bims-tremyl 2022-11-13 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2022–11–13
34 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Dysregulated lipid synthesis by oncogenic IDH1 mutation is a targetable synthetic lethal vulnerability.
Genetic deletion and pharmacologic inhibition of E3 ubiquitin ligase HOIP impairs the propagation of myeloid leukemia.
Ascertaining QUAZARs: slow-motion and light-speed development of oral azacitidine and decitabine.
Differences in classification schemata for myelodysplastic/myeloproliferative overlap neoplasms.
Real world molecular characterisation and clonal evolution of acute myeloid leukaemia reveals therapeutic opportunities and challenges.
Clofarabine and busulfan myeloablative conditioning in allogeneic hematopoietic cell transplant for patients with active myeloid malignancies.
Not only mutations but also tumorigenesis can be substantially attributed to DNA damage from reactive oxygen species in RUNX1::RUNX1T1-fusion-positive acute myeloid leukemia.
Gata1s mutant mice display persistent defects in the erythroid lineage.
Clinical Outcomes of Acute Myeloid Leukemia Patients Harboring the RUNX1 Mutation: Is It Still an Unfavorable Prognosis? A Cohort Study and Meta-Analysis.
Secreted Mutant Calreticulins As Rogue Cytokines in Myeloproliferative Neoplasms.
A phase I/II open-label study of molibresib for the treatment of relapsed/refractory hematologic malignancies.
Current and emerging pharmacotherapy for the treatment of childhood acute myeloid leukemia.
Retinoid X receptor promotes hematopoietic stem cell fitness and quiescence and preserves hematopoietic homeostasis.
Cause of death and excess mortality in patients with lower-risk myelodysplastic syndromes (MDS): A report from the European MDS registry.
The Potential Role of 3D In Vitro Acute Myeloid Leukemia Culture Models in Understanding Drug Resistance in Leukemia Stem Cells.
The PIP4K2 inhibitor THZ-P1-2 exhibits antileukemia activity by disruption of mitochondrial homeostasis and autophagy.
Molecular characterization of acquired resistance to KRAS G12C-EGFR inhibition in colorectal cancer.
AML gets upSET when its dietary needs are unMet.
CD1d-dependent rewiring of lipid metabolism in macrophages regulates innate immune responses.
A novel therapeutic bispecific format based on synthetic orthogonal heterodimers enables T cell activity against Acute myeloid leukemia.
Inherited cancer predisposing mutations in patients with therapy-related myeloid neoplasms.
Molecular Pathogenesis of Myeloproliferative Neoplasms.
Haploidentical haematopoietic stem cell transplantation for TP53-mutated acute myeloid leukaemia.
Clonal hematopoiesis in cardiovascular disease and therapeutic implications.
Chronic inflammation decreases HSC fitness by activating the druggable Jak/Stat3 signaling pathway.
Enhanced T cell effector activity by targeting the Mediator kinase module.
TET2 deficiency sensitizes tumor cells to statins by reducing HMGCS1 expression.
Human bone marrow organoids for disease modelling, discovery and validation of therapeutic targets in hematological malignancies.
Transcriptomics of acute myeloid leukaemia core bone marrow biopsies reveals distinct therapy response-specific osteo-mesenchymal profiles.
Genetic basis and molecular profiling in myeloproliferative neoplasms.
Identification of hematopoietic stem cells residing in the meninges of adult mice at steady state.
Loss of bisecting GlcNAcylation on MCAM of bone marrow stoma determined pro-tumoral niche in MDS/AML.
Factors associated with clonal hematopoiesis and interaction with marrow environment.
A uniform conditioning regimen of busulfan, fludarabine, and antithymocyte globulin for allogeneic haematopoietic cell transplantation from haploidentical family, matched sibling, or unrelated donors-A single-centre, prospective, explorative study.

Cancer Discov. 2022 Nov 10. pii: CD-21-0218. [Epub ahead of print]

Dysregulated lipid synthesis by oncogenic IDH1 mutation is a targetable synthetic lethal vulnerability.

Daniel Thomas, Manhong Wu, Yusuke Nakauchi, Ming Zheng, Chloe Al Thompson-Peach, Kelly Lim, Niklas Landberg, Thomas Köhnke, Nirmal Robinson, Satinder Kaur, Monika Kutyna, Melissa Stafford, Devendra Hiwase, Andreas Reinisch, Gary Peltz, Ravindra Majeti.

Isocitrate dehydrogenase 1 and 2 (IDH) are mutated in multiple cancers and drive production of (R)-2-hydroxyglutarate (2HG). We identified a lipid synthesis enzyme (acetyl CoA carboxylase 1, ACC1) as a synthetic lethal target in mutant IDH1 (mIDH1), but not mIDH2, cancers. Here, we analyzed the metabolome of primary acute myeloid leukemia (AML) blasts and identified a mIDH1-specific reduction in fatty acids. mIDH1 also induced a switch to beta-oxidation indicating reprogramming of metabolism towards a reliance on fatty acids. Compared to mIDH2, mIDH1 AML displayed depletion of NADPH with defective reductive carboxylation that was not rescued by the mIDH1-specific inhibitor ivosidenib. In xenograft models, a lipid-free diet markedly slowed the growth of mIDH1 AML, but not healthy CD34+ HSPCs or mIDH2 AML. Genetic and pharmacologic targeting of ACC1 resulted in growth inhibition of mIDH1 cancers, not reversible by ivosidenib. Critically, pharmacologic targeting of ACC1 improved sensitivity of mIDH1 AML to venetoclax.

DOI: https://doi.org/10.1158/2159-8290.CD-21-0218
Leukemia. 2022 Nov 09.

Genetic deletion and pharmacologic inhibition of E3 ubiquitin ligase HOIP impairs the propagation of myeloid leukemia.

Koji Jimbo, Ayuna Hattori, Shuhei Koide, Takahiro Ito, Katsuhiro Sasaki, Kazuhiro Iwai, Yasuhito Nannya, Atsushi Iwama, Arinobu Tojo, Takaaki Konuma.

We investigated the role of Hoip, a catalytic subunit of linear ubiquitin chain assembly complex (LUBAC), in adult hematopoiesis and myeloid leukemia by using both conditional deletion of Hoip and small-molecule chemical inhibitors of Hoip. Conditional deletion of Hoip led to significantly longer survival and marked depletion of leukemia burden in murine myeloid leukemia models. Nevertheless, a competitive transplantation assay showed the reduction of donor-derived cells in the bone marrow of recipient mice was relatively mild after conditional deletion of Hoip. Although both Hoip-deficient hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs) impaired the maintenance of quiescence, conditional deletion of Hoipinduced apoptosis in LSCs but not HSCs in vivo. Structure-function analysis revealed that LUBAC ligase activity and the interaction of LUBAC subunits were critical for the propagation of leukemia. Hoip regulated oxidative phosphorylation pathway independently of nuclear factor kappa B pathway in leukemia, but not in normal hematopoietic cells. Finally, the administration of thiolutin, which inhibits the catalytic activity of Hoip, improved the survival of recipients in murine myeloid leukemia and suppressed propagation in the patient-derived xenograft model of myeloid leukemia. Collectively, these data indicate that inhibition of LUBAC activity may be a valid therapeutic target for myeloid leukemia.

DOI: https://doi.org/10.1038/s41375-022-01750-7
Leuk Lymphoma. 2022 Nov 12. 1-15

Ascertaining QUAZARs: slow-motion and light-speed development of oral azacitidine and decitabine.

Jonathan Feld, Douglas Tremblay, Shyamala C Navada, Lewis R Silverman.

  Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are devastating diseases that frequently rely on the use of parenteral hypomethylating agents (HMAs), either as monotherapy or in combination, as first-line treatment for many patients. Two new oral HMAs, decitabine/cedazuridine (DC) for use in place of azacitidine or decitabine in MDS, and azacitidine (CC-486) for use as maintenance treatment in AML, were recently approved by the FDA. We will discuss the development of these oral HMAs, including the advantages/disadvantages in transitioning to oral HMAs and an in depth look at the pivotal phase III trials that led to their FDA approval - ASCERTAIN for DC and QUAZAR-AML-001 for CC-486. We also review how these agents have been and are being studied in other malignancies, and examine the future role that these exciting novel agents will play in both MDS and AML.

Keywords:  Hypomethylating agent; acute myeloid leukemia; azacitidine; decitabine; myelodysplastic syndromes; oral chemotherapy

DOI:  https://doi.org/10.1080/10428194.2022.2142051
Leukemia. 2022 Nov 05.

Differences in classification schemata for myelodysplastic/myeloproliferative overlap neoplasms.

Mrinal M Patnaik, Amer M Zeidan, Eric Padron, Uwe Platzbecker, David A Sallman, Amy E DeZern, Rafael Bejar, Mikkael Sekeres, Justin Taylor, Richard F Little, Jan P Bewersdorf, Tae Kon Kim, Nina Kim, Christopher S Hourigan, Matteo G Dela Porta, Maximilian Stahl, David Steensma, Mina L Xu, Olatoyosi Odenike, Hetty Carraway, Pierre Fenaux, Aziz Nazha, Rami Komrokji, Sanam Loghavi, Zhuoer Xie, Robert Hasserjian, Michael Savona, John M Bennett.

DOI: https://doi.org/10.1038/s41375-022-01754-3
Pathology. 2022 Oct 13. pii: S0031-3025(22)00269-0. [Epub ahead of print]

Real world molecular characterisation and clonal evolution of acute myeloid leukaemia reveals therapeutic opportunities and challenges.

Ricky Nelles, Louise Seymour, Joshua Richmond, Steven Lane.

  Acute myeloid leukaemia (AML) is an aggressive haematological malignancy with poor prognosis. Increasing understanding of the molecular mechanisms driving clonal proliferation has resulted in advancements in classification and available therapeutic targets. Fms-related tyrosine kinase 3 (FLT3) mutations are prognostically important and offer options for targeted inhibition, however they are not stable and can emerge or disappear at relapse. Our aim was to review diagnostic testing of consecutive cases of newly diagnosed and relapsed AML reported across Queensland in comparison to available literature. We conducted a retrospective review of 1531 samples from 1231 patients to identify patterns of molecular testing and AML subtypes in our cohort. Outcomes included World Health Organization (WHO) classification, European LeukaemiaNet (ELN) risk category and rates of missed FLT3 mutation testing. Patients aged <60 years had significantly more favourable risk AML (48% vs 25%, p<0.01), with favourable risk chromosomal translocations [t(8;21) and inv(16)] being more common. Thirteen patients (1%) did not have FLT3 mutation testing at diagnosis, with 103 relapse samples (39%) not being tested. Eighteen patients (10%) had FLT3 mutations lost at relapse, with five patients (3%) developing new FLT3 mutations at relapse. This study identifies the subtypes and risk stratification of a large cohort of AML patients over an extended period. The relatively high rate of absent FLT3 mutation testing at relapse as well as FLT3 loss or gain highlights the potential missed opportunities for salvage treatment strategies.

Keywords:  FLT3; Myeloid; genetics; leukaemia; molecular

DOI:  https://doi.org/10.1016/j.pathol.2022.07.019
Transplant Cell Ther. 2022 Nov 03. pii: S2666-6367(22)01742-0. [Epub ahead of print]

Clofarabine and busulfan myeloablative conditioning in allogeneic hematopoietic cell transplant for patients with active myeloid malignancies.

Matthew P Connor, Alison W Loren, Elizabeth O Hexner, Mary Ellen Martin, Saar I Gill, Selina M Luger, James K Mangan, Alexander E Perl, Shannon R McCurdy, Keith W Pratz, Colleen Timlin, Craig W Freyer, Alison Carulli, Christopher Catania, Jacqueline Smith, Lauren Hollander, Alexis M Zebrowski, Edward A Stadtmauer, David L Porter, Noelle V Frey.

BACKGROUND: Patients with refractory or relapsed and refractory myeloid malignancies have a poor prognosis. Allogeneic hematopoietic cell transplant (HCT) with myeloablative conditioning (MAC) in patients with active, chemotherapy-refractory myeloid disease is historically associated with high rates of relapse and non-relapse mortality. A MAC regimen combining clofarabine with busulfan (Clo/Bu4) has been described to exhibit anti-leukemic activity with acceptable toxicity in patients ≤ 70 years old.
OBJECTIVES: To describe clinical outcomes of a real-world population of patients with active myeloid malignancies undergoing allogeneic HCT with Clo/Bu4 MAC.
STUDY DESIGN: In a single-center, retrospective descriptive analysis, we identified patients who underwent HCT for myeloid malignancies not in remission using Clo/Bu4 MAC between 2012 and 2020. We report event-free (EFS) and overall survival (OS), cumulative incidence of relapse, non-relapse mortality (NRM), and incidence and severity of acute and chronic graft-versus-host disease (GVHD).
RESULTS: We identified 69 patients with a median age of 60 years (range 22-70). Most patients had relapsed/refractory or primary refractory acute myeloid leukemia (AML, n = 55), or refractory myelodysplastic syndrome (MDS, n = 12); one patient had chronic myeloid leukemia and one had blastic plasmacytoid dendritic cell neoplasm. Fifty patients (72.5%) had complete remission at day 100 after transplant. Two-year EFS and OS were 30% (95% CI 20-44) and 40% (95% CI 29-54), respectively. Patients with AML had 2-year EFS and OS of 28% (95% CI 18-44) and 38% (95% CI 27-54), respectively; those with MDS had 2-year EFS and OS of 47% (95% CI 25-88) and 56% (95% CI 33-94), respectively. Cumulative incidence of relapse at 2 years was 39% (95% CI 27-51) for all patients: 45% (95% CI 31-58) in AML and 18% (95% CI 2-45) in MDS. NRM at 2 years was 31% (95% CI 20-42): 27% (95% CI 15-39) in AML and 35% (95% CI 10-63) in MDS. The total incidence of aGVHD of any severity was 80%. Incidence of grade 3-4 aGVHD at was 22%. In patients who achieved remission, those who required systemic immunosuppression for aGVHD (58%) had poorer 2-year EFS (29% versus 54%, p = 0.05) and 2-year OS (39% versus 70%, p = 0.04) compared to those who did not. The 2-year cumulative incidence of cGVHD was 44% (95% CI 28-58).
CONCLUSIONS: Clo/Bu4 MAC followed by allogeneic HCT for patients with active myeloid malignancies is an effective transplant strategy up to age 70, particularly for those with advanced MDS. High incidence of and poor outcomes associated with aGVHD highlight the importance of optimizing preventative strategies.

DOI: https://doi.org/10.1016/j.jtct.2022.10.027
Leukemia. 2022 Nov 11.

Not only mutations but also tumorigenesis can be substantially attributed to DNA damage from reactive oxygen species in RUNX1::RUNX1T1-fusion-positive acute myeloid leukemia.

Jeffrey D Mandell, J Nick Fisk, Ethan Cyrenne, Mina L Xu, Vincent L Cannataro, Jeffrey P Townsend.

DOI: https://doi.org/10.1038/s41375-022-01752-5
Blood Adv. 2022 Nov 09. pii: bloodadvances.2022008124. [Epub ahead of print]

Gata1s mutant mice display persistent defects in the erythroid lineage.

Te Ling, Kevin Zhang, Jiayue Yang, Sandeep Gurbuxani, John D Crispino.

GATA1 mutations that result in loss of the N-terminal 83 amino acids are a feature of myeloid leukemia in children with Down syndrome (ML-DS), rare familial cases of dyserythropoietic anemia, and a subset of cases of Diamond-Blackfan Anemia (DBA). The Gata1s mouse model, which expresses only the short GATA1 isoform that begins at methionine 84, has been shown to have a defect in hematopoiesis, specially impaired erythropoiesis with expanded megakaryopoiesis, during gestation. However, the mice were reported to not show any post-natal phenotype. Here we demonstrate that Gata1s mutant mice display macrocytic anemia and features of aberrant megakaryopoiesis throughout life, culminating in profound splenomegaly and bone marrow fibrosis. These data support the use of this animal model for studies of GATA1 deficiencies.

DOI: https://doi.org/10.1182/bloodadvances.2022008124
Cancers (Basel). 2022 Oct 26. pii: 5239. [Epub ahead of print]14(21):

Clinical Outcomes of Acute Myeloid Leukemia Patients Harboring the RUNX1 Mutation: Is It Still an Unfavorable Prognosis? A Cohort Study and Meta-Analysis.

Tarinee Rungjirajittranon, Theerapat Siriwannangkul, Smith Kungwankiattichai, Nattawut Leelakanok, Wannaphorn Rotchanapanya, Pongthep Vittayawacharin, Benjamaporn Mekrakseree, Kamolchanok Kulchutisin, Weerapat Owattanapanich.

  Acute myeloid leukemia (AML) with mutated RUNX1 (RUNX1mut) is considered to have an unfavorable prognosis. However, recent studies have reported comparable survival outcomes with wild-type RUNX1 (RUNX1wt). To assess the clinical outcomes of AML with and without RUNX1mut, we performed a prospective cohort study and systematic review and meta-analysis. The study enrolled 135 patients (27 with RUNX1mut; 108 with RUNX1wt). There were no significant differences in the median OS and RFS of the RUNX1mut and RUNX1wt groups (9.1 vs. 12.2 months; p = 0.268 and 7.8 vs. 14.6 months; p = 0.481, respectively). A subgroup analysis of de novo AML patients with intermediate-risk cytogenetics showed similar outcomes. Our meta-analysis pooled data from 23 studies and our study. The complete remission rate was significantly lower in the RUNX1mut group (pooled odds ratio: 0.42). The OS, RFS, and event-free survival rates also favored the RUNX1wt group (pooled risk ratios: 1.36, 1.37, and 1.37, respectively). A subgroup analysis of de novo AML patients with intermediate-risk cytogenetics demonstrated nearly identical OS and RFS outcomes. This study confirms that patients with AML and RUNX1mut had poor prognoses. Nonetheless, in de novo AML with intermediate-risk cytogenetics, the survival outcomes of both groups were comparable.

Keywords:  RUNX1; acute myeloid leukemia; genetic; molecular; mutation; next-generation sequencing

DOI:  https://doi.org/10.3390/cancers14215239
Blood. 2022 Nov 10. pii: blood.2022016846. [Epub ahead of print]

Secreted Mutant Calreticulins As Rogue Cytokines in Myeloproliferative Neoplasms.

Christian Pecquet, Nicolas Papadopoulos, Thomas Balligand, Ilyas Chachoua, Amandine Tisserand, Gaëlle Vertenoeil, Audrey Nédélec, Didier Vertommen, Anita Roy, Caroline Marty, Harini Nivarthi, Jean-Philippe Defour, Mira El-Khoury, Eva Hug, Andrea Majoros, Erica Xu, Oleh Zagrijtschuk, Tudor Emanuel Fertig, Daciana S Marta, Heinz Gisslinger, Bettina Gisslinger, Martin Schalling, Ilaria Carola Casetti, Elisa Rumi, Daniela Pietra, Chiara Cavalloni, Luca Arcaini, Mario Cazzola, Norio Komatsu, Yoshihiko Kihara, Yoshitaka Sunami, Yoko Edahiro, Marito Araki, Roman Lesyk, Veronika Buxhofer-Ausch, Sonja Heibl, Florence Pasquier, Isabelle Plo, William Vainchenker, Robert Kralovics, Stefan N Constantinescu.

Mutant calreticulin (CALR) proteins resulting from a -1/+2 frameshifting mutation of the CALR exon 9 carry a novel C-terminal amino-acid sequence and drive the development of myeloproliferative neoplasms (MPNs). Mutant CALRs were shown to interact with and activate the thrombopoietin receptor (TpoR/MPL) in the same cell. We report that mutant CALR proteins are secreted and can be found in patient plasma at levels up to 160ng/mL, with a mean of 25.64ng/mL. Plasma mutant CALR is found in complex with soluble Transferrin Receptor 1 (sTFRC) that acts as a carrier protein and increases CALR mutant half-life. Recombinant mutant CALR proteins bound and activated the TpoR on cell lines and primary megakaryocytic progenitors from CALR-mutated patients where they drive Tpo-independent colony formation. Importantly, the CALR-sTFRC complex remains functional for TpoR activation. By bioluminescence resonance energy transfer assay, we show that mutant CALR proteins produced in one cell can specifically interact in trans with the TpoR on a target cell. Cells that carry both TpoR and mutant CALR are hypersensitive to exogenous CALR mutant proteins in comparison to cells that only carry TpoR, and respond to levels of CALR mutant proteins similar to those in patient plasma. This is consistent with CALR mutated cells exposing at the cell-surface TpoR carrying immature N-linked sugars. Thus, secreted mutant CALR proteins will act more specifically on the MPN clone. In conclusion, a chaperone, CALR, can turn into a rogue cytokine through somatic mutation of its encoding gene.

DOI: https://doi.org/10.1182/blood.2022016846
Clin Cancer Res. 2022 Nov 09. pii: CCR-22-1284. [Epub ahead of print]

A phase I/II open-label study of molibresib for the treatment of relapsed/refractory hematologic malignancies.

Mark A Dawson, Gautam Borthakur, Brian Huntly, Anastasios Karadimitris, Adrian Alegre, Aristeidis Chaidos, Dan T Vogl, Daniel A Pollyea, Faith E Davies, Gareth J Morgan, Jacob Glass, Manali Kamdar, Maria-Victoria Mateos Manteca, Natalia Tovar, Paul Yeh, Regina García Delgado, Faisal Basheer, Ludovica Marando, Paolo Gallipoli, Anastasia Wyce, Anu Shilpa Krishnatry, Olena Barbash, Evi Bakirtzi, Geraldine Ferron-Brady, Natalie O Karpinich, Michael T McCabe, Shawn W Foley, Thierry Horner, Arindam Dhar, Brandon E Kremer, Michael Dickinson.

PURPOSE: Molibresib is a selective, small molecule inhibitor of the BET protein family. This was an open-label, two-part, Phase I/II study investigating molibresib monotherapy for the treatment of hematological malignancies (NCT01943851).
EXPERIMENTAL DESIGN: Part 1 (dose escalation) determined the recommended Phase 2 dose (RP2D) of molibresib in patients with acute myeloid leukemia (AML), non-Hodgkin's lymphoma (NHL), or multiple myeloma. Part 2 (dose expansion) investigated the safety and efficacy of molibresib at the RP2D in patients with relapsed/refractory myelodysplastic syndrome (MDS; as well as AML evolved from antecedent MDS) or cutaneous T cell lymphoma (CTCL). The primary endpoint in Part 1 was safety and the primary endpoint in Part 2 was objective response rate (ORR).
RESULTS: There were 111 patients enrolled (87 in Part 1, 24 in Part 2). Molibresib RP2Ds of 75 mg QD (for MDS) and 60 mg QD (for CTCL) were selected. Most common Grade 3+ AEs included thrombocytopenia (37%), anemia (15%) and febrile neutropenia (15%). Six patients achieved complete responses (three in Part 1 [two AML, one NHL], three in Part 2 [MDS]), and seven patients achieved partial responses (six in Part 1 [four AML, two NHL], one in Part 2 [MDS]). The ORRs for Part 1, Part 2, and the total study population were 10% (95% CI: 4.8-18.7), 25% (95% CI: 7.3-52.4), and 13% (95% CI: 6.9-20.6), respectively.
CONCLUSIONS: While anti-tumor activity was observed with molibresib, use was limited by gastrointestinal and thrombocytopenia toxicities. Investigations of molibresib as part of combination regimens may be warranted.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-1284
Expert Opin Pharmacother. 2022 Nov 08.

Current and emerging pharmacotherapy for the treatment of childhood acute myeloid leukemia.

Branko Cuglievan, David McCall, Lindsay Robusto, M Estela Mireles, Suzanne C Gettys.

   INTRODUCTION: Pediatric acute myeloid leukemia (AML) is a rare disease that is profoundly heterogeneous at a molecular and clinical level. Although, in recent clinical trials, the 5-year event-free survival rates for childhood AML ranged between 49% and 64%, bone marrow relapse still occurs in up to one-third of cases. New therapies are required to continue progress in this aggressive hematological disease. Optimistically, we anticipate that the next challenge may be not a lack of appropriate therapies but an abundance of potentially effective strategies and a question of how best to incorporate them into pediatric clinical practice.
AREAS COVERED: The focus of this review is to highlight all promising agents currently under investigation for pediatric AML, including nucleoside analogs, epigenetic modifiers, targeted small molecule inhibitors, monoclonal antibodies, novel chemotherapeutics, and immunotherapies.
EXPERT OPINION: While AML outcomes have improved over time for pediatric AML patients, our challenge is how to improve outcomes with our new knowledge of genetic and epigenetic aberrations. We posit to incorporate active therapy options into combination strategies and utilize targeted and immunotherapy approaches, as more opportunities are available.

Keywords:  AML; Children; Menin; Menin Inhibitors; Pediatric; Pediatric AML

DOI:  https://doi.org/10.1080/14656566.2022.2145186
Blood. 2022 Nov 08. pii: blood.2022016832. [Epub ahead of print]

Retinoid X receptor promotes hematopoietic stem cell fitness and quiescence and preserves hematopoietic homeostasis.

María Piedad Menéndez-Gutiérrez, Jesús Porcuna, Ramesh C Nayak, Ana Paredes, Haixia Niu, Vanessa Núñez, Aditi Paranjpe, Manuel J Jose Gómez, Anukana Bhattacharjee, Daniel J Schnell, Fátima Sánchez-Cabo, John S S Welch, Nathan Salomonis, Jose Cancelas, Mercedes Ricote.

Hematopoietic stem cells (HSCs) balance self-renewal and differentiation to maintain hematopoietic fitness throughout life. In steady-state conditions, HSC exhaustion is prevented by the maintenance of most HSCs in a quiescent state, with cells entering the cell cycle only occasionally. HSC quiescence is regulated by retinoid and fatty-acid ligands of transcriptional factors of the nuclear retinoid X receptor (RXR) family. Here, we show that dual deficiency for hematopoietic RXRa and RXRb induces HSC exhaustion, myeloid cell/megakaryocyte differentiation, and myeloproliferative-like disease. RXRa and RXRb maintain HSC quiescence, survival, and chromatin compaction; moreover, transcriptome changes in RXRa;RXRb-deficient HSCs include premature acquisition of an aging-like HSC signature, MYC pathway upregulation, and RNA intron retention. Fitness loss and associated RNA transcriptome and splicing alterations in RXRa;RXRb-deficient HSCs are prevented by Myc haploinsufficiency. Our study reveals the critical importance of RXRs for the maintenance of HSC fitness and their protection from premature aging.

DOI: https://doi.org/10.1182/blood.2022016832
Br J Haematol. 2022 Nov 06.

Cause of death and excess mortality in patients with lower-risk myelodysplastic syndromes (MDS): A report from the European MDS registry.

EUMDS Registry Participants

  Information on causes of death (CoDs) and the impact of myelodysplastic syndromes (MDS) on survival in patients with lower-risk MDS (LR-MDS) is limited. A better understanding of the relationship between disease characteristics, clinical interventions and CoDs may improve outcomes of patients with LR-MDS. We prospectively collected data on patients with LR-MDS in the European MDS registry from 2008 to 2019. Clinical, laboratory and CoDs data were obtained. To examine MDS-specific survival, relative survival (RS) was estimated using national life tables. Of 2396 evaluated subjects, 900 died (median overall survival [OS]: 4.7 years; median follow-up: 3.5 years). The most common CoDs were acute myeloid leukaemia/MDS (20.1%), infection (17.8%) and cardiovascular disease (CVD; 9.8%). Patients with isolated del(5q) and with red cell transfusion needed during the disease course, had a higher risk of fatal CVD. The 5-year OS was 47.3% and the 5-year RS was 59.6%, indicating that most patients died due to their underlying MDS. Older patients (aged >80 years) and the lowest-risk patients were more likely to die from competing causes. This study shows that MDS and its related complications play crucial role in the outcome of patients with LR-MDS.

Keywords:  causes of death; myelodysplastic syndromes; relative survival

DOI:  https://doi.org/10.1111/bjh.18542
Cancers (Basel). 2022 Oct 26. pii: 5252. [Epub ahead of print]14(21):

The Potential Role of 3D In Vitro Acute Myeloid Leukemia Culture Models in Understanding Drug Resistance in Leukemia Stem Cells.

Basil Al-Kaabneh, Benjamin Frisch, Omar S Aljitawi.

  The complexity of the bone marrow (BM) microenvironment makes studying hematological malignancies in vitro a challenging task. Three-dimensional cell cultures are being actively studied, particularly due to their ability to serve as a bridge of the gap between 2D cultures and animal models. The role of 3D in vitro models in studying the mechanisms of chemotherapeutic resistance and leukemia stem cells (LSCs) in acute myeloid leukemia (AML) is not well-reviewed. We present an overview of 3D cell models used for studying AML, emphasizing the recent advancements in microenvironment modeling, chemotherapy testing, and resistance.

Keywords:  acute myeloid leukemia (AML); allogeneic hematopoietic stem cell transplant (Allo-HSCT); bone marrow (BM); decellularized Wharton jelly matrix (DWJM); extra cellular matrix (ECM); hematopoietic stem/progenitor cells (HSPCs); leukemia stem cells (LSCs); mesenchymal stem cells (MSCs); minimum residual disease (MRD); myelodysplastic syndrome (MDS)

DOI:  https://doi.org/10.3390/cancers14215252
Blood Cancer J. 2022 Nov 09. 12(11): 151

The PIP4K2 inhibitor THZ-P1-2 exhibits antileukemia activity by disruption of mitochondrial homeostasis and autophagy.

Keli Lima, Diego Antonio Pereira-Martins, Lívia Bassani Lins de Miranda, Juan Luiz Coelho-Silva, Giovana da Silva Leandro, Isabel Weinhäuser, Rita de Cássia Cavaglieri, Aline de Medeiros Leal, Wellington Fernandes da Silva, Ana Paula Alencar de Lima Lange, Elvira Deolinda Rodrigues Pereira Velloso, Emmanuel Griessinger, Jacobien R Hilberink, Emanuele Ammatuna, Gerwin Huls, Jan Jacob Schuringa, Eduardo Magalhães Rego, João Agostinho Machado-Neto.

The treatment of acute leukemia is challenging because of the genetic heterogeneity between and within patients. Leukemic stem cells (LSCs) are relatively drug-resistant and frequently relapse. Their plasticity and capacity to adapt to extracellular stress, in which mitochondrial metabolism and autophagy play important roles, further complicates treatment. Genetic models of phosphatidylinositol-5-phosphate 4-kinase type 2 protein (PIP4K2s) inhibition have demonstrated the relevance of these enzymes in mitochondrial homeostasis and autophagic flux. Here, we uncovered the cellular and molecular effects of THZ-P1-2, a pan-inhibitor of PIP4K2s, in acute leukemia cells. THZ-P1-2 reduced cell viability and induced DNA damage, apoptosis, loss of mitochondrial membrane potential, and the accumulation of acidic vesicular organelles. Protein expression analysis revealed that THZ-P1-2 impaired autophagic flux. In addition, THZ-P1-2 induced cell differentiation and showed synergistic effects with venetoclax. In primary leukemia cells, LC-MS/MS-based proteome analysis revealed that sensitivity to THZ-P1-2 is associated with mitochondrial metabolism, cell cycle, cell-of-origin (hematopoietic stem cell and myeloid progenitor), and the TP53 pathway. The minimal effects of THZ-P1-2 observed in healthy CD34+ cells suggest a favorable therapeutic window. Our study provides insights into the pharmacological inhibition of PIP4K2s targeting mitochondrial homeostasis and autophagy, shedding light on a new class of drugs for acute leukemia.

DOI: https://doi.org/10.1038/s41408-022-00747-w
Cancer Discov. 2022 Nov 10. pii: CD-22-0405. [Epub ahead of print]

Molecular characterization of acquired resistance to KRAS G12C-EGFR inhibition in colorectal cancer.

Rona Yaeger, Riccardo Mezzadra, Jenna Sinopoli, Yu Bian, Michelangelo Marasco, Esther Kaplun, Yijun Gao, HuiYong Zhao, Arnaud Da Cruz Paula, Yingjie Zhu, Almudena Chaves Perez, Kalyani Chadalavada, Edison Tse, Sudhir Chowdhry, Sydney Bowker, Qing Chang, Besnik Qeriqi, Britta Weigelt, Gouri J Nanjangud, Michael F Berger, Hirak Der-Torossian, Kenna Anderes, Nicholas D Socci, Jinru Shia, Gregory J Riely, Yonina R Murciano-Goroff, Bob T Li, James G Christensen, Jorge S Reis-Filho, David B Solit, Elisa de Stanchina, Scott W Lowe, Neal Rosen, Sandra Misale.

With the combination of KRAS G12C and EGFR inhibitors, KRAS is becoming a druggable target in colorectal cancer. However, secondary resistance limits its efficacy. Using cell lines, patient-derived xenografts, and patient samples, we detected a heterogeneous pattern of putative resistance alterations expected primarily to prevent inhibition of ERK signaling by drugs at progression. Serial analysis of patient blood samples on treatment demonstrates that most of these alterations are detected at a low frequency except for KRAS G12C amplification, a recurrent resistance mechanism that rises in step with clinical progression. Upon drug withdrawal, resistant cells with KRAS G12C amplification undergo oncogene-induced senescence, and progressing patients experience a rapid fall in levels of this alteration in circulating DNA. In this new state, drug resumption is ineffective as mTOR signaling is elevated. However, our work exposes a potential therapeutic vulnerability, whereby therapies that target the senescence response may overcome acquired resistance.

DOI: https://doi.org/10.1158/2159-8290.CD-22-0405
Blood. 2022 Nov 10. 140(19): 2003-2004

AML gets upSET when its dietary needs are unMet.

Paolo Gallipoli.

DOI: https://doi.org/10.1182/blood.2022018008
Nat Commun. 2022 Nov 07. 13(1): 6723

CD1d-dependent rewiring of lipid metabolism in macrophages regulates innate immune responses.

Phillip M Brailey, Lauren Evans, Juan Carlos López-Rodríguez, Anthony Sinadinos, Victoria Tyrrel, Gavin Kelly, Valerie O'Donnell, Peter Ghazal, Susan John, Patricia Barral.

Alterations in cellular metabolism underpin macrophage activation, yet little is known regarding how key immunological molecules regulate metabolic programs in macrophages. Here we uncover a function for the antigen presenting molecule CD1d in the control of lipid metabolism. We show that CD1d-deficient macrophages exhibit a metabolic reprogramming, with a downregulation of lipid metabolic pathways and an increase in exogenous lipid import. This metabolic rewiring primes macrophages for enhanced responses to innate signals, as CD1d-KO cells show higher signalling and cytokine secretion upon Toll-like receptor stimulation. Mechanistically, CD1d modulates lipid import by controlling the internalization of the lipid transporter CD36, while blocking lipid uptake through CD36 restores metabolic and immune responses in macrophages. Thus, our data reveal CD1d as a key regulator of an inflammatory-metabolic circuit in macrophages, independent of its function in the control of T cell responses.

DOI: https://doi.org/10.1038/s41467-022-34532-x
Oncogene. 2022 Nov 10.

A novel therapeutic bispecific format based on synthetic orthogonal heterodimers enables T cell activity against Acute myeloid leukemia.

Alan Burke, Florence Borot, Xing Du, Michael Churchill, Jian Ding, Albert Mridul Grass, Philip DeSouza, Abdullah Mahmood Ali, Siddhartha Mukherjee.

Many therapeutic bispecific T-cell engagers (BiTEs) are in clinical trials. A modular and efficient process to create BiTEs would accelerate their development and clinical applicability. In this study, we present the design, production, and functional activity of a novel bispecific format utilizing synthetic orthogonal heterodimers to form a multichain modular design. Further addition of an immunoglobulin hinge region allowed a stable covalent linkage between the heterodimers. As proof-of-concept, we utilized CD33 and CD3 binding scFvs to engage leukemia cells and T-cells respectively. We provide evidence that this novel bispecific T-cell engager (termed IgGlue-BiTE) could bind both CD3+ and CD33+ cells and facilitates robust T-cell mediated cytotoxicity on AML cells in vitro. In a mouse model of minimal residual disease, we showed that the novel IgGlue-BiTE greatly extended survival, and mice of this treatment group were free of leukemia in the bone marrow. These findings suggest that the IgGlue-BiTE allows for robust simultaneous engagement with both antigens of interest in a manner conducive to T cell cytotoxicity against AML. These results suggest a compelling modular system for bispecific antibodies, as the CD3- and CD33-binding domains can be readily swapped with domains binding to other cancer- or immune cell-specific antigens.

DOI: https://doi.org/10.1038/s41388-022-02532-2
Br J Haematol. 2022 Nov 09.

Inherited cancer predisposing mutations in patients with therapy-related myeloid neoplasms.

Andrew J Shih, Tomi Jun, Andrew D Skol, Riyue Bao, Lei Huang, Sapana Vora, Megan E McNerney, Eric A Hungate, Michelle M Le Beau, Richard A Larson, Aaron Elliott, Hsiao-Mei Lu, Robert Huether, Felicia Hernandez, Friedrich Stölzel, James M Allan, Kenan Onel.

  Some patients with therapy-related myeloid neoplasms (t-MN) may have unsuspected inherited cancer predisposition syndrome (CPS). We propose a set of clinical criteria to identify t-MN patients with high risk of CPS (HR-CPS). Among 225 t-MN patients with an antecedent non-myeloid malignancy, our clinical criteria identified 52 (23%) HR-CPS patients. Germline whole-exome sequencing identified pathogenic or likely pathogenic variants in 10 of 27 HR-CPS patients compared to 0 of 9 low-risk CPS patients (37% vs. 0%, p = 0.04). These simple clinical criteria identify t-MN patients most likely to benefit from genetic testing for inherited CPS.

Keywords:  cancer predisposition; germline; leukaemia; therapy-related myeloid neoplasm; whole-exome sequencing

DOI:  https://doi.org/10.1111/bjh.18543
Curr Hematol Malig Rep. 2022 Nov 07.

Molecular Pathogenesis of Myeloproliferative Neoplasms.

Benjamin Rolles, Ann Mullally.

   PURPOSE OF REVIEW: Myeloproliferative neoplasms (MPNs) are chronic hematological malignancies characterized by increased proliferation of MPN stem and myeloid progenitor cells with or without bone marrow fibrosis that typically lead to increased peripheral blood cell counts. The genetic and cytogenetic alterations that initiate and drive the development of MPNs have largely been defined, and we summarize these here.
RECENT FINDINGS: In recent years, advances in understanding the pathogenesis of MPNs have defined a long-preclinical phase in JAK2-mutant MPN, identified genetic loci associated with MPN predisposition and uncovered mechanistic insights in CALR-mutant MPN. The integration of molecular genetics into prognostic risk models is well-established in myelofibrosis and ongoing studies are interrogating the prognostic implications of concomitant mutations in ET and PV. Despite all these advances, the field is deficient in clonally selective therapies to effectively target the MPN clone at any stage of disease, from pre-clinical to advanced. Although the biological understanding of the pathogenesis of MPNs has progressed quickly, substantial knowledge gaps remain, including in the molecular mechanisms underlying MPN progression and myelofibrotic transformation. An ongoing goal for the MPN field is to translate advances in biological understanding to improved treatments for patients.

Keywords:  Clonal hematopoiesis; JAK2; Janus kinase; MPN; Myeloid diseases; Myeloproliferative Neoplasms

DOI:  https://doi.org/10.1007/s11899-022-00685-1
Br J Haematol. 2022 Nov 08.

Haploidentical haematopoietic stem cell transplantation for TP53-mutated acute myeloid leukaemia.

Ting Huang, Lanping Xu, Xiaohui Zhang, Yingjun Chang, Xiaodong Mo, Yuqian Sun, Xiaojun Huang, Yu Wang.

  Acute myeloid leukaemia (AML) patients with tumour protein p53 (TP53) mutations are often resistant to chemotherapy and have worse clinical outcomes than patients without TP53 mutations. In this study, we compared clinical outcomes of patients with AML with and without TP53 mutations who underwent haploidentical haematopoietic stem cell transplantation (haplo-HSCT). For the TP53-mutation group and TP53 wild-type group, the 2-year cumulative incidence of relapse (CIR) was (39.0% vs. 21.2% respectively, p = 0.088), the 2-year non-relapse mortality (NRM) rate was (3.2% vs. 8.4% respectively, p = 0.370), the 2-year leukaemia-free survival (LFS) was (57.7% vs. 71.3% respectively, p = 0.205), the 2-year overall survival (OS) rate was (69.9% vs. 81.3% respectively, p = 0.317), the 100-day cumulative incidence of Grade II-IV acute graft-versus-host disease (GvHD) was (6.5% vs. 20.7% respectively, p = 0.074), the 2-year cumulative incidence of chronic GvHD was (52.3% vs. 53.1% respectively, p = 0.493) and the 2-year GvHD-free/relapse-free survival (GRFS) was (57.7% vs. 69.6% respectively, p = 0.347). Our data showed that there were no significant differences in 2-year clinical outcomes between the two groups. Multivariable analysis showed TP53 mutations had no significant impact on CIR, NRM, OS, GvHD, LFS or GRFS. Our findings suggest that patients with AML with TP53 mutations may at least partially benefit from haplo-HSCT. Haplo-HSCT might be the recommended treatment for such patients.

Keywords:  TP53 gene; acute myeloid leukaemia; haematological malignancies; haploidentical haematopoietic stem cell transplantation

DOI:  https://doi.org/10.1111/bjh.18538
Nat Cardiovasc Res. 2022 Feb;1(2): 116-124

Clonal hematopoiesis in cardiovascular disease and therapeutic implications.

Alan R Tall, Jose J Fuster.

Clonal hematopoiesis arises from somatic mutations that provide a fitness advantage to hematopoietic stem cells and the outgrowth of clones of blood cells. Clonal hematopoiesis commonly involves mutations in genes that are involved in epigenetic modifications, signaling and DNA damage repair. Clonal hematopoiesis has emerged as a major independent risk factor in atherosclerotic cardiovascular disease, thrombosis and heart failure. Studies in mouse models of clonal hematopoiesis have shown an increase in atherosclerosis, thrombosis and heart failure, involving increased myeloid cell inflammatory responses and inflammasome activation. Although increased inflammatory responses have emerged as a common underlying principle, some recent studies indicate mutation-specific effects. The discovery of the association of clonal hematopoiesis with cardiovascular disease and the recent demonstration of benefit of anti-inflammatory treatments in human cardiovascular disease converge to suggest that anti-inflammatory treatments should be directed to individuals with clonal hematopoiesis. Such treatments could target specific inflammasomes, common downstream mediators such as IL-1β and IL-6, or mutations linked to clonal hematopoiesis.

DOI: https://doi.org/10.1038/s44161-021-00015-3
EMBO Rep. 2022 Nov 07. e54729

Chronic inflammation decreases HSC fitness by activating the druggable Jak/Stat3 signaling pathway.

Srdjan Grusanovic, Petr Danek, Maria Kuzmina, Miroslava K Adamcova, Monika Burocziova, Romana Mikyskova, Karolina Vanickova, Sladjana Kosanovic, Jana Pokorna, Milan Reinis, Tomas Brdicka, Meritxell Alberich-Jorda.

  Chronic inflammation represents a major threat to human health since long-term systemic inflammation is known to affect distinct tissues and organs. Recently, solid evidence demonstrated that chronic inflammation affects hematopoiesis; however, how chronic inflammation affects hematopoietic stem cells (HSCs) on the mechanistic level is poorly understood. Here, we employ a mouse model of chronic multifocal osteomyelitis (CMO) to assess the effects of a spontaneously developed inflammatory condition on HSCs. We demonstrate that hematopoietic and nonhematopoietic compartments in CMO BM contribute to HSC expansion and impair their function. Remarkably, our results suggest that the typical features of murine multifocal osteomyelitis and the HSC phenotype are mechanistically decoupled. We show that the CMO environment imprints a myeloid gene signature and imposes a pro-inflammatory profile on HSCs. We identify IL-6 and the Jak/Stat3 signaling pathway as critical mediators. However, while IL-6 and Stat3 blockage reduce HSC numbers in CMO mice, only inhibition of Stat3 activity significantly rescues their fitness. Our data emphasize the detrimental effects of chronic inflammation on stem cell function, opening new venues for treatment.

Keywords:  IL-6/Jak/Stat3; chronic inflammation; chronic multifocal osteomyelitis; hematopoietic stem cells; niche

DOI:  https://doi.org/10.15252/embr.202254729
Science. 2022 Nov 11. 378(6620): eabn5647

Enhanced T cell effector activity by targeting the Mediator kinase module.

Katherine A Freitas, Julia A Belk, Elena Sotillo, Patrick J Quinn, Maria C Ramello, Meena Malipatlolla, Bence Daniel, Katalin Sandor, Dorota Klysz, Jeremy Bjelajac, Peng Xu, Kylie A Burdsall, Victor Tieu, Vandon T Duong, Micah G Donovan, Evan W Weber, Howard Y Chang, Robbie G Majzner, Joaquin M Espinosa, Ansuman T Satpathy, Crystal L Mackall.

T cells are the major arm of the immune system responsible for controlling and regressing cancers. To identify genes limiting T cell function, we conducted genome-wide CRISPR knockout screens in human chimeric antigen receptor (CAR) T cells. Top hits were MED12 and CCNC, components of the Mediator kinase module. Targeted MED12 deletion enhanced antitumor activity and sustained the effector phenotype in CAR- and T cell receptor-engineered T cells, and inhibition of CDK8/19 kinase activity increased expansion of nonengineered T cells. MED12-deficient T cells manifested increased core Meditator chromatin occupancy at transcriptionally active enhancers-most notably for STAT and AP-1 transcription factors-and increased IL2RA expression and interleukin-2 sensitivity. These results implicate Mediator in T cell effector programming and identify the kinase module as a target for enhancing potency of antitumor T cell responses.

DOI: https://doi.org/10.1126/science.abn5647
Oncogene. 2022 Nov 08.

TET2 deficiency sensitizes tumor cells to statins by reducing HMGCS1 expression.

Si-Jia Sun, Ying-Jie Ai, Kun-Long Duan, Jin-Ye Zhang, Cheng Zhang, Yi-Ping Sun, Yue Xiong, Kun-Liang Guan, Hai-Xin Yuan.

TET2 (ten-eleven-translocation) protein is a Fe(II)- and α-ketoglutarate-dependent dioxygenase that catalyzes DNA demethylation to regulate gene expression. While TET2 gene is frequently mutated in hematological cancer, its enzymatic activity is also compromised in various solid tumors. Whether TET2 deficiency creates vulnerability for cancer cells has not been studied. Here we reported that TET2 deficiency is associated with the change of lipid metabolism processes in acute myeloid leukemia (AML) patient. We demonstrate that statins, the inhibitors of β-Hydroxy β-methylglutaryl-CoA (HMG-CoA) reductase and commonly used cholesterol-lowering medicines, significantly sensitize TET2 deficient tumor cells to apoptosis. TET2 directly regulates the expression of HMG-CoA synthase (HMGCS1) by catalyzing demethylation on its promoter region, and conversely TET2 deficiency leads to significant down-regulation of HMGCS1 expression and the mevalonate pathway. Consistently, overexpression of HMGCS1 in TET2-deficient cells rescues statin-induced apoptosis. We further reveal that decrease of geranylgeranyl diphosphate (GGPP), an intermediate metabolite in the mevalonate pathway, is responsible for statin-induced apoptosis. GGPP shortage abolishes normal membrane localization and function of multiple small GTPases, leading to cell dysfunction. Collectively, our study reveals a vulnerability in TET2 deficient tumor and a potential therapeutic strategy using an already approved safe medicine.

DOI: https://doi.org/10.1038/s41388-022-02531-3
Cancer Discov. 2022 Nov 09. pii: CD-22-0199. [Epub ahead of print]

Human bone marrow organoids for disease modelling, discovery and validation of therapeutic targets in hematological malignancies.

Abdullah O Khan, Antonio Rodriguez-Romera, Jasmeet S Reyat, Aude-Anais Olijnik, Michela Colombo, Guanlin Wang, Wei Xiong Wen, Nikolaos Sousos, Lauren C Murphy, Beata Grygielska, Gina Perrella, Christopher B Mahony, Rebecca E Ling, Natalina E Elliott, Christina Simoglou Karali, Andrew P Stone, Samuel Kemble, Emily A Cutler, Adele K Fielding, Adam P Croft, David Bassett, Gowsihan Poologasundarampillai, Anindita Roy, Sarah Gooding, Julie Rayes, Kellie R Machlus, Bethan Psaila.

A lack of models that recapitulate the complexity of human bone marrow has hampered mechanistic studies of normal and malignant hematopoiesis and the validation of novel therapies. Here, we describe a step-wise, directed-differentiation protocol in which organoids are generated from iPSCs committed to mesenchymal, endothelial and hematopoietic lineages. These 3-dimensional structures capture key features of human bone marrow - stroma, lumen-forming sinusoids and myeloid cells including pro-platelet forming megakaryocytes. The organoids supported the engraftment and survival of cells from patients with blood malignancies, including cancer types notoriously difficult to maintain ex vivo. Fibrosis of the organoid occurred following TGFβ stimulation and engraftment with myelofibrosis but not healthy donor-derived cells, validating this platform as a powerful tool for studies of malignant cells and their interactions within a human bone marrow-like milieu. This enabling technology is likely to accelerate discovery and prioritization of novel targets for bone marrow disorders and blood cancers.

DOI: https://doi.org/10.1158/2159-8290.CD-22-0199
Br J Haematol. 2022 Nov 10.

Transcriptomics of acute myeloid leukaemia core bone marrow biopsies reveals distinct therapy response-specific osteo-mesenchymal profiles.

Diana O Treaba, Dennis M Bonal, Anna Chorzalska, Mireia Castillo-Martin, Alissa Oakes, Makayla Pardo, Max Petersen, Christoph Schorl, Kelsey Hopkins, Dean Melcher, Ting C Zhao, Olin Liang, Eui-Young So, John Reagan, Adam J Olszewski, James Butera, Douglas C Anthony, Peter Rintels, Peter Quesenberry, Patrycja M Dubielecka.

  While the bone marrow (BM) microenvironment is significantly remodelled in acute myeloid leukaemia (AML), molecular insight into AML-specific alterations in the microenvironment has been historically limited by the analysis of liquid marrow aspirates rather than core biopsies that contain solid-phase BM stroma. We assessed the effect of anthracycline- and cytarabine-based induction chemotherapy on both haematopoietic and non-haematopoietic cells directly in core BM biopsies using RNA-seq and histological analysis. We compared matched human core BM biopsies at diagnosis and 2 weeks after cytarabine- and anthracycline-based induction therapy in responders (<5% blasts present after treatment) and non-responders (≥5% blasts present after treatment). Our data indicated enrichment in vimentin (VIM), platelet-derived growth factor receptor beta (PDGFRB) and Snail family transcriptional repressor 2 (SNAI2) transcripts in responders, consistent with the reactivation of the mesenchymal population in the BM stroma. Enrichment of osteoblast maturation-related transcripts of biglycan (BGN), osteopontin (SPP1) and osteonectin (SPARC) was observed in non-responders. To the best of our knowledge, this is the first report demonstrating distinct osteogenic and mesenchymal transcriptome profiles specific to AML response to induction chemotherapy assessed directly in core BM biopsies. Detailing treatment response-specific alterations in the BM stroma may inform optimised therapeutic strategies for AML.

Keywords:  AML induction therapy; acute myeloid leukaemia; core bone marrow biopsies; mesenchymal stem cells; osteoblasts

DOI:  https://doi.org/10.1111/bjh.18513
Blood. 2022 Nov 08. pii: blood.2022017578. [Epub ahead of print]

Genetic basis and molecular profiling in myeloproliferative neoplasms.

Damien Luque Paz, Robert Kralovics, Radek C Skoda.

BCR::ABL1-negative myeloproliferative neoplasms (MPN) are clonal diseases originating from a single hematopoietic stem cell (HSC) that cause excessive production of mature blood cells. The three subtypes polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are diagnosed according to the World Health Organization (WHO) and International Consensus Classification (ICC) criteria. Acquired gain-of-function mutations in one of three disease driver genes, JAK2, CALR and MPL are the causative events that can alone initiate and promote MPN disease without requiring additional cooperating mutations. JAK2-p.V617F is present in >95% of PV patients, and also in about half of the patients with ET or PMF. ET and PMF are also caused by mutations in CALR or MPL. In ~10% of MPN patients, called "triple negative", none of the known driver gene mutations can be detected. The common theme between the three driver gene mutations and "triple-negative" MPN is that the JAK/STAT signaling pathway is constitutively activated. We review the recent advances in our understanding of the early events after the acquisition of a driver gene mutation. Not the acquisition of driver gene mutations, but rather the expansion of the clone is the limiting factor that determines the frequency at which MPN disease develops with a long latency. Factors that control the conversion from clonal hematopoiesis to MPN include inherited predisposition, presence of additional mutations and inflammation. The complete knowledge of the mutational landscape in individual MPN patients is now increasingly being used to predict outcome and chose the optimal therapy.

DOI: https://doi.org/10.1182/blood.2022017578
Cell Rep. 2022 Nov 08. pii: S2211-1247(22)01457-7. [Epub ahead of print]41(6): 111592

Identification of hematopoietic stem cells residing in the meninges of adult mice at steady state.

Chunxiao Niu, Jijun Yu, Tao Zou, Yuchen Lu, Lijiao Deng, Hongfang Yun, Chuan-Yimu Si, Xian Wu, Hui Jiang, Tingting Guo, Mengyao Wu, Tongtong Kan, Jiannan Feng, Chao Yuan, Xiqin Yang, Qianqian Cheng, Jie Dong, Qingyang Wang, Jiyan Zhang.

  Steady-state extramedullary hematopoiesis during adulthood is an emerging field of great interest. The meninges contain both innate and adaptive immune cells, which provide immunosurveillance of the central nervous system (CNS). Hematopoietic progenitors that give rise to meningeal immune cells remain elusive. Here, we report that steady-state meninges of adult mice host hematopoietic stem cells (HSCs), as defined by long-term, efficient, multi-lineage reconstitution and self-renewal capacity in the meninges, blood, spleen, and bone marrow of sublethally irradiated adult recipients. HSCs lodge in the meninges after birth with local expression of pro-hematopoietic niche factors. Meningeal HSCs are locally maintained in homeostasis and get replenished from the blood only when the resident pool is reduced. With a tissue-specific expression profile, meningeal HSCs can provide the CNS with a constant supply of leukocytes more adapted to local microenvironment.

Keywords:  CP: Stem cell research; HSCs; extramedullary hematopoiesis; meninges; niche; transplantation

DOI:  https://doi.org/10.1016/j.celrep.2022.111592
Leukemia. 2022 Nov 05.

Loss of bisecting GlcNAcylation on MCAM of bone marrow stoma determined pro-tumoral niche in MDS/AML.

Jingjing Feng, Yi Wang, Bingxin Li, Xinwen Yu, Lei Lei, Jinpeng Wu, Xin Zhang, Qiushi Chen, Yue Zhou, Junjie Gou, Hongjiao Li, Zengqi Tan, Zhijun Dai, Xiang Li, Feng Guan.

Bone marrow (BM) stroma plays key roles in supporting hematopoietic stem cell (HSC) growth. Glycosylation contributes to the interactions between HSC and surrounding microenvironment. We observed that bisecting N-acetylglucosamine (GlcNAc) structures, in BM stromal cells were significantly lower for MDS/AML patients than for healthy subjects. Malignant clonal cells delivered exosomal miR-188-5p to recipient stromal cells, where it suppressed bisecting GlcNAc by targeting MGAT3 gene. Proteomic analysis revealed reduced GlcNAc structures and enhanced expression of MCAM, a marker of BM niche. We characterized MCAM as a bisecting GlcNAc-bearing target protein, and identified Asn 56 as bisecting GlcNAc modification site on MCAM. MCAM on stromal cell surface with reduced bisecting GlcNAc bound strongly to CD13 on myeloid cells, activated responding ERK signaling, and thereby promoted myeloid cell growth. Our findings, taken together, suggest a novel mechanism whereby MDS/AML clonal cells generate a self-permissive niche by modifying glycosylation level of stromal cells.

DOI: https://doi.org/10.1038/s41375-022-01748-1
J Bone Miner Metab. 2022 Nov 08.

Factors associated with clonal hematopoiesis and interaction with marrow environment.

Yasuhito Nannya.

  Clonal hematopoiesis (CH) is an expansion of clones in individuals without any hematologic abnormalities, often carrying the driver mutations implicated in myeloid tumors, such as DNMT3A, TET2, and ASXL1. Most notably, CH is an age-related event, accounting for ~ 10% of cases in people over 60 years old. CH may also be correlated with a previous history of cancer treatment with chemotherapeutic drugs/radiation and infection episodes. The link between aging and CH acquisition is best explained by the enhanced inflammatory level in the bone marrow environment, which in turn expands hematopoietic cell clones with mutations in myeloid drivers. This positive feedback accounts for not only increased incidence of subsequent myeloid tumors in CH carriers but also for increased all-cause mortality and cardiovascular diseases (CVD). Recent evidence from large-scale epidemiological studies with genetic profiles, and mice models that recapitulate hematopoietic clones harboring driver gene mutations has revealed the detailed pathophysiology of CH clones represented by specific driver mutations, especially regarding expansion mechanisms under environmental factors and how they alter the environment. This review introduces the current knowledge of CH with a special focus on its interaction with the marrow environment.

Keywords:  Aging; Bone marrow environment; Clonal hematopoiesis

DOI:  https://doi.org/10.1007/s00774-022-01380-0
Br J Haematol. 2022 Nov 12.

A uniform conditioning regimen of busulfan, fludarabine, and antithymocyte globulin for allogeneic haematopoietic cell transplantation from haploidentical family, matched sibling, or unrelated donors-A single-centre, prospective, explorative study.

Yunsuk Choi, Eun-Ji Choi, Han-Seung Park, Jung-Hee Lee, Je-Hwan Lee, Young-Shin Lee, Young-A Kang, Mijin Jeon, Ji Min Woo, Hyeran Kang, Seunghyun Baek, Su Mi Kim, Chae-Eun Bong, Kyoo-Hyung Lee.

  In a prospective, explorative study, the donor-source difference of haploidentical family (HF), matched sibling (MS), and unrelated donors (UD) was evaluated for the outcome of haematopoietic cell transplantations (HCT) in 101 patients with acute myeloid leukaemia (AML) in complete remission (CR). To eliminate compounding effects, a uniform conditioning regimen containing antithymocyte globulin (ATG) was used. After transplantation, there was a significantly higher cumulative incidence of acute graft-versus-host disease (GVHD) in HF-HCT patients (49%, 7%, and 16% for HF-, MS- and UD-HCT respectively; p < 0.001). A quarter of acute GVHD cases observed in HF-HCT patients occurred within three days of engraftment and were characterized by diffuse skin rash, fever, weight gain, and hypoalbuminaemia. This peri-engraftment acute GVHD was not observed in MS-HCT or UD-HCT patients. Additionally, a significantly higher proportion of HF-HCT patients achieved complete donor chimaerism in the peripheral mononuclear cells at one month (88%, 46%, and 69% for HF-, MS- and UD-HCT respectively; p = 0.001). There was no significant difference in engraftment, chronic GVHD, leukaemia recurrence, non-relapse mortality, and patient survival. In patients with AML in CR who received HCT using ATG-containing conditioning, stronger donor-patient alloreactivity was observed in HF-HCT, in terms of increased acute GVHD and higher likelihood of complete donor chimaerism.

Keywords:  acute myeloid leukaemia; allogeneic haematopoietic cell transplantation; antithymocyte globulin; donor type; outcome

DOI:  https://doi.org/10.1111/bjh.18550