolution. To address this issue, we conditionally inactivated the adhesion molecule JAM-C expressed by haematopoietic stem cells (HSC) and LSC in an inducible iMLL-AF9-driven AML mouse model. Deletion of Jam3 (encoding JAM-C) before induction of the leukemia-initiating iMLL-AF9 fusion resulted in a shift from long term to short term-HSC expansion, without affecting disease initiation and progression. In vitro experiments showed that JAM-C controlled leukemic cell nesting irrespective of the bone marrow stromal cells used. RNA sequencing performed on leukemic HSC isolated from diseased mice revealed that genes upregulated in Jam3-deficient animals belonged to Activation Protein-1 (AP-1) and TNF-/NFB pathways. Human orthologs of dysregulated genes allowed to identify a score based on AP-1/TNF-a gene expression that was distinct and complementary from LSC-17 score. Sub-stratification of AML patients with LSC-17 and AP-1/TNF-genes signature defined four groups with median survival ranging from below one year to a median not reached after 8 years. Finally, coculture experiments showed that AP-1 activation in leukemic cells was dependent on the nature of stromal cells. Altogether, our results identify the AP-1/TNF- gene signature as a proxy of LSC anchoring in specific bone marrow niches which improves the prognosis value of the LSC-17 score. NCT02320656.

DOI: https://doi.org/10.1182/bloodadvances.2023011747
J Clin Invest. 2024 Jun 17. pii: e169245. [Epub ahead of print]134(12):

Alkynyl nicotinamides show antileukemic activity in drug-resistant acute myeloid leukemia.

Baskar Ramdas, Neetu Dayal, Ruchi Pandey, Elizabeth Larocque, Rahul Kanumuri, Santhosh Kumar Pasupuleti, Sheng Liu, Chrysi Kanellopoulou, Elizabeth Fei Yin Chu, Rodrigo Mohallem, Saniya Virani, Gaurav Chopra, Uma K Aryal, Rena Lapidus, Jun Wan, Ashkan Emadi, Laura S Haneline, Frederick W Holtsberg, M Javad Aman, Herman O Sintim, Reuben Kapur.

  Activating mutations of FLT3 contribute to deregulated hematopoietic stem and progenitor cell (HSC/Ps) growth and survival in patients with acute myeloid leukemia (AML), leading to poor overall survival. AML patients treated with investigational drugs targeting mutant FLT3, including Quizartinib and Crenolanib, develop resistance to these drugs. Development of resistance is largely due to acquisition of cooccurring mutations and activation of additional survival pathways, as well as emergence of additional FLT3 mutations. Despite the high prevalence of FLT3 mutations and their clinical significance in AML, there are few targeted therapeutic options available. We have identified 2 novel nicotinamide-based FLT3 inhibitors (HSN608 and HSN748) that target FLT3 mutations at subnanomolar concentrations and are potently effective against drug-resistant secondary mutations of FLT3. These compounds show antileukemic activity against FLT3ITD in drug-resistant AML, relapsed/refractory AML, and in AML bearing a combination of epigenetic mutations of TET2 along with FLT3ITD. We demonstrate that HSN748 outperformed the FDA-approved FLT3 inhibitor Gilteritinib in terms of inhibitory activity against FLT3ITD in vivo.

Keywords:  Hematology; Hematopoietic stem cells; Stem cells

DOI:  https://doi.org/10.1172/JCI169245
Ann Hematol. 2024 Jul 05.

FRACTION: protocol of a phase II study of Fedratinib and Nivolumab combination in patients with myelofibrosis and resistance or suboptimal response to JAK-inhibitor treatment of the German MPN study group (GSG-MPN).

Susanne Isfort, Nikolas von Bubnoff, Haifa Kathrin Al-Ali, Heiko Becker, Thorsten Götze, Philipp le Coutre, Martin Griesshammer, Claudia Moskwa, Luisa Wohn, Johanna Riedel, Francesca Palandri, Kirsi Manz, Andreas Hochhaus, Konstanze Döhner, Florian H Heidel.

  Development of Janus-kinase (JAK) inhibitors has revolutionized the therapeutic landscape for patients with myeloproliferative neoplasia (MPN). Following approval of the first JAK1/2-inhibitor Ruxolitinib, symptoms of this inflammatory disease, characterized by splenomegaly, release of inflammatory cytokines and appearance of thrombosis, could be effectively reduced for the first time. However, JAK-inhibitor treatment is limited in several aspects: 1) duration of response: 3 years after initiation of therapy more than 50% of patients have discontinued JAK-inhibitor treatment due to lack of efficacy or resistance; 2) reduction of disease burden: while effective in reducing inflammation and constitutional symptoms, JAK-inhibitors fail to reduce the malignant clone in the majority of patients and therefore lack long-term efficacy. Early clinical trials for patients with myelofibrosis (MF) have tried to address these issues for patients with suboptimal response to Ruxolitinib therapy while combination therapies with Fedratinib are rare. Recent reports provided first evidence on how the JAK2-V617F mutated myeloid cells may influence T-cell responses. JAK2-V617F promoted the synthesis of PD-L1 in MPN cells leading to limited anti-neoplastic T-cell responses, metabolic changes in T-cells and eventually JAK2-V617F-driven immune-escape of MPN cells. These findings may facilitate the use of immunotherapeutic approaches for JAK-mutated clones. Immune checkpoints refer to a variety of inhibitory pathways that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. The FRACTION study is a single arm, open label Phase II trial investigating the combination of Fedratinib with the PD-1 inhibitor Nivolumab in patients with myelofibrosis and suboptimal or lack of response to JAK-inhibitor therapy. Over a 12 months period the trial assesses longer term outcomes, particularly the effects on clinical outcomes, such as induction of clinical remissions, quality of life and improvement of anemia. No prospective clinical trial data exist for combinations of JAK- and immune-checkpoint-inhibitors in the planned MF study population and this study will provide new findings that may contribute to advancing the treatment landscape for MF patients with suboptimal responses and limited alternatives.

Keywords:  Checkpoint-inhibitor; Disease modification; Fedratinib; Myelofibrosis (MF); Myeloproliferative Neoplasms (MPN); Nivolumab

DOI:  https://doi.org/10.1007/s00277-024-05867-w
Int J Hematol. 2024 Jul 04.

High-dose cytarabine plus gemtuzumab ozogamicin as consolidation therapy in patients with favorable- or intermediate-risk acute myeloid leukemia.

Shuki Oya, Hidetoshi Ozawa, Satoshi Morishige, Yoshimi Maehiro, Masahiro Umeda, Yusuke Takaki, Toshinobu Fukuyama, Yoshitaka Yamasaki, Takayuki Nakamura, Maki Yamaguchi, Kazutoshi Aoyama, Fumihiko Mouri, Koji Nagafuji.

  Previous prospective randomized trials have investigated the efficacy of gemtuzumab ozogamicin in the frontline treatment of acute myeloid leukemia (AML). We evaluated the efficacy of high-dose cytarabine with GO as consolidation therapy in 20 patients with favorable- or intermediate-risk AML in first complete remission. They included six patients with wild-type nucleophosmin (NPM1) core binding factor (CBF), ten with NPM1-mutated non-CBF, and four with wild-type NPM1 non-CBF. The median follow-up for the entire cohort was 62.0 months. The three-year overall survival (OS) and relapse-free survival (RFS) rates were 72.2% and 77.8%, respectively. OS and RFS were significantly higher for NPM1-mutated non-CBF AML than for wild-type NPM1 non-CBF AML (p = 0.001). We also examined the CD33 single-nucleotide polymorphism (SNP) rs12459419, which has been reported to influence the therapeutic efficacy of GO and CD33 expression. The CD33 expression ratio was higher in CD33 SNP C/C than in C/T (83.1% vs. 49.8%, p = 0.035), but 3-year OS and RFS did not differ significantly. These results suggest that consolidation therapy with high-dose cytarabine plus GO is highly effective in transplant-ineligible elderly patients and may be a reasonable treatment, especially for NPM1-mutated AML.

Keywords:   NPM1-mutated AML; Consolidation therapy; Gemtuzumab ozogamicin

DOI:  https://doi.org/10.1007/s12185-024-03814-z
Leuk Lymphoma. 2024 Jul 04. 1-11

Acute myeloid leukemia (AML) with chromosome 3 inversion: biology, management, and clinical outcome.

Abdulrahman Alhajahjeh, Jan Philipp Bewersdorf, Rebecca P Bystrom, Amer M Zeidan, Shai Shimony, Maximilian Stahl.

  Acute myeloid leukemia (AML) is a complex hematological malignancy characterized by diverse genetic alterations, each with distinct clinical implications. Chromosome 3 inversion (inv(3)) is a rare genetic anomaly found in approximately 1.4-1.6% of AML cases, which profoundly affects prognosis. This review explores the pathophysiology of inv(3) AML, focusing on fusion genes like GATA2::EVI1 or GATA2::MECOM. These genetic rearrangements disrupt critical cellular processes and lead to leukemia development. Current treatment modalities, including intensive chemotherapy (IC), hypomethylating agents (HMAs) combined with venetoclax, and allogeneic stem cell transplantation are discussed, highlighting outcomes achieved and their limitations. The review also addresses subgroups of inv(3) AML, describing additional mutations and their impact on treatment response. The poor prognosis associated with inv(3) AML underscores the urgent need to develop more potent therapies for this AML subtype. This comprehensive overview aims to contribute to a deeper understanding of inv(3) AML and guide future research and treatment strategies.

Keywords:  Acute myeloid leukemia (AML); chromosome abnormality; hematological malignancy; high-risk group

DOI:  https://doi.org/10.1080/10428194.2024.2367040
Leukemia. 2024 Jul 04.

Treatment-free remission after third-line therapy with asciminib in chronic myeloid leukemia with an atypical e19a2 BCR::ABL1 transcript and T315I mutation.

Philipp Ernst, Jenny Rinke, Georg-Nikolaus Franke, Frank Dicker, Torsten Haferlach, Thomas Ernst, Andreas Hochhaus.

DOI: https://doi.org/10.1038/s41375-024-02327-2
Sci Rep. 2024 Jul 05. 14(1): 15550

SLPI overexpression in hMSCs could be implicated in the HSC gene expression profile in AML.

Pedro L Azevedo, Simone Maradei, Ricardo de Sá Bigni, Jordana Santos Ramires Aragao, Eliana Abdelhay, Renata Binato.

Acute myeloid leukaemia (AML) is a severe haematological neoplasm that originates from the transformation of haematopoietic stem cells (HSCs) into leukaemic stem cells (LSCs). The bone marrow (BM) microenvironment, particularly that of mesenchymal stromal cells (hMSCs), plays a crucial role in the maintenance of HSCs. In this context, we explored whether alterations in the secretome of hMSCs derived from AML patients (hMSC-AML) could impact HSC gene expression. Proteomic analysis revealed that the secretome of coculture assays with hMSC-AMLs and HSC from healthy donor is altered, with increased levels of secretory leukocyte protease inhibitor (SLPI), a protein associated with important processes for maintenance of the haematopoietic niche that has already been described to be altered in several tumours. Increased SLPI expression was also observed in the BM plasma of AML patients. Transcriptome analysis of HSCs cocultured with hMSC-AML in comparison with HSCs cocultured with hMSC-HD revealed altered expression of SLPI target genes associated with the cell cycle, proliferation, and apoptosis. Important changes were identified, such as increased expression levels of CCNA2, CCNE2, CCND2, CD133 and CDK1 and decreased levels of CDKN2A and IGFBP3, among others. Overall, these findings suggest that the altered secretome of coculture assays with hMSC-AMLs and HSC from healthy donor, particularly increased SLPI expression, can contribute to gene expression changes in HSCs, potentially influencing important molecular mechanisms related to AML development and progression.

DOI: https://doi.org/10.1038/s41598-024-66400-7
Blood Adv. 2024 Jul 05. pii: bloodadvances.2023012457. [Epub ahead of print]

Conditioning with anti-CD47 and anti-CD117 plus JAK inhibition enables toxic payload-free allogeneic transplantation.

Stephen P Persaud, Aditya R Yelamali, Julie K Ritchey, John F DiPersio.

DOI: https://doi.org/10.1182/bloodadvances.2023012457
Haematologica. 2024 Jul 04.

LSD1/KDM1A and GFI1B repress endothelial fate and induce hematopoietic fate in induced pluripotent stem cell-derived hemogenic endotheliums.

Huan Zhang, Marten Hansen, Franca Di Summa, Marieke Von Lindern, Nynke Gillemans, Wilfred F J Van IJcken, Arthur Flohr Svendsen, Sjaak Philipsen, Bert Van der Reijden, Eszter Varga, Emile Van den Akker.

Differentiation of induced pluripotent stem cells (iPSCs) into hematopoietic lineages offers great therapeutic potential. During embryogenesis, hemogenic endothelium (HE) gives rise to hematopoietic stem and progenitor cells through the endothelial-to-hematopoietic transition (EHT). Understanding this process using iPSCs is key to generating functional hematopoietic stem cells (HSCs), a currently unmet challenge. In this study, we examined the role of the transcriptional factor GFI1B and its co-factor LSD1/KDM1A in EHT. To this end, we employed patient-derived iPSC lines with a dominant negative dysfunctional GFI1BQ287* and irreversible pharmacological LSD1/KDM1A inhibition in healthy iPSC lines. The formation of HE remained unaffected; however, hematopoietic output was severely reduced in both conditions. Single-cell RNA sequencing (scRNAseq) performed on the CD144+/CD31+ population derived from healthy iPSCs revealed similar expression dynamics of genes associated with in vivo EHT. Interestingly, LSD1/KDM1A inhibition in healthy lines before EHT resulted in a complete absence of hematopoietic output. However, uncommitted HE cells did not display GFI1B expression, suggesting a timed transcriptional program. To test this hypothesis, we ectopically expressed GFI1B in uncommitted HE cells, leading to downregulation of endothelial genes and upregulation of hematopoietic genes, including GATA2, KIT, RUNX1, and SPI1. Thus, we demonstrate that LSD1/KDM1A and GFI1B can function at distinct temporal points in different cellular subsets during EHT. Although GFI1B is not detected in uncommitted HE cells, its ectopic expression allows for partial hematopoietic specification. These data indicate that precisely timed expression of specific transcriptional regulators during EHT is crucial to the eventual outcome of EHT.

DOI: https://doi.org/10.3324/haematol.2024.285214
Leuk Res. 2024 Jun 21. pii: S0145-2126(24)00111-5. [Epub ahead of print]143 107545

Less is more: An analysis of venetoclax and hypomethylating agent post-induction treatment modifications in AML.

Stephanie Boisclair, Edward Zhou, Phyu Naing, Richa Thakur, Erin Jou, Bradley Goldberg, Douglas E Gladstone, Steven L Allen, Jonathan E Kolitz, David W Chitty.

  Venetoclax (Ven) combined with a hypomethylating agent (HMA) enhances survival in elderly/unfit acute myeloid leukemia (AML) patients, yet often necessitates regimen modifications due to intolerance. However, it is unclear how these modifications affect patient outcome. This retrospective cohort study evaluates the impact of post-induction HMA/Ven regimen modifications on disease progression and survival. This study reviewed 142 AML patients treated with HMA/Ven within the Northwell Health System from January 2019 to December 2022. To assess the impact of post-induction regimen modifications, patients were grouped according to median days between cycles (≤34 or ≥35 days cycle intervals) and median Ven days per cycle (≤14 or ≥15 days/cycle) based on only cycle 3 and beyond. Kaplan-Meier and Cox proportional hazard regression analyses were employed for univariate and multivariate assessments, respectively. There was no significant difference in median progression-free survival (mPFS)(11.6 vs 11.8 months, p = 0.73) or median overall survival (mOS)(15.1 vs 21.8 months, p = 0.16) between cycle interval groups. However, there was a clinically and statistically significant advantage in mPFS (15.8 vs 8.7 months, p = 0.01) and mOS (24.7 vs 11.3 months, p = 0.006) for patients with a median of ≤14 Ven days/cycle compared to ≥15 Ven days/cycle. Multivariate analysis demonstrated that ≤14 days of Ven for cycle 3 and beyond was an independent predictor of decreased mortality (HR 0.18, CI 0.07-0.48, p = 0.0007). Extended cycle intervals did not adversely affect mortality while reduced Ven duration per cycle post-induction was associated with improved survival in elderly AML patients.

Keywords:  Acute myeloid leukemia; Hypomethylating agents; Survival outcomes; Venetoclax

DOI:  https://doi.org/10.1016/j.leukres.2024.107545
Methods Mol Biol. 2024 Jul 06.

Isolation of Human Hematopoietic Stem Cells from an Apheresis Sample.

Pınar Siyah, Fatih Kocabaş.

  The hematopoietic system constantly produces new blood cells through hematopoiesis, and maintaining this balance is vital for human health. This balance is maintained by self-renewing hematopoietic stem cells (HSCs) and various progenitor cells. Under typical circumstances, HSCs are not abundantly found in peripheral blood; hence, their mobilization from the bone marrow is vital. Hematopoietic growth factors achieve this effectively, enabling mobilization and thus allowing blood sample and thus HSC collection via apheresis. Securing a sufficient supply of HSCs is vital for successful hematopoietic reconstitution and the rapid integration of committed cells. Thus, isolation and expansion of HSCs are crucial for convenient extraction, production of transplantable quantities, genetic modifications for enhanced therapeutic efficacy, and as a source of increased/expanded/synthesized blood cells in vitro. In conclusion, the isolation and expansion of HSCs play pivotal roles in both regenerative medicine and hematology. This protocol describes the isolation of human HSCs by providing an overview of the primary method for isolating human hematopoietic stem cells from apheresis blood samples and sheds light on human HSC studies and developments in research and medicine.

Keywords:  Apheresis; HSC isolation; Hematopoiesis; Hematopoietic stem cell transplantation (HSCT); Hematopoietic stem cells; Peripheral blood; Stem cell expansion

DOI:  https://doi.org/10.1007/7651_2024_557
Blood. 2024 Jul 03. pii: blood.2023023719. [Epub ahead of print]

Momelotinib for the treatment of myelofibrosis.

Prithviraj Bose.

In September 2023, the Food and Drug Administration approved momelotinib for the treatment of myelofibrosis (MF) with anemia, marking the fourth US regulatory approval of a Janus kinase (JAK) inhibitor for MF. A positive opinion from the European Medicines Agency followed in November 2023. Momelotinib's ability to address splenomegaly, symptoms and anemia, including in thrombocytopenic patients (platelets ≥25 x 109/L), the ease of switching from ruxolitinib, and good tolerability uniquely position it to substantially impact the MF treatment landscape.

DOI: https://doi.org/10.1182/blood.2023023719
Clin Lymphoma Myeloma Leuk. 2024 Jun 12. pii: S2152-2650(24)00228-3. [Epub ahead of print]

Detection of PNH Clones can Aid in the Distinction of Aplastic Anemia vs Inherited BM Failure Syndromes: A Single Center Experience and Review of the Literature.

Patrice Nasnas, Jianhua Ling, Yoheved Gerstein, Sa A Wang, Sanam Loghavi, Danielle Hammond, Guillermo Montalban-Bravo, Jayastu Senapati, Naveen Pemmaraju, Jessie Corredor, Sherry Pierce, Michael Roth, Farhad Ravandi, Branko Cuglievan, Tapan Kadia, Courtney D DiNardo.



Keywords:  Diagnosis; Flow cytometry; Similar entities; Therapy outcome

DOI:  https://doi.org/10.1016/j.clml.2024.06.001
Leuk Res. 2024 Jun 19. pii: S0145-2126(24)00105-X. [Epub ahead of print]143 107539

Identification of clonal relationship and prognostic significance in acute myeloid leukemia patients with concomitant increase in mast cells.

Zhifang Xu, Ting Zhang, Jian Hao, Dan Liu, Minglin Hong, Shaotong Dong, Ju Deng, Fanggang Ren, Yaofang Zhang, Hongwei Wang.



Keywords:  Acute myeloid leukemia (AML); Droplet digital polymerase chain reaction (dd PCR); Flow cytometry (FCM); KIT mutations; Mast cells (MC); Prognosis

DOI:  https://doi.org/10.1016/j.leukres.2024.107539
Mol Cancer. 2024 Jul 05. 23(1): 138

Distinct pattern of genomic breakpoints in CML and BCR::ABL1-positive ALL: analysis of 971 patients.

Lenka Hovorkova, Lucie Winkowska, Justina Skorepova, Manuela Krumbholz, Adela Benesova, Vaclava Polivkova, Julia Alten, Michela Bardini, Claus Meyer, Rathana Kim, Toby N Trahair, Emmanuelle Clappier, Sabina Chiaretti, Michelle Henderson, Rosemary Sutton, Lucie Sramkova, Jan Stary, Katerina Machova Polakova, Rolf Marschalek, Markus Metzler, Giovanni Cazzaniga, Gunnar Cario, Jan Trka, Marketa Zaliova, Jan Zuna.

   BACKGROUND: The BCR::ABL1 is a hallmark of chronic myeloid leukemia (CML) and is also found in acute lymphoblastic leukemia (ALL). Most genomic breaks on the BCR side occur in two regions - Major and minor - leading to p210 and p190 fusion proteins, respectively.
METHODS: By multiplex long-distance PCR or next-generation sequencing technology we characterized the BCR::ABL1 genomic fusion in 971 patients (adults and children, with CML and ALL: pediatric ALL: n = 353; pediatric CML: n = 197; adult ALL: n = 166; adult CML: n = 255 patients) and designed "Break-App" web tool to allow visualization and various analyses of the breakpoints. Pearson's Chi-Squared test, Kolmogorov-Smirnov test and logistic regression were used for statistical analyses.
RESULTS: Detailed analysis showed a non-random distribution of breaks in both BCR regions, whereas ABL1 breaks were distributed more evenly. However, we found a significant difference in the distribution of breaks between CML and ALL. We found no association of breakpoints with any type of interspersed repeats or DNA motifs. With a few exceptions, the primary structure of the fusions suggests non-homologous end joining being responsible for the BCR and ABL1 gene fusions. Analysis of reciprocal ABL1::BCR fusions in 453 patients showed mostly balanced translocations without major deletions or duplications.
CONCLUSIONS: Taken together, our data suggest that physical colocalization and chromatin accessibility, which change with the developmental stage of the cell (hence the difference between ALL and CML), are more critical factors influencing breakpoint localization than presence of specific DNA motifs.

Keywords:  ABL1; Acute lymphoblastic leukemia; BCR; Chronic myeloid leukemia; Genomic breakpoints

DOI:  https://doi.org/10.1186/s12943-024-02053-4
EMBO J. 2024 Jul 01.

YTHDC1 m6A-dependent and m6A-independent functions converge to preserve the DNA damage response.

Daniel Elvira-Blázquez, José Miguel Fernández-Justel, Aida Arcas, Luisa Statello, Enrique Goñi, Jovanna González, Benedetta Ricci, Sara Zaccara, Ivan Raimondi, Maite Huarte.

  Cells have evolved a robust and highly regulated DNA damage response to preserve their genomic integrity. Although increasing evidence highlights the relevance of RNA regulation, our understanding of its impact on a fully efficient DNA damage response remains limited. Here, through a targeted CRISPR-knockout screen, we identify RNA-binding proteins and modifiers that participate in the p53 response. Among the top hits, we find the m6A reader YTHDC1 as a master regulator of p53 expression. YTHDC1 binds to the transcription start sites of TP53 and other genes involved in the DNA damage response, promoting their transcriptional elongation. YTHDC1 deficiency also causes the retention of introns and therefore aberrant protein production of key DNA damage factors. While YTHDC1-mediated intron retention requires m6A, TP53 transcriptional pause-release is promoted by YTHDC1 independently of m6A. Depletion of YTHDC1 causes genomic instability and aberrant cancer cell proliferation mediated by genes regulated by YTHDC1. Our results uncover YTHDC1 as an orchestrator of the DNA damage response through distinct mechanisms of co-transcriptional mRNA regulation.

Keywords:  DDR; RNAPII Pausing; Splicing; YTHDC1; p53

DOI:  https://doi.org/10.1038/s44318-024-00153-x
Blood. 2024 Jul 05. pii: blood.2023023400. [Epub ahead of print]

Homoharringtonine Inhibits the NOTCH/MYC Pathway and Exhibits Anti-Tumor Effects in T-Cell Acute Lymphoblastic Leukemia.

Shanshan Suo, Dandan Zhao, Fenglin Li, Yi Zhang, Sonia Rodriguez-Rodriguez, Le Xuan Truong Truong Nguyen, Lucy Y Ghoda, Nadia Carlesso, Guido Marcucci, Bin Zhang, Jie Jin.

We report on the antileukemic activity of homoharringtonine (HHT) in T-ALL. We showed that HHT inhibited NOTCH/MYC pathway and induced a significantly longer survival in T-ALL mouse and patient-derived xenograft models, therefore supporting HHT as a promising agent for T-ALL.

DOI: https://doi.org/10.1182/blood.2023023400
Blood. 2024 Jul 05. pii: blood.2024025106. [Epub ahead of print]

Novel MAGIC composite scores using both clinical symptoms and biomarkers best predict treatment outcomes of acute GVHD.

Yu Akahoshi, Nikolaos Spyrou, Daniela Weber, Paibel Aguayo-Hiraldo, Francis Ayuketang Ayuk, Chantiya Chanswangphuwana, Hannah K Choe, Matthias Eder, Aaron M Etra, Stephan A Grupp, Elizabeth O Hexner, William J Hogan, Carrie L Kitko, Sabrina Kraus, Monzr M Al Malki, Pietro Merli, Muna Qayed, Ran Reshef, Tal Schechter, Evelyn Ullrich, Ingrid Vasova, Matthias Wölfl, Robert Zeiser, Janna Baez, Rahnuma Beheshti, Gilbert W Eng, Sigrun Gleich, Nikolaos Katsivelos, Steven Kowalyk, George Morales, Rachel Young, Yi-Bin Chen, Ryotaro Nakamura, John E Levine, James L M Ferrara.

Acute graft-vs-host disease (GVHD) grading systems that use only clinical symptoms at treatment initiation such as Minnesota risk identify standard and high risk categories but lack a low risk category suitable to minimize immunosuppressive strategies. We developed a new grading system that includes a low risk stratum based on clinical symptoms alone and determined whether the incorporation of biomarkers would improve the model's prognostic accuracy. We randomly divided 1863 patients in the Mount Sinai Acute GVHD International Consortium (MAGIC) who were treated for GVHD into training and validation cohorts. Patients in the training cohort were divided into 14 groups based on similarity of clinical symptoms and similar NRM; we used a classification and regression tree (CART) algorithm to create three Manhattan risk groups that produced a significantly higher area under the receiver operating characteristic curve (AUC) for 6-month NRM than the Minnesota risk classification (0.69 vs. 0.64, P=0.009) in the validation cohort. We integrated serum GVHD biomarker scores with Manhattan risk using patients with available serum samples and again used a CART algorithm to establish three MAGIC composite scores that significantly improved prediction of NRM compared to Manhattan risk (AUC, 0.76 vs. 0.70, P=0.010). Each increase in MAGIC composite score also corresponded to a significant decrease in day 28 treatment response (80% vs. 63% vs. 30%, P<0.001). We conclude that the MAGIC composite score more accurately predicts response to therapy and long term outcomes than systems based on clinical symptoms alone and may help guide clinical decisions and trial design.

DOI: https://doi.org/10.1182/blood.2024025106
Blood. 2024 Jul 05. pii: blood.2023022751. [Epub ahead of print]

Outcome of Hematopoietic Stem Cell Transplantation in 813 Pediatric Patients with Fanconi Anemia.

Su Han Lum, Diderik-Jan Eikema, Brian Piepenbroek, Robert Wynn, Sujith Samarasinghe, Arnaud Dalissier, Krzysztof Kałwak, Mouhab F Ayas, Rose-Marie Hamladji, M Akif Yeşilipek, Jean-Hugues Dalle, Duygu Uckan-Cetinkaya, Marc B Bierings, Osman Alphan Kupesiz, Khalid Halahleh, Elena Skorobogatova, Gülyüz Öztürk, Maura Faraci, Cecile Renard, Pamela Evans, Selim Corbacioglu, Franco Locatelli, Carlo Dufour, Antonio Maria Risitano, Régis Peffault de Latour.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only established curative option for Fanconi anemia (FA) associated bone marrow failure (BMF)/aplastic anemia (AA) and hematological malignancy. We performed a retrospective multicenter study on 813 FA children undergoing first HSCT between 2010 and 2018. Median duration of follow-up was 3.7 years (interquartile range, 3.4-4.0). Median age at transplant was 8.8 years (6.5-18.1). Overall survival (OS), event-free survival (EFS) and GvHD-free, relapse-free survival (GRFS) at 5 years were 83% (80-86%), 78% (75-81%) and 70% (67-74%) respectively. OS was comparable between matched family donor (MFD, n=441, 88%) and matched unrelated donor (MUD, n=162, 86%) and was superior to that of mismatched family or unrelated donor (MMFD/MMUD, n=144, 72%) and haploidentical donor (HID) (n=66, 70%, p<0.001). In multivariable analysis, a transplant indication of acute myeloid leukaemia/myelodysplastic syndrome compared to AA/BMF, use of MMFD/MMUD and HID compared to MFD, Fludarabine-Cyclophosphamide (FluCy) + other conditioning compared to FluCy independently predicted inferior OS, while alemtuzumab compared to ATG was associated with better OS. Age  10 years was associated with worse EFS and GRFS. Cumulative incidences (CIN) of primary and secondary graft failure were 2% (1-3%) and 3% (2-4%) respectively. CIN of grade II-IV acute GvHD, grade III-IV acute GvHD and chronic GvHD were 23% (20-26%), 12% (10-15%) and 8% (6-10%) respectively. The 5-year CIN of secondary malignancy was 2% (1-3%). These data suggest that HSCT should be offered to Fanconi Anemia patients with AA/BMF at a younger age in the presence of a well-matched donor.

DOI: https://doi.org/10.1182/blood.2023022751
Eur J Haematol. 2024 Jul 05.

Aberrant early hematopoietic progenitor formation marks the onset of hematopoietic defects in Shwachman-Diamond syndrome.

Alejandra Lagos-Monzon, Stephanie Ng, Alice M Luca, Hongbing Li, Mathura Sabanayagam, Mariana Benicio, Houtan Moshiri, Richard Armstrong, Chetan Tailor, Marion Kennedy, Eyal Grunebaum, Gordon Keller, Yigal Dror.

  Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure disorder that often presents at infancy. Progress has been made in revealing causal mutated genes (SBDS and others), ribosome defects, and hematopoietic aberrations in SDS. However, the mechanism underlying the hematopoietic failure remained unknown, and treatment options are limited. Herein, we investigated the onset of SDS embryonic hematopoietic impairments. We generated SDS and control human-derived induced pluripotent stem cells (iPSCs). SDS iPSCs recapitulated the SDS hematological phenotype. Detailed stepwise evaluation of definitive hematopoiesis revealed defects that started at the early emerging hematopoietic progenitor (EHP) stage after mesoderm and hemogenic endothelium were normally induced. Hematopoietic potential of EHPs was markedly reduced, and the introduction of SBDS in SDS iPSCs improved colony formation. Transcriptome analysis revealed reduced expression of ribosome and oxidative phosphorylation-related genes in undifferentiated and differentiated iPSCs. However, certain pathways (e.g., DNA replication) and genes (e.g., CHCHD2) were exclusively or more severely dysregulated in EHPs compared with earlier and later stages. To our knowledge, this study offers for the first time an insight into the embryonic onset of human hematopoietic defects in an inherited bone marrow failure syndrome and reveals cellular and molecular aberrations at critical stages of hematopoietic development toward EHPs.

Keywords:  Shwachman–Diamond syndrome; bone marrow failure; differentiation; disease modelling; hematopoietic stem cell; human induced pluripotent stem cells; transcriptional analysis

DOI:  https://doi.org/10.1111/ejh.14260
Clin Cancer Res. 2024 Jul 05.

Perspectives on drug development for the treatment of chronic myeloid leukemia in pregnant patients and patients who are breastfeeding.

Jorge E Cortes, Elisabetta Abruzzese, Elyce H Cardonick, Sonia Hernandez-Diaz, Jamie Gutierrez, Mary Sullivan Sardegna, Erica Torres-Chavez, Miriam Dinatale, Catherine C Lerro, Brenda J Gehrke, Stacy S Shord, R Angelo de Claro, Marc R Theoret, Peter J DeMaria, Kelly J Norsworthy.

Tyrosine kinase inhibitors (TKI) have improved the outcome and life expectancy of patients with chronic myeloid leukemia (CML). Patients are diagnosed with CML at younger ages, and patients treated for CML may become pregnant or choose to breastfeed. The information available to date on the safety of TKIs during pregnancy and lactation and the optimal management of these patients is largely anecdotal, based on personal or small-group experience, and heterogeneous. A panel of interested parties was convened by US Food and Drug Administration (FDA) to analyze the current data and discuss possible solutions. Possible solutions include prospective data collection, in clinical trials and in routine clinical practice, a more uniform and specific data collection, and greater coordination among involved entities. Since patients with cancer are living longer, frequently receiving therapies for extended periods of time (or for life), data on appropriate management of patients through different reproductive phases of life are needed. It is thus time to change our approach for how to study treatment of cancer (including CML) during pregnancy or breastfeeding to develop evidence-based guidelines for safe and effective patient care.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-0826
Am J Hematol. 2024 Jul 02.

Targeting exhausted cytotoxic T cells through CTLA-4 inhibition promotes elimination of neoplastic cells in human myelofibrosis xenografts.

MYNERVA (Myeloid NEoplasms Research Venture AIRC) investigators

Myeloproliferative neoplasms represent a group of clonal hematopoietic disorders of which myelofibrosis (MF) is the most aggressive. In the context of myeloid neoplasms, there is a growing recognition of the dysregulation of immune response and T-cell function as significant contributors to disease progression and immune evasion. We investigated cytotoxic T-cell exhaustion in MF to restore immune response against malignant cells. Increased expression of inhibitory receptors like CTLA-4 was observed on cytotoxic T cells from MF patients together with a reduced secretion of IFNɣ and TNFɑ. CTLA-4 ligands CD80 and CD86 were increased on MF granulocytes and monocytes highlighting a possible role for myeloid cells in suppressing T-cell activation in MF patients. Unlike healthy donors, the activation of cytotoxic T cells from MF patients was attenuated in the presence of myeloid cells and restored when T cells were cultured alone or treated with anti-CTLA-4. Moreover, anti-CTLA-4 treatment promoted elimination of neoplastic monocytes and granulocytes in a co-culture system with cytotoxic T cells. To test CTLA-4 inhibition in vivo, patient-derived xenografts were generated by transplanting MF CD34+ cells and by infusing homologous T cells in NSGS mice. CTLA-4 blockade reduced human myeloid chimerism and led to T-cell expansion in spleen and bone marrow. Overall, these findings shed light on T-cell dysfunction in MF and suggest that CTLA-4 blockade can boost the cytotoxic T cell-mediated immune response against tumor cells.

DOI: https://doi.org/10.1002/ajh.27428
Blood Adv. 2024 Jul 05. pii: bloodadvances.2024012655. [Epub ahead of print]

Nilotinib vs. Dasatinib in Achieving MR4.5 for de novo Chronic Myeloid Leukemia: the Randomized JALSG CML212 Study.

Itaru Matsumura, Shigeki Ohtake, Yoshiko Atsuta, Mio Kurata, Yosuke Minami, Naoto Takahashi, Chiaki Nakaseko, Noriyoshi Iriyama, Katsumichi Fujimaki, Kazuhiko Kakihana, Yoji Ogasawara, Takaaki Ono, Masaya Okada, Tetsuzo Tauchi, Toshihiro Miyamoto, Kazunori Ohnishi, Emiko Sakaida, Shin Fujisawa, Yukio Kobayashi, Norio Asou, Tomoki Naoe, Hitoshi Kiyoi, Yasushi Miyazaki.

Treatment-free remission (TFR) is a new therapeutic goal for chronic myeloid leukemia in chronic phase (CML-CP). Deep molecular response (DMR) is a prerequite condition for TFR. The Japan Adult Leukemia Study Group (JALSG) conducted a multicentral prospective randomized phase 3 CML212 study for de novo CML-CP to compare the cumulative achievement of MR4.5 (international scale [IS] BCR::ABL1≤0.0032%) by 18 months between nilotinib and dasatinib as a primary endpoint. A total of 454 patients were randomly assigned to the nilotinib 300 mg, bid arm or dasatinib 100 mg, qd arm (both, n=227). BCR::ABL1 mRNA levels were monitored every three months. Study treatment was stopped if the patients were judged as failure by the European LekemiaNet (ELN) 2009 criteria or showed intolerance. The cumulative achievement rates of MR4.5 by 18 months were 32.6% (95% confidence interval [CI]: 26.5-39.1%) in the nilotinib arm and 30.8% (95% CI: 24.9-37.3%) in the dasatinib arm with no significant difference (p=0.66). Also, the cumulative achievement rates of early molecular response (EMR), complete cytogenetic response (CCyR) and major molecular response (MMR), MR4.0 by 12, 18, 24, and 36 months were almost the same between the two arms. At 36 months, 66.5% and 65.0% patients continued nilotinib and dasatinib, respectively (p=0.76). There was no significant difference in progression-free survival (PFS) or overall survival (OS) between the two arms by log-rank tests (PFS, p=0.58; OS, p=0.64). These results suggest that nilotinib and dasatinib would be equally effective for de novo CML-CP patients with similar continuity. UMIN Clinical Trials Registry (#UMIN000007909).

DOI: https://doi.org/10.1182/bloodadvances.2024012655
Nat Commun. 2024 Jul 03. 15(1): 5604

DCAF15 control of cohesin dynamics sustains acute myeloid leukemia.

Grant P Grothusen, Renxu Chang, Zhendong Cao, Nan Zhou, Monika Mittal, Arindam Datta, Phillip Wulfridge, Thomas Beer, Baiyun Wang, Ning Zheng, Hsin-Yao Tang, Kavitha Sarma, Roger A Greenberg, Junwei Shi, Luca Busino.

The CRL4-DCAF15 E3 ubiquitin ligase complex is targeted by the aryl-sulfonamide molecular glues, leading to neo-substrate recruitment, ubiquitination, and proteasomal degradation. However, the physiological function of DCAF15 remains unknown. Using a domain-focused genetic screening approach, we reveal DCAF15 as an acute myeloid leukemia (AML)-biased dependency. Loss of DCAF15 results in suppression of AML through compromised replication fork integrity and consequent accumulation of DNA damage. Accordingly, DCAF15 loss sensitizes AML to replication stress-inducing therapeutics. Mechanistically, we discover that DCAF15 directly interacts with the SMC1A protein of the cohesin complex and destabilizes the cohesin regulatory factors PDS5A and CDCA5. Loss of PDS5A and CDCA5 removal precludes cohesin acetylation on chromatin, resulting in uncontrolled chromatin loop extrusion, defective DNA replication, and apoptosis. Collectively, our findings uncover an endogenous, cell autonomous function of DCAF15 in sustaining AML proliferation through post-translational control of cohesin dynamics.

DOI: https://doi.org/10.1038/s41467-024-49882-x
Cancer Invest. 2024 Jul 03. 1-14

Myeloproliferative Neoplasms Transcriptome Reveals Pro-Inflammatory Signature and Enrichment in Peripheral Blood Monocyte-Related Genes.

Vitor Leonardo Bassan, Rafaela de Freitas Martins Felício, Kelen Cristina Ribeiro Malmegrim de Farias, Fabíola Attié de Castro.

  Myeloproliferative neoplasms (MPN) are hematological diseases associated with genetic driver mutations in the JAK2, CALR, and MPL genes and exacerbated oncoinflammatory status. Analyzing public microarray data from polycythemia vera (n = 41), essential thrombocythemia (n = 21), and primary myelofibrosis (n = 9) patients' peripheral blood by in silico approaches, we found that pro-inflammatory and monocyte-related genes were differentially expressed in MPN patients' transcriptome. Genes related to cell activation, secretion of pro-inflammatory and pro-angiogenic mediators, activation of neutrophils and platelets, coagulation, and interferon pathway were upregulated in monocytes compared to controls. Together, our results suggest that molecular alterations in monocytes may contribute to oncoinflammation in MPN.

Keywords:  Monocytes; immune cells; inflammation; myeloproliferative neoplasms; transcriptome

DOI:  https://doi.org/10.1080/07357907.2024.2371371
Cell Rep. 2024 Jul 04. pii: S2211-1247(24)00765-4. [Epub ahead of print]43(7): 114436

Interface-guided phenotyping of coding variants in the transcription factor RUNX1.

Kivilcim Ozturk, Rebecca Panwala, Jeanna Sheen, Kyle Ford, Nathan Jayne, Andrew Portell, Dong-Er Zhang, Stephan Hutter, Torsten Haferlach, Trey Ideker, Prashant Mali, Hannah Carter.

  Single-gene missense mutations remain challenging to interpret. Here, we deploy scalable functional screening by sequencing (SEUSS), a Perturb-seq method, to generate mutations at protein interfaces of RUNX1 and quantify their effect on activities of downstream cellular programs. We evaluate single-cell RNA profiles of 115 mutations in myelogenous leukemia cells and categorize them into three functionally distinct groups, wild-type (WT)-like, loss-of-function (LoF)-like, and hypomorphic, that we validate in orthogonal assays. LoF-like variants dominate the DNA-binding site and are recurrent in cancer; however, recurrence alone does not predict functional impact. Hypomorphic variants share characteristics with LoF-like but favor protein interactions, promoting gene expression indicative of nerve growth factor (NGF) response and cytokine recruitment of neutrophils. Accessible DNA near differentially expressed genes frequently contains RUNX1-binding motifs. Finally, we reclassify 16 variants of uncertain significance and train a classifier to predict 103 more. Our work demonstrates the potential of targeting protein interactions to better define the landscape of phenotypes reachable by missense mutations.

Keywords:  CP: Genomics; CP: Molecular biology; Perturb-seq; RNA-seq; cancer; coding variant; interface; protein-protein interaction; single-cell; transcription factor

DOI:  https://doi.org/10.1016/j.celrep.2024.114436
Blood Adv. 2024 Jul 05. pii: bloodadvances.2024013182. [Epub ahead of print]

RISK-ADAPTED MRD-DIRECTED THERAPY FOR YOUNG ACUTE MYELOID LEUKEMIA ADULTS: 6-YEAR UPDATE OF THE GIMEMA AML1310 TRIAL.

Adriano Venditti, Alfonso Piciocchi, Anna Candoni, Valentina Arena, Raffaele Palmieri, Carla Fili, Angelo Michele Carella, Valeria Calafiore, Roberto Cairoli, Paolo De Fabritiis, Gabriella Storti, Prassede Salutari, Francesco Lanza, Giovanni Martinelli, Antonio Curti, Mario Luppi, Claudia Ingrosso, Maria Paola Martelli, Antonio Cuneo, Francesco Albano, Antonino Mulè, Agostino Tafuri, Laura Cudillo, Alessia Tieghi, Nicola Stefano Fracchiolla, Debora Capelli, Silvia Maria Trisolini, Caterina Alati, Edoardo La Sala, Luca Maurillo, Maria Ilaria Del Principe, Maria Antonietta Irno Consalvo, Maria Domenica Divona, Tiziana Ottone, Raffaella Cerretti, Giuseppe Sconocchia, Maria Teresa Voso, Paola Fazi, Marco Vignetti, Francesco Buccisano.

DOI: https://doi.org/10.1182/bloodadvances.2024013182
Cell Stem Cell. 2024 Jun 25. pii: S1934-5909(24)00215-7. [Epub ahead of print]

Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening.

Chengfang Zhou, Mei Kuang, Yin Tao, Jianming Wang, Yu Luo, Yinghao Fu, Zhe Chen, Yuanyuan Liu, Zhigang Li, Weiru Wu, Li Wang, Ying Dou, Junping Wang, Yu Hou.

  Mitochondria are key regulators of hematopoietic stem cell (HSC) homeostasis. Our research identifies the transcription factor Nynrin as a crucial regulator of HSC maintenance by modulating mitochondrial function. Nynrin is highly expressed in HSCs under both steady-state and stress conditions. The knockout Nynrin diminishes HSC frequency, dormancy, and self-renewal, with increased mitochondrial dysfunction indicated by abnormal mPTP opening, mitochondrial swelling, and elevated ROS levels. These changes reduce HSC radiation tolerance and promote necrosis-like phenotypes. By contrast, Nynrin overexpression in HSCs diminishes irradiation (IR)-induced lethality. The deletion of Nynrin activates Ppif, leading to overexpression of cyclophilin D (CypD) and further mitochondrial dysfunction. Strategies such as Ppif haploinsufficiency or pharmacological inhibition of CypD significantly mitigate these effects, restoring HSC function in Nynrin-deficient mice. This study identifies Nynrin as a critical regulator of mitochondrial function in HSCs, highlighting potential therapeutic targets for preserving stem cell viability during cancer treatment.

Keywords:  Nynrin; Ppif; ROS; hematopoietic stem cells; irradiation; mPTP opening; mitochondrial membrane potential; mitochondrial metabolism; mitochondrial swelling; radiotherapy

DOI:  https://doi.org/10.1016/j.stem.2024.06.007
Nat Commun. 2024 Jul 02. 15(1): 5570

Epigenetic-based differentiation therapy for Acute Myeloid Leukemia.

Edurne San José-Enériz, Naroa Gimenez-Camino, Obdulia Rabal, Leire Garate, Estibaliz Miranda, Nahia Gómez-Echarte, Fernando García, Stella Charalampopoulou, Elena Sáez, Amaia Vilas-Zornoza, Patxi San Martín-Uriz, Luis V Valcárcel, Naroa Barrena, Diego Alignani, Luis Esteban Tamariz-Amador, Ana Pérez-Ruiz, Sebastian Hilscher, Mike Schutkowski, Ana Alfonso-Pierola, Nicolás Martinez-Calle, María José Larrayoz, Bruno Paiva, María José Calasanz, Javier Muñoz, Marta Isasa, José Ignacio Martin-Subero, Antonio Pineda-Lucena, Julen Oyarzabal, Xabier Agirre, Felipe Prósper.

Despite the development of novel therapies for acute myeloid leukemia, outcomes remain poor for most patients, and therapeutic improvements are an urgent unmet need. Although treatment regimens promoting differentiation have succeeded in the treatment of acute promyelocytic leukemia, their role in other acute myeloid leukemia subtypes needs to be explored. Here we identify and characterize two lysine deacetylase inhibitors, CM-444 and CM-1758, exhibiting the capacity to promote myeloid differentiation in all acute myeloid leukemia subtypes at low non-cytotoxic doses, unlike other commercial histone deacetylase inhibitors. Analyzing the acetylome after CM-444 and CM-1758 treatment reveals modulation of non-histone proteins involved in the enhancer-promoter chromatin regulatory complex, including bromodomain proteins. This acetylation is essential for enhancing the expression of key transcription factors directly involved in the differentiation therapy induced by CM-444/CM-1758 in acute myeloid leukemia. In summary, these compounds may represent effective differentiation-based therapeutic agents across acute myeloid leukemia subtypes with a potential mechanism for the treatment of acute myeloid leukemia.

DOI: https://doi.org/10.1038/s41467-024-49784-y