bims-tremyl 2023-04-23 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2023–04–23
34 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

UBTF tandem duplications define a distinct subtype of adult de novo acute myeloid leukemia.
Spectrum of clonal hematopoiesis in VEXAS syndrome.
Patient-Derived iPSCs Faithfully Represent the Genetic Diversity and Cellular Architecture of Human Acute Myeloid Leukemia.
Resistance to energy metabolism - targeted therapy of AML cells residual in the bone marrow microenvironment.
Entospletinib with decitabine in acute myeloid leukemia with mutant TP53 or complex karyotype: A phase 2 substudy of the Beat AML Master Trial.
Co-targeting BCL-XL and BCL-2 by PROTAC 753B eliminates leukemia cells and enhances efficacy of chemotherapy by targeting senescent cells.
Persistent Molecular Disease in Adult Patients With AML Evaluated With Whole-Exome and Targeted Error-Corrected DNA Sequencing.
Targeting MCL1-driven anti-apoptotic pathways to overcome hypomethylating agent resistance in RAS -mutated chronic myelomonocytic leukemia.
FLT3 inhibitors upregulate CXCR4 and E-selectin ligands via ERK suppression in AML cells and CXCR4/E-selectin inhibition enhances anti-leukemia efficacy of FLT3-targeted therapy in AML.
Obesity induced inflammation exacerbates clonal hematopoiesis.
Characterization of the MYB-inhibitory potential of the Pan-HDAC inhibitor LAQ824.
Acute myeloid leukaemia.
RNA binding protein SYNCRIP maintains proteostasis and self-renewal of hematopoietic stem and progenitor cells.
STIMULUS-MDS2 design and rationale: a phase III trial with the anti-TIM-3 sabatolimab (MBG453) + azacitidine in higher risk MDS and CMML-2.
Patients with secondary acute myeloid leukemia undergoing allogeneic stem-cell transplant have inferior outcomes than de novo acute myeloid leukemia regardless minimal residual disease level by flow cytometry.
Clonal Hematopoiesis: Origins and determinants of evolution.
Exposure to microbial products followed by loss of Tet2 promotes myelodysplastic syndrome via remodeling HSCs.
iPSC models of leukemia come of age.
Subclinical minute FLT3-ITD clone can be detected in clinically FLT3-ITD-negative acute myeloid leukaemia at diagnosis.
Comprehensive response criteria for myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions: a proposal from the MLN International Working Group.
Myelodysplastic syndromes disable human CD271 + VCAM1 + CD146 + niches supporting normal hematopoietic stem/progenitor cells.
Cytopenic myelofibrosis: prevalence, relevance, and treatment.
Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation.
Revisiting the prognostic role of FLT3 mutations in acute myelogenous leukemia.
MDM2 inhibition enhances immune checkpoint inhibitor efficacy by increasing IL-15 and MHC class II production.
FDA Analysis of Ineligibility for Acute Myeloid Leukemia Clinical Trials by Race and Ethnicity.
Ten years after ruxolitinib approval for myelofibrosis: a review of clinical efficacy.
Li-Fraumeni Syndrome-Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death.
Age-related loss of chromosome Y is associated with levels of sex hormone binding globulin and clonal hematopoiesis defined by TET2, TP53, and CBL mutations.
Intestinal permeability of stem cell transplant patients correlates with systemic acute phase responses and dysbiosis.
Health-related quality of life of patients with resistant/intolerant chronic phase chronic myeloid leukemia treated with asciminib or bosutinib in the phase 3 ASCEMBL trial.
Alternative donor BMT with post-transplant cyclophosphamide as initial therapy for acquired severe aplastic anemia.
JAK2 inhibitor treatment of anemia in myelofibrosis.
RNA binding induces an allosteric switch in Cyp33 to repress MLL1-mediated transcription.

Leukemia. 2023 Apr 21.

UBTF tandem duplications define a distinct subtype of adult de novo acute myeloid leukemia.

Nicolas Duployez, Loïc Vasseur, Rathana Kim, Laëtitia Largeaud, Marie Passet, Anaïs L'Haridon, Pierre Lemaire, Laurène Fenwarth, Sandrine Geffroy, Nathalie Helevaut, Karine Celli-Lebras, Lionel Adès, Delphine Lebon, Céline Berthon, Alice Marceau-Renaut, Meyling Cheok, Juliette Lambert, Christian Récher, Emmanuel Raffoux, Jean-Baptiste Micol, Arnaud Pigneux, Claude Gardin, Eric Delabesse, Jean Soulier, Mathilde Hunault, Hervé Dombret, Raphael Itzykson, Emmanuelle Clappier, Claude Preudhomme.

Tandem duplications (TDs) of the UBTF gene have been recently described as a recurrent alteration in pediatric acute myeloid leukemia (AML). Here, by screening 1946 newly diagnosed adult AML, we found that UBTF-TDs occur in about 3% of patients aged 18-60 years, in a mutually exclusive pattern with other known AML subtype-defining alterations. The characteristics of 59 adults with UBTF-TD AML included young age (median 37 years), low bone marrow (BM) blast infiltration (median 25%), and high rates of WT1 mutations (61%), FLT3-ITDs (51%) and trisomy 8 (29%). BM morphology frequently demonstrates dysmyelopoiesis albeit modulated by the co-occurrence of FLT3-ITD. UBTF-TD patients have lower complete remission (CR) rates (57% after 1 course and 76% after 2 courses of intensive chemotherapy [ICT]) than UBTF-wild-type patients. In patients enrolled in the ALFA-0702 study (n = 614 patients including 21 with UBTF-TD AML), the 3-year disease-free survival (DFS) and overall survival of UBTF-TD patients were 42.9% (95%CI: 23.4-78.5%) and 57.1% (95%CI: 39.5-82.8%) and did not significantly differ from those of ELN 2022 intermediate/adverse risk patients. Finally, the study of paired diagnosis and relapsed/refractory AML samples suggests that WT1-mutated clones are frequently selected under ICT. This study supports the recognition of UBTF-TD AML as a new AML entity in adults.

DOI: https://doi.org/10.1038/s41375-023-01906-z
Blood. 2023 Apr 21. pii: blood.2022018774. [Epub ahead of print]

Spectrum of clonal hematopoiesis in VEXAS syndrome.

Fernanda Gutierrez-Rodrigues, Yael Kusne, Jenna Fernandez, Terra L Lasho, Ruba N Shalhoub, Xiaoyang Ma, Hugh Alessi, Christy M Finke, Matthew J Koster, Abhishek A Mangaonkar, Kenneth J Warrington, Kebede Begna, Zhuoer Xie, Amanda K Ombrello, David S Viswanatha, Marcela A Ferrada, Lorena Wilson, Ronald S Go, Taxiarchis V Kourelis, Kaaren K Reichard, Horatiu Olteanu, Ivana Darden, Dalton Hironaka, Lemlem Alemu, Sachiko Kajigaya, Rodrigo T Calado, Emma M Groarke, Sofia Rosenzweig, Daniel L Kastner, Katherine R Calvo, Colin O Wu, Peter C Grayson, Neal S Young, David B Beck, Bhavisha A Patel, Mrinal M Patnaik.

VEXAS is caused by somatic mutations in UBA1 (UBA1mut) and characterized by heterogenous systemic auto-inflammation and progressive hematologic manifestations, meeting criteria for myelodysplastic syndrome (MDS) and plasma cell dyscrasias. The landscape of myeloid-related gene mutations leading to typical clonal hematopoiesis (CH) in these patients is unknown. Retrospectively, we screened 80 VEXAS patients for CH in their peripheral blood (PB) and correlated findings with clinical outcomes in 77. UBA1mutwere most common at hotspot p.M41 (median variant allele frequency/VAF = 75%). Typical CH mutations co-occurred with UBA1mut in 60% of patients, mostly in DNMT3A and TET2, and were not associated with inflammatory or hematologic manifestations. In prospective single-cell proteogenomic sequencing (scDNA), UBA1mutwas the dominant clone, present mostly in branched clonal trajectories. Based on integrated bulk and scDNA analyses, clonality in VEXAS followed two major patterns: with either typical CH preceding UBA1mutselection in a clone (Pattern 1), or occurring as an UBA1mutsubclone or in independent clones (Pattern 2). VAF in PB differed markedly between DNMT3A and TET2 clones (median VAF of 25% vs 1%). DNMT3A and TET2 clones associated with hierarchies representing patterns 1 and 2, respectively. Overall survival for all patients was 60% at 10 years. Transfusion-dependent anemia, moderate thrombocytopenia, and typical CH mutations, each correlated with poor outcome. In VEXAS, UBA1mut cells are the primary cause of systemic inflammation and marrow failure, being a new molecularly defined somatic entity associated with MDS. VEXAS-associated MDS is distinct from classical MDS in its presentation and clinical course.

DOI: https://doi.org/10.1182/blood.2022018774
Blood Cancer Discov. 2023 Apr 17. OF1-OF18

Patient-Derived iPSCs Faithfully Represent the Genetic Diversity and Cellular Architecture of Human Acute Myeloid Leukemia.

Andriana G Kotini, Saul Carcamo, Nataly Cruz-Rodriguez, Malgorzata Olszewska, Tiansu Wang, Deniz Demircioglu, Chan-Jung Chang, Elsa Bernard, Mark P Chao, Ravindra Majeti, Hanzhi Luo, Michael G Kharas, Dan Hasson, Eirini P Papapetrou.

The reprogramming of human acute myeloid leukemia (AML) cells into induced pluripotent stem cell (iPSC) lines could provide new faithful genetic models of AML, but is currently hindered by low success rates and uncertainty about whether iPSC-derived cells resemble their primary counterparts. Here we developed a reprogramming method tailored to cancer cells, with which we generated iPSCs from 15 patients representing all major genetic groups of AML. These AML-iPSCs retain genetic fidelity and produce transplantable hematopoietic cells with hallmark phenotypic leukemic features. Critically, single-cell transcriptomics reveal that, upon xenotransplantation, iPSC-derived leukemias faithfully mimic the primary patient-matched xenografts. Transplantation of iPSC-derived leukemias capturing a clone and subclone from the same patient allowed us to isolate the contribution of a FLT3-ITD mutation to the AML phenotype. The results and resources reported here can transform basic and preclinical cancer research of AML and other human cancers.
SIGNIFICANCE: We report the generation of patient-derived iPSC models of all major genetic groups of human AML. These exhibit phenotypic hallmarks of AML in vitro and in vivo, inform the clonal hierarchy and clonal dynamics of human AML, and exhibit striking similarity to patient-matched primary leukemias upon xenotransplantation. See related commentary by Doulatov.

DOI: https://doi.org/10.1158/2643-3230.BCD-22-0167
Cancer Drug Resist. 2023 ;6(1): 138-150

Resistance to energy metabolism - targeted therapy of AML cells residual in the bone marrow microenvironment.

Yoko Tabe, Marina Konopleva.

  In response to the changing availability of nutrients and oxygen in the bone marrow microenvironment, acute myeloid leukemia (AML) cells continuously adjust their metabolic state. To meet the biochemical demands of their increased proliferation, AML cells strongly depend on mitochondrial oxidative phosphorylation (OXPHOS). Recent data indicate that a subset of AML cells remains quiescent and survives through metabolic activation of fatty acid oxidation (FAO), which causes uncoupling of mitochondrial OXPHOS and facilitates chemoresistance. For targeting these metabolic vulnerabilities of AML cells, inhibitors of OXPHOS and FAO have been developed and investigated for their therapeutic potential. Recent experimental and clinical evidence has revealed that drug-resistant AML cells and leukemic stem cells rewire metabolic pathways through interaction with BM stromal cells, enabling them to acquire resistance against OXPHOS and FAO inhibitors. These acquired resistance mechanisms compensate for the metabolic targeting by inhibitors. Several chemotherapy/targeted therapy regimens in combination with OXPHOS and FAO inhibitors are under development to target these compensatory pathways.

Keywords:  Bone marrow microenvironment; acute myeloid leukemia; energy metabolism; fatty acid oxidation; mitochondria; oxidative phosphorylation

DOI:  https://doi.org/10.20517/cdr.2022.133
Cancer. 2023 Apr 20.

Entospletinib with decitabine in acute myeloid leukemia with mutant TP53 or complex karyotype: A phase 2 substudy of the Beat AML Master Trial.

Vu H Duong, Amy S Ruppert, Alice S Mims, Uma Borate, Eytan M Stein, Maria R Baer, Wendy Stock, Tibor Kovacsovics, William Blum, Martha L Arellano, Gary J Schiller, Rebecca L Olin, James M Foran, Mark R Litzow, Tara L Lin, Prapti A Patel, Matthew C Foster, Robert L Redner, Zeina Al-Mansour, Christopher R Cogle, Ronan T Swords, Robert H Collins, Jo-Anne Vergilio, Nyla A Heerema, Leonard Rosenberg, Ashley O Yocum, Sonja Marcus, Timothy Chen, Franchesca Druggan, Mona Stefanos, Theophilus J Gana, Abigail B Shoben, Brian J Druker, Amy Burd, John C Byrd, Ross L Levine, Michael M Boyiadzis.

   BACKGROUND: Patients with acute myeloid leukemia (AML) who have tumor protein p53 (TP53) mutations or a complex karyotype have a poor prognosis, and hypomethylating agents are often used. The authors evaluated the efficacy of entospletinib, an oral inhibitor of spleen tyrosine kinase, combined with decitabine in this patient population.
METHODS: This was a multicenter, open-label, phase 2 substudy of the Beat AML Master Trial (ClinicalTrials.gov identifier NCT03013998) using a Simon two-stage design. Eligible patients aged 60 years or older who had newly diagnosed AML with mutations in TP53 with or without a complex karyotype (cohort A; n = 45) or had a complex karyotype without TP53 mutation (cohort B; n = 13) received entospletinib 400 mg twice daily with decitabine 20 mg/m2 on days 1-10 every 28 days for up to three induction cycles, followed by up to 11 consolidation cycles, in which decitabine was reduced to days 1-5. Entospletinib maintenance was given for up to 2 years. The primary end point was complete remission (CR) and CR with hematologic improvement by up to six cycles of therapy.
RESULTS: The composite CR rates for cohorts A and B were 13.3% (95% confidence interval, 5.1%-26.8%) and 30.8% (95% confidence interval, 9.1%-61.4%), respectively. The median duration of response was 7.6 and 8.2 months, respectively, and the median overall survival was 6.5 and 11.5 months, respectively. The study was stopped because the futility boundary was crossed in both cohorts.
CONCLUSIONS: The combination of entospletinib and decitabine demonstrated activity and was acceptably tolerated in this patient population; however, the CR rates were low, and overall survival was short. Novel treatment strategies for older patients with TP53 mutations and complex karyotype remain an urgent need.

Keywords:  acute myeloid leukemia; decitabine; entospletinib; hypomethylating agents; tumor protein p53 (TP53)

DOI:  https://doi.org/10.1002/cncr.34780
Haematologica. 2023 Apr 20.

Co-targeting BCL-XL and BCL-2 by PROTAC 753B eliminates leukemia cells and enhances efficacy of chemotherapy by targeting senescent cells.

Yannan Jia, Lina Han, Cassandra L Ramage, Zhe Wang, Connie C Weng, Lei Yang, Simona Colla, Helen Ma, Weiguo Zhang, Michael Andreeff, Naval Daver, Nitin Jain, Naveen Pemmaraju, Kapil Bhalla, Satu Mustjoki, Peiyi Zhang, Guangrong Zheng, Daohong Zhou, Qi Zhang, Marina Konopleva.

BCL-XL and BCL-2 are key anti-apoptotic proteins and validated cancer targets. 753B is a novel BCL-XL/BCL-2 proteolysis targeting chimera (PROTAC) that targets both BCL-XL and BCL-2 to the Von Hippel-Lindau (VHL) E3 ligase, leading to BCL-XL/BCL-2 ubiquitination and degradation selectively in cells expressing VHL. Because platelets lack VHL expression, 753B spares on-target platelet toxicity caused by the first generation dual BCL-XL/BCL-2 inhibitor navitoclax (ABT-263). Here, we report pre-clinical single-agent activity of 753B against different leukemia subsets. 753B effectively reduced cell viability and induced dose-dependent degradation of BCL-XL and BCL-2 in a subset of hematopoietic cell lines, AML primary samples and in vivo PDX AML model. We further demonstrated the senolytic activity of 753B which enhanced the efficacy of chemotherapy by targeting chemotherapy-induced cellular senescence. These results provide a pre-clinical rationale for the utility of 753B in AML therapy, and suggest that 753B could produce an added therapeutic benefit by overcoming cellular senescence-induced chemoresistance when combined with chemotherapy.

DOI: https://doi.org/10.3324/haematol.2022.281915
JCO Precis Oncol. 2023 Apr;7 e2200559

Persistent Molecular Disease in Adult Patients With AML Evaluated With Whole-Exome and Targeted Error-Corrected DNA Sequencing.

Michael J Slade, Reza Ghasemi, Michelle O'Laughlin, Tasha Burton, Robert S Fulton, Haley J Abel, Eric J Duncavage, Timothy J Ley, Meagan A Jacoby, David H Spencer.

PURPOSE: Persistent molecular disease (PMD) after induction chemotherapy predicts relapse in AML. In this study, we used whole-exome sequencing (WES) and targeted error-corrected sequencing to assess the frequency and mutational patterns of PMD in 30 patients with AML.
MATERIALS AND METHODS: The study cohort included 30 patients with adult AML younger than 65 years who were uniformly treated with standard induction chemotherapy. Tumor/normal WES was performed for all patients at presentation. PMD analysis was evaluated in bone marrow samples obtained during clinicopathologic remission using repeat WES and analysis of patient-specific mutations and error-corrected sequencing of 40 recurrently mutated AML genes (MyeloSeq).
RESULTS: WES for patient-specific mutations detected PMD in 63% of patients (19/30) using a minimum variant allele fraction (VAF) of 2.5%. In comparison, MyeloSeq identified persistent mutations above 0.1% VAF in 77% of patients (23/30). PMD was usually present at relatively high levels (>2.5% VAFs), such that WES and MyeloSeq agreed for 73% of patients despite differences in detection limits. Mutations in DNMT3A, ASXL1, and TET2 (ie, DTA mutations) were persistent in 16 of 17 patients, but WES also detected non-DTA mutations in 14 of these patients, which for some patients distinguished residual AML cells from clonal hematopoiesis. Surprisingly, MyeloSeq detected additional variants not identified at presentation in 73% of patients that were consistent with new clonal cell populations after chemotherapy.
CONCLUSION: PMD and clonal hematopoiesis are both common in patients with AML in first remission. These findings demonstrate the importance of baseline testing for accurate interpretation of mutation-based tumor monitoring assays for patients with AML and highlight the need for clinical trials to determine whether these complex mutation patterns correlate with clinical outcomes in AML.

DOI: https://doi.org/10.1200/PO.22.00559
bioRxiv. 2023 Apr 08. pii: 2023.04.07.535928. [Epub ahead of print]

Targeting MCL1-driven anti-apoptotic pathways to overcome hypomethylating agent resistance in RAS -mutated chronic myelomonocytic leukemia.

Guillermo Montalban-Bravo, Feiyang Ma, Natthakan Thongon, Hui Yang, Irene Ganan- Gomez, Juanjo Jose Rodriguez-Sevilla, Vera Adema, Bethany Wildeman, Pamela Lockyer, Yi June Kim, Tomoyuki Tanaka, Faezeh Darbaniyan, Shivam Pancholy, Geoffrey Zhang, Gheath Al-Atrash, Karen Dwyer, Koichi Takahashi, Guillermo Garcia-Manero, Hagop Kantarjian, Simona Colla.

RAS pathway mutations, which are present in 30% of patients with chronic myelomonocytic leukemia (CMML) at diagnosis, confer a high risk of resistance to and progression after hypomethylating agent (HMA) therapy, the current standard of care for the disease. Using single-cell, multi-omics technologies, we sought to dissect the biological mechanisms underlying the initiation and progression of RAS pathway-mutated CMML. We found that RAS pathway mutations induced the transcriptional reprogramming of hematopoietic stem and progenitor cells (HSPCs), which underwent proliferation and monocytic differentiation in response to cell-intrinsic and -extrinsic inflammatory signaling that also impaired immune cells' functions. HSPCs expanded at disease progression and relied on the NF- K B pathway effector MCL1 to maintain their survival, which explains why patients with RAS pathway- mutated CMML do not benefit from BCL2 inhibitors such as venetoclax. Our study has implications for developing therapies to improve the survival of patients with RAS pathway- mutated CMML.

DOI: https://doi.org/10.1101/2023.04.07.535928
Leukemia. 2023 Apr 21.

FLT3 inhibitors upregulate CXCR4 and E-selectin ligands via ERK suppression in AML cells and CXCR4/E-selectin inhibition enhances anti-leukemia efficacy of FLT3-targeted therapy in AML.

Yannan Jia, Weiguo Zhang, Mahesh Basyal, Kyung Hee Chang, Lauren Ostermann, Jared K Burks, Charlie Ly, Hong Mu-Mosley, Qi Zhang, Xin Han, William E Fogler, John L Magnani, Arnaud Lesegretain, Anna A Zal, Tomasz Zal, Michael Andreeff.

DOI: https://doi.org/10.1038/s41375-023-01897-x
J Clin Invest. 2023 Apr 18. pii: e163968. [Epub ahead of print]

Obesity induced inflammation exacerbates clonal hematopoiesis.

Santhosh Kumar Pasupuleti, Baskar Ramdas, Sarah S Burns, Lakshmi Reddy Palam, Rahul Kanumuri, Ramesh Kumar, Taruni R Pandhiri, Utpal Dave, Nanda Kumar Yellapu, Xinyu Zhou, Chi Zhang, George E Sandusky, Zhi Yu, Michael C Honigberg, Alexander G Bick, Gabriel K Griffin, Abhishek Niroula, Benjamin L Ebert, Sophie Paczesny, Pradeep Natarajan, Reuben Kapur.

  Characterized by the accumulation of somatic mutations in blood cell lineages, clonal hematopoiesis (CH) of indeterminate potential (CHIP) is frequent in ageing, involves expansion of mutated hematopoietic stem and progenitor cells (HSC/Ps) that leads to an increased risk of hematologic malignancy. However, risk factors that contribute to CHIP-associated CH are poorly understood. Obesity induces a pro-inflammatory state and fatty bone marrow (FBM), which may influence CHIP-associated pathologies. We analyzed exome sequencing and clinical data from 47,466 individuals with validated CHIP in UK Biobank. CHIP was present in 5.8% of the study population and was associated with a significant increase in waist-to-hip ratio (WHR). Mouse models of obesity and CHIP driven by heterozygosity of Tet2, Dnmt3a, Asxl1 and Jak2 resulted in exacerbated expansion of mutant HSC/Ps due in part to excessive inflammation. Our results show that obesity is highly associated with CHIP and a pro-inflammatory state can potentiate progression of CHIP to more significant hematologic neoplasia. Calcium channel blocker, nifedipine or SKF-96365, either alone or in combination with metformin, MCC950 or anakinra (IL-1 receptor antagonist), suppressed the growth of mutant CHIP cells and partially restored normal hematopoiesis. Targeting CHIP mutant cells with these drugs could be a potential therapeutic approach to treat CH and its associated abnormalities in obese individuals.

Keywords:  Cancer; Hematology; Hematopoietic stem cells; Inflammation

DOI:  https://doi.org/10.1172/JCI163968
BBA Adv. 2022 ;2 100034

Characterization of the MYB-inhibitory potential of the Pan-HDAC inhibitor LAQ824.

Maria V Yusenko, Karl-Heinz Klempnauer.

  A large body of work has shown that MYB acts as a master transcription regulator in hematopoietic cells and has pinpointed MYB as a potential drug target for acute myeloid leukemia (AML). Here, we have examined the MYB-inhibitory potential of the HDAC inhibitor LAQ824, which was identified in a screen for novel MYB inhibitors. We show that nanomolar concentrations of LAQ824 and the related HDAC inhibitors vorinostat and panobinostat interfere with MYB function in two ways, by inducing its degradation and inhibiting its activity. Reporter assays show that the inhibition of MYB activity by LAQ824 involves the MYB transactivation domain and the cooperation of MYB with co-activator p300, a key MYB interaction partner and driver of MYB activity. In AML cells, LAQ824-induced degradation of MYB is accompanied by expression of myeloid differentiation markers and apoptotic and necrotic cell death. The ability of LAQ824 to inhibit MYB activity is supported by the observation that down-regulation of direct MYB target genes MYC and GFI1 occurs without apparent decrease of MYB expression already after 2 h of treatment with LAQ824. Furthermore, ectopic expression of an activated version of MYB In HL60 cells counteracts the induction of myeloid differentiation by LAQ824. Overall, our data identify LAQ824 and related HDAC inhibitors as potent MYB-inhibitory agents that exert dual effects on MYB expression and activity in AML cells.

Keywords:  HDAC inhibitor; Inhibitor; LAQ824; MYB; Myeloid leukemia; p300

DOI:  https://doi.org/10.1016/j.bbadva.2021.100034
Lancet. 2023 Apr 14. pii: S0140-6736(23)00108-3. [Epub ahead of print]

Acute myeloid leukaemia.

Courtney D DiNardo, Harry P Erba, Sylvie D Freeman, Andrew H Wei.

Progress in acute myeloid leukaemia treatment is occurring at an unprecedented pace. The past decade has witnessed an increasingly improved scientific understanding of the underlying biology of acute myeloid leukaemia, leading to enhanced prognostication tools and refined risk assessments, and most especially incorporating measurable residual disease (MRD) into longitudinal risk assessments. The classification of acute myeloid leukaemia has recently been updated by WHO and the International Consensus Classification (ICC). Recommendations for prognostic stratification, response assessment, and MRD determination have also been updated by the European LeukemiaNet. Treatment options have evolved substantially in the last 5 years for patients with newly diagnosed acute myeloid leukaemia, leading to improved outcomes in intensively treated patients and those more appropriate for non-intensive chemotherapy. More effective targeted treatment options in the relapsed setting are also available, further advancing the treatment armamentarium and improving patient outcomes.

DOI: https://doi.org/10.1016/S0140-6736(23)00108-3
Nat Commun. 2023 Apr 21. 14(1): 2290

RNA binding protein SYNCRIP maintains proteostasis and self-renewal of hematopoietic stem and progenitor cells.

Florisela Herrejon Chavez, Hanzhi Luo, Paolo Cifani, Alli Pine, Karen L Chu, Suhasini Joshi, Ersilia Barin, Alexandra Schurer, Mandy Chan, Kathryn Chang, Grace Y Q Han, Aspen J Pierson, Michael Xiao, Xuejing Yang, Lindsey M Kuehm, Yuning Hong, Diu T T Nguyen, Gabriela Chiosis, Alex Kentsis, Christina Leslie, Ly P Vu, Michael G Kharas.

Tissue homeostasis is maintained after stress by engaging and activating the hematopoietic stem and progenitor compartments in the blood. Hematopoietic stem cells (HSCs) are essential for long-term repopulation after secondary transplantation. Here, using a conditional knockout mouse model, we revealed that the RNA-binding protein SYNCRIP is required for maintenance of blood homeostasis especially after regenerative stress due to defects in HSCs and progenitors. Mechanistically, we find that SYNCRIP loss results in a failure to maintain proteome homeostasis that is essential for HSC maintenance. SYNCRIP depletion results in increased protein synthesis, a dysregulated epichaperome, an accumulation of misfolded proteins and induces endoplasmic reticulum stress. Additionally, we find that SYNCRIP is required for translation of CDC42 RHO-GTPase, and loss of SYNCRIP results in defects in polarity, asymmetric segregation, and dilution of unfolded proteins. Forced expression of CDC42 recovers polarity and in vitro replating activities of HSCs. Taken together, we uncovered a post-transcriptional regulatory program that safeguards HSC self-renewal capacity and blood homeostasis.

DOI: https://doi.org/10.1038/s41467-023-38001-x
Future Oncol. 2023 Apr 21.

STIMULUS-MDS2 design and rationale: a phase III trial with the anti-TIM-3 sabatolimab (MBG453) + azacitidine in higher risk MDS and CMML-2.

Amer M Zeidan, Aristoteles Giagounidis, Mikkael A Sekeres, Zhijian Xiao, Guillermo F Sanz, Marlies Van Hoef, Fei Ma, Sabine Hertle, Valeria Santini.

  Patients with higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) unfit for hematopoietic stem cell transplantation have poor outcomes. Novel therapies that provide durable benefit with favorable tolerability and clinically meaningful improvement in survival are needed. T-cell immunoglobulin domain and mucin domain-3 (TIM-3) is an immuno-myeloid regulator expressed on immune and leukemic stem cells in myeloid malignancies. Sabatolimab is a novel immunotherapy targeting TIM-3 with a potential dual mechanism of reactivating the immune system and directly targeting TIM-3+ leukemic blasts suppressing the growth of cancer cells. Here, we describe the aims and design of the phase III STIMULUS-MDS2 trial, which aims to demonstrate the potential for sabatolimab plus azacitidine to improve survival for patients with higher-risk MDS and CMML-2 (NCT04266301). Clinical Trial Registration: NCT04266301 (ClinicalTrials.gov).

Keywords:  clinical trials; hematologic/leukemia; immunotherapy; novel therapy

DOI:  https://doi.org/10.2217/fon-2022-1237
Hematol Oncol. 2023 Apr 20.

Patients with secondary acute myeloid leukemia undergoing allogeneic stem-cell transplant have inferior outcomes than de novo acute myeloid leukemia regardless minimal residual disease level by flow cytometry.

Claudia Núñez-Torrón Stock, Carlos Jiménez Chillón, Fernando Martín Moro, Juan Marquet Palomanes, Kyra Velázquez Kennedy, Miguel Piris Villaespesa, Ernesto Roldán Santiago, Eulalia Rodríguez Martín, Anabelle Chinea Rodríguez, Valentín García Gutiérrez, Gemma Moreno Jiménez, Javier López Jiménez, Pilar Herrera Puente.

  Secondary acute myeloid leukemia (s-AML) patients have a poor prognosis and currently the only curative therapy is allogeneic stem-cell transplant (HSCT). However, we do not yet know whether transplantation is sufficient to reverse the poor prognosis compared to de novo AML patients. We analyzed survival after HSCT comparing a cohort of 58 patients with s-AML versus 52 de novo patients who were transplanted between 2012 and 2020. Patients with s-AML had worse event-free survival (EFS) (p = 0.001) and overall survival (OS) (p < 0.001) compared to de novo AML due to an increased risk of relapse (p = 0.06) and non-relapse mortality (p = 0.03). The main difference in survival was observed in patients who achieved complete remission (CR) before HSCT (EFS p = 0.002 OS and <0.001), regardless minimal residual disease (MRD) by |multiparametric flow cytometry cohorts. In patients transplanted with active disease (AD), the prognosis was adverse in both s-AML and de novo AML groups (EFS p = 0.869 and OS p = 0.930). After excluding patients with AD, we stratified the cohort according to conditioning intensity, noticing that s-AML who received MAC had comparable outcomes to de novo AML, but the survival differences remained among reduce intensity conditioning group. In conclusion, transplanted s-AML patients have worse survival among patients in CR before HSCT, regardless of MRD level by flow cytometry compared to de novo AML. MAC patients had similar outcomes irrespective of leukemia ontogeny.

Keywords:  acute myeloid leukemia; allogeneic bone marrow transplantation; flow cytometry; minimal residual disease; secondary leukemia

DOI:  https://doi.org/10.1002/hon.3160
Leuk Res. 2023 Apr 14. pii: S0145-2126(23)00061-9. [Epub ahead of print]129 107076

Clonal Hematopoiesis: Origins and determinants of evolution.

Lourdes M Mendez, Mrinal M Patnaik.

  The accrual of somatic mutations is a byproduct of aging. When a clone bearing a somatic genetic alteration, conferring comparative competitive advantage, displays sufficient outgrowth to become detectable amongst an otherwise polyclonal background in the hematopoietic system, this is called clonal hematopoiesis (CH). Somatic genetic alterations observed in CH include point mutations in cancer related genes, mosaic chromosomal alterations or a combination of these. Interestingly, clonal hematopoiesis (CH) can also occur with somatic variants in genes without a known role in cancer and in the absence of a somatic genetic alteration through a process that has been described as 'genetic drift'. Clonal hematopoiesis of indeterminate significance (CHIP), is age-related and defined by the presence of somatic point mutations in cancer related genes, in the absence of cytopenias or a diagnosis of hematologic neoplasm, with a variant allele fraction ≥ 2 %. Remarkably, the increased mortality associated with CHIP is largely due to cardiovascular disease. Subsequently, CHIP has been associated with a myriad of age-related conditions such as Alzheimer's Disease, osteoporosis, CVA and COPD. CHIP is associated with an increased risk of hematologic malignancies, particularly myeloid neoplasms, with the risk rising with increasing clone size and clonal complexity. Mechanisms regulating clonal evolution and progression to hematologic malignancies remain to be defined. However, observations on context specific CH arising in the setting of bone marrow failure states, or on exposure to chemotherapy and radiation therapy, suggest that CH reflects context specific selection pressures and constraint-escape mechanisms.

Keywords:  CCUS; CHIP; Clonal evolution; Clonal hematopoiesis; Clonal origin; Mosaic chromosomal alterations

DOI:  https://doi.org/10.1016/j.leukres.2023.107076
J Exp Med. 2023 Jul 03. pii: e20220962. [Epub ahead of print]220(7):

Exposure to microbial products followed by loss of Tet2 promotes myelodysplastic syndrome via remodeling HSCs.

Takako Yokomizo-Nakano, Ai Hamashima, Sho Kubota, Jie Bai, Supannika Sorin, Yuqi Sun, Kenta Kikuchi, Mihoko Iimori, Mariko Morii, Akinori Kanai, Atsushi Iwama, Gang Huang, Daisuke Kurotaki, Hitoshi Takizawa, Hirotaka Matsui, Goro Sashida.

Aberrant innate immune signaling in myelodysplastic syndrome (MDS) hematopoietic stem/progenitor cells (HSPCs) has been implicated as a driver of the development of MDS. We herein demonstrated that a prior stimulation with bacterial and viral products followed by loss of the Tet2 gene facilitated the development of MDS via up-regulating the target genes of the Elf1 transcription factor and remodeling the epigenome in hematopoietic stem cells (HSCs) in a manner that was dependent on Polo-like kinases (Plk) downstream of Tlr3/4-Trif signaling but did not increase genomic mutations. The pharmacological inhibition of Plk function or the knockdown of Elf1 expression was sufficient to prevent the epigenetic remodeling in HSCs and diminish the enhanced clonogenicity and the impaired erythropoiesis. Moreover, this Elf1-target signature was significantly enriched in MDS HSPCs in humans. Therefore, prior infection stress and the acquisition of a driver mutation remodeled the transcriptional and epigenetic landscapes and cellular functions in HSCs via the Trif-Plk-Elf1 axis, which promoted the development of MDS.

DOI: https://doi.org/10.1084/jem.20220962
Blood Cancer Discov. 2023 Apr 17. pii: BCD-23-0041. [Epub ahead of print]

iPSC models of leukemia come of age.

Sergei Doulatov.

In this issue of Blood Cancer Discovery, Kotini and colleagues present a strategy for large scale reprogramming of primary human AMLs to iPSCs. They show that hematopoietic differentiation of AML iPSCs gives rise to transplantable leukemias with remarkable molecular similarity to the original patients' AML, providing new models and insights into disease.

DOI: https://doi.org/10.1158/2643-3230.BCD-23-0041
Br J Haematol. 2023 Apr 17.

Subclinical minute FLT3-ITD clone can be detected in clinically FLT3-ITD-negative acute myeloid leukaemia at diagnosis.

Shota Yokoyama, Masahiro Onozawa, Shota Yoshida, Naoki Miyashita, Hiroyuki Kimura, Shogo Takahashi, Toshihiro Matsukawa, Hideki Goto, Shinichi Fujisawa, Kosuke Miki, Daisuke Hidaka, Junichi Hashiguchi, Kentaro Wakasa, Makoto Ibata, Yukari Takeda, Akio Shigematsu, Katsuya Fujimoto, Yutaka Tsutsumi, Akio Mori, Toshimichi Ishihara, Yasutaka Kakinoki, Takeshi Kondo, Daigo Hashimoto, Takanori Teshima.

  Recent advances in next-generation sequencing (NGS) have enabled the detection of subclinical minute FLT3-ITD. We selected 74 newly diagnosed, cytogenetically normal acute myeloid leukaemia (AML) samples in which FLT3-ITD was not detected by gel electrophoresis. We sequenced them using NGS and found minute FLT3-ITDs in 19 cases. We compared cases with clinically relevant FLT3-ITD (n = 37), cases with minute FLT3-ITD (n = 19) and cases without detectable FLT3-ITD (n = 55). Molecular characteristics (location and length) of minute FLT3-ITD were similar to those of clinically relevant FLT3-ITD. Survival of cases with minute FLT3-ITD was similar to that of cases without detectable FLT3-ITD, whereas the relapse rate within 1 year after onset was significantly higher in cases with minute FLT3-ITD. We followed 18 relapsed samples of cases with clinically FLT3-ITD-negative at diagnosis. Two of 3 cases with minute FLT3-ITD relapsed with progression to clinically relevant FLT3-ITD. Two of 15 cases in which FLT3-ITD was not detected by NGS relapsed with the emergence of minute FLT3-ITD, and one of them showed progression to clinically relevant FLT3-ITD at the second relapse. We revealed the clonal dynamics of subclinical minute FLT3-ITD in clinically FLT3-ITD-negative AML. Minute FLT3-ITD at the initial AML can expand to become a dominant clone at relapse.

Keywords:  Hokkaido Leukemia Net (HLN); acute myeloid leukaemia (AML); clonal diversity; minute FLT3-ITD; next-generation sequencing (NGS); relapse

DOI:  https://doi.org/10.1111/bjh.18800
Leukemia. 2023 Apr 19.

Comprehensive response criteria for myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions: a proposal from the MLN International Working Group.

William Shomali, Philomena Colucci, Tracy I George, Jean-Jacques Kiladjian, Cheryl Langford, Jay L Patel, Andreas Reiter, Alessandro M Vannucchi, Jason Gotlib.

DOI: https://doi.org/10.1038/s41375-023-01859-3
bioRxiv. 2023 Apr 10. pii: 2023.04.09.536176. [Epub ahead of print]

Myelodysplastic syndromes disable human CD271 + VCAM1 + CD146 + niches supporting normal hematopoietic stem/progenitor cells.

Yuko Kawano, Hiroki Kawano, Dalia Ghoneim, Thomas J Fountaine, Daniel K Byun, Mark W LaMere, Jason H Mendler, TzuChieh Ho, Noah A Salama, Jason R Myers, Siba El Hussein, Benjamin J Frisch, John M Ashton, Mitra Azadniv, Jane L Liesveld, Youmna Kfoury, David T Scadden, Michael W Becker, Laura M Calvi.

Mesenchymal stem/stromal cells (MSCs) within the bone marrow microenvironment (BMME) support normal hematopoietic stem and progenitor cells (HSPCs). However, the heterogeneity of human MSCs has limited the understanding of their contribution to clonal dynamics and evolution to myelodysplastic syndromes (MDS). We combined three MSC cell surface markers, CD271, VCAM-1 (Vascular Cell Adhesion Molecule-1) and CD146, to isolate distinct subsets of human MSCs from bone marrow aspirates of healthy controls (Control BM). Based on transcriptional and functional analysis, CD271 + CD106 + CD146 + (NGFR+/VCAM1+/MCAM+/Lin-; NVML ) cells display stem cell characteristics, are compatible with murine BM-derived Leptin receptor positive MSCs and provide superior support for normal HSPCs. MSC subsets from 17 patients with MDS demonstrated shared transcriptional changes in spite of mutational heterogeneity in the MDS clones, with loss of preferential support of normal HSPCs by MDS-derived NVML cells. Our data provide a new approach to dissect microenvironment-dependent mechanisms regulating clonal dynamics and progression of MDS.
Key Points: Subsets of human bone marrow derived mesenchymal stromal cells provide differential support of hematopoietic stem and progenitor cells.MDS-derived CD271+VCAM-1+CD146+ mesenchymal stromal cells lose their ability to support hematopoietic stem and progenitor cells.

DOI: https://doi.org/10.1101/2023.04.09.536176
Expert Opin Pharmacother. 2023 Apr 17. 1-12

Cytopenic myelofibrosis: prevalence, relevance, and treatment.

Pankit Vachhani, Srdan Verstovsek, Prithviraj Bose.

   INTRODUCTION: Cytopenic myelofibrosis is increasingly recognized as a phenotype of myelofibrosis presenting with low blood counts, lower driver mutation allele burden, increased likelihood of arising de novo, i.e. primary myelofibrosis, greater genomic complexity, worse survival, and higher rates of leukemic transformation compared to the more traditional 'myeloproliferative' phenotype. Both anemia and thrombocytopenia are very common, often coexist, and can be worsened by treatment. Several JAK inhibitors with different kinome profiles are now available for routine clinical use. Additionally, ancillary therapies can also provide some, albeit non-durable, benefit.
AREAS COVERED: In this review, we discuss the prevalence and clinical significance of cytopenias in myelofibrosis. We then discuss the various Janus kinase (JAK) inhibitors and ancillary therapies available with a special focus on their use in cytopenic populations, ability to improve cytopenias, and notable adverse events. Articles included were selected through literature searches using the PubMed database.
EXPERT OPINION: Pacritinib and momelotinib are new treatment options for patients with cytopenic myelofibrosis. These JAK inhibitors are less myelosuppressive and allow for cytopenia stabilization or improvement while providing additional benefits. It is likely that their use will expand and these newer JAK inhibitors will become backbones for future combinations with novel, 'disease modifying' agents.

Keywords:  Myelofibrosis; anemia; momelotinib; myelodepletive; pacritinib; ruxolitinib; thrombocytopenia

DOI:  https://doi.org/10.1080/14656566.2023.2203318
Res Sq. 2023 Apr 05. pii: rs.3.rs-2773498. [Epub ahead of print]

Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation.

Simona Pagliuca, Carmelo Gurnari, Colin Hercus, Sébastien Hergalant, Sanghee Hong, Adele Dhuyser, Maud D'Aveni, Alice Aarnink, Marie Thérèse Rubio, Pierre Feugier, Francesca Ferraro, Hetty E Carraway, Ronald Sobecks, Betty K Hamilton, Navneet S Majhail, Valeria Visconte, Jaroslaw P Maciejewski.

Graft-versus-leukemia (GvL) reactions are responsible for the effectiveness of allogeneic hematopoietic cell transplantation as a treatment modality for myeloid neoplasia, whereby donor T- effector cells recognize leukemia neoantigens. However, a substantial fraction of patients experience relapses because of the failure of the immunological responses to control leukemic outgrowth. Here, through a broad immunogenetic study, we demonstrate that germline and somatic reduction of human leucocyte antigen (HLA) heterogeneity enhances the risk of leukemic recurrence. We show that preexistent germline-encoded low evolutionary divergence of class II HLA genotypes constitutes an independent factor associated with disease relapse and that acquisition of clonal somatic defects in HLA alleles may lead to escape from GvL control. Both class I and II HLA genes are targeted by somatic mutations as clonal selection factors potentially impairing cellular immune reactions and response to immunomodulatory strategies. These findings define key molecular modes of post-transplant leukemia escape contributing to relapse.

DOI: https://doi.org/10.21203/rs.3.rs-2773498/v1
Expert Rev Hematol. 2023 Apr 17. 1-7

Revisiting the prognostic role of FLT3 mutations in acute myelogenous leukemia.

Håkon Reikvam.

   INTRODUCTION: Approximately one-third of patients with acute myelogenous leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. The features regarding prognostic impact of FLT3 mutated AML have been widely investigated and debated in the last decades, and the significance of this mutation is constantly evolving.
AREAS COVERED: In this article, the significance of the FLT3 mutation and various aspects of this mutation are discussed in the light of new understanding and research progress in past years. The recently updated European Leukemia Net (ELN) guidelines are reviewed and discussed, special emphasis given to the the improvement in therapeutic approaches for FLT3 mutated AML.
EXPERT OPINION: Aspects related to FLT3 mutated AML include the type of mutation in addition to FLT3-internal tandem duplication (ITD) length, location, and allelic ratio. Furthermore, the coexistence of cytogenetic variants and molecular genetic mutations utterly complicate the evaluation of the prognostic impact. In addition, introduction of FLT3 inhibitors and establishment of measurable residual disease (MRD) monitoring have entered the treatment and evaluation armamentarium in the handling of AML patients, resulting in improved prognosis for these patients. However, future research to optimize the treatment of FLT3 mutated AML is highly desired.

Keywords:  Acute myelogenous leukemia; FLT3; prognosis; stem cell transplantation; targeted therapy

DOI:  https://doi.org/10.1080/17474086.2023.2202849
Mol Cancer Res. 2023 Apr 18. pii: MCR-22-0898. [Epub ahead of print]

MDM2 inhibition enhances immune checkpoint inhibitor efficacy by increasing IL-15 and MHC class II production.

Marlene Langenbach, Sophie Giesler, Stefan Richtsfeld, Sara da Costa-Pereira, Lukas Rindlisbacher, Tobias Wertheimer, Lukas M Braun, Geoffroy Andrieux, Sandra Duquesne, Dietmar Pfeifer, Nadine M Woessner, Hans D Menssen, Sanaz Taromi, Justus Duyster, Melanie Boerries, Tilman Brummer, Bruce R Blazar, Susana Minguet, Patrick Turko, Mitchell P Levesque, Burkhard Becher, Robert Zeiser.

The treatment of metastatic melanoma patients with immune checkpoint inhibitors (ICI) leads to impressive response rates but primary and secondary resistance to ICI reduce progression-free survival. Novel strategies that interfere with resistance mechanisms are key to further improve patient outcome during ICI therapy. P53 is often inactivated by mouse-double-minute-2 (MDM2), which may decrease immunogenicity of melanoma cells. We analyzed primary patient-derived melanoma cell lines, performed bulk sequencing analysis of patient-derived melanoma samples and used melanoma mouse models to investigate the role of MDM2-inhibition for enhanced ICI therapy. We found increased expression of IL-15 and MHC-II in murine melanoma cells upon p53 induction by MDM2-inhibition. MDM2-inhibitor induced MHC-II and IL-15-production, which was p53 dependent as p53 knockdown blocked the effect. Lack of IL-15-receptor in hematopoietic cells or IL-15 neutralization reduced the MDM2-inhibition/p53-induction mediated anti-tumor immunity. p53 induction by MDM2-inhibition caused anti-melanoma immune memory as T cells isolated from MDM2-inhibitor treated melanoma bearing mice exhibited anti-melanoma activity in secondary melanoma-bearing mice. In patient-derived melanoma cells p53 induction by MDM2-inhibition increased IL-15 and MHC-II. IL-15 and CIITA expression was associated with a more favorable prognosis in patients bearing WT but not TP53 mutated melanoma. Implications: MDM2-inhibition represents a novel strategy to enhance IL-15 and MHC-II-production, which disrupts the immunosuppressive tumor microenvironment. Based on our findings a clinical trial combining MDM2-inhibition with anti-PD-1 immunotherapy for metastatic melanoma is planned.

DOI: https://doi.org/10.1158/1541-7786.MCR-22-0898
Clin Lymphoma Myeloma Leuk. 2023 Mar 30. pii: S2152-2650(23)00109-X. [Epub ahead of print]

FDA Analysis of Ineligibility for Acute Myeloid Leukemia Clinical Trials by Race and Ethnicity.

Dianne Pulte, Laura Fernandes, Guo Wei, Ashley Woods, Kelly J Norsworthy, Nicole Gormley, Bindu Kanapuru, Thomas E Gwise, Richard Pazdur, Julie Schneider, Marc R Theoret, Lola A Fashoyin-Aje, R Angelo de Claro.

   BACKGROUND: Patients of certain racial and ethnic groups have been underrepresented in clinical trials for treatment of malignancy. One potential barrier to participation is entry requirements that lead to patients in various racial and ethnic groups not meeting eligibility criteria for studies (ie, "screen failure"). The objective of this study was to analyze the rates and reasons for trial ineligibility by race and ethnicity in trials of acute myeloid leukemia (AML) submitted to the U.S. Food and Drug Administration (FDA) between 2016 and 2019.
MATERIALS AND METHODS: Multicenter, global clinical trials submitted to the FDA to support AML drugs and biologics. We examined the rate of ineligibility among participants screened for studies of AML therapies submitted to the FDA from 2016 to 2019. Data were extracted from 13 trials used in approval evaluations, including race, screen status, and reason for ineligibility.
RESULTS: Overall, patients in historically underrepresented racial and ethnic groups were less likely to meet entry criteria for studies compared to White patients, with 26.7% of White patients, 29.4% of Black patients, and 35.9% of Asian patients not meeting entry criteria. Lack of relevant disease mutation was the reason for ineligibility more frequently among Black and Asian patients. The findings were limited by the small number of underrepresented patients screened for participation.
CONCLUSION: Our results suggest that entry requirements for studies may put underrepresented patients at a disadvantage, leading to less eligible patients and thus lower participation in clinical trials.

Keywords:  Eligibility criteria; Health care disparities; Screening

DOI:  https://doi.org/10.1016/j.clml.2023.03.012
Leuk Lymphoma. 2023 Apr 20. 1-19

Ten years after ruxolitinib approval for myelofibrosis: a review of clinical efficacy.

Naveen Pemmaraju, Prithviraj Bose, Raajit Rampal, Aaron T Gerds, Angela Fleischman, Srdan Verstovsek.

  Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by splenomegaly, abnormal cytokine expression, cytopenias, and progressive bone marrow fibrosis. The disease often manifests with burdensome symptoms and is associated with reduced survival. Ruxolitinib, an oral Janus kinase (JAK) 1 and JAK2 inhibitor, was the first agent approved for MF. As a first-in-class targeted treatment, ruxolitinib approval transformed the MF treatment approach and remains standard of care. In addition, targeted inhibition of JAK1/JAK2 signaling, a key molecular pathway underlying MF pathogenesis, and the large volume of literature evaluating ruxolitinib, have led to a better understanding of the disease and improved management in general. Here we review ruxolitinib efficacy in patients with MF in the 10 years following approval, including demonstration of clinical benefit in the phase 3 COMFORT-I/II trials, real-world evidence, translational studies, and expanded access data. Lastly, future directions for MF treatment are discussed, including ruxolitinib-based combination therapies.

Keywords:  Janus kinase; Myelofibrosis; myeloproliferative neoplasm; ruxolitinib

DOI:  https://doi.org/10.1080/10428194.2023.2196593
Cancer Discov. 2023 Apr 17. OF1-OF24

Li-Fraumeni Syndrome-Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death.

Joshua H Choe, Tatsuya Kawase, An Xu, Asja Guzman, Aleksandar Z Obradovic, Ana Maria Low-Calle, Bita Alaghebandan, Ananya Raghavan, Kaitlin Long, Paul M Hwang, Joshua D Schiffman, Yan Zhu, Ruiying Zhao, Dung-Fang Lee, Chen Katz, Carol Prives.

Cancer-relevant mutations in the oligomerization domain (OD) of the p53 tumor suppressor protein, unlike those in the DNA binding domain, have not been well elucidated. Here, we characterized the germline OD mutant p53(A347D), which occurs in cancer-prone Li-Fraumeni syndrome (LFS) patients. Unlike wild-type p53, mutant p53(A347D) cannot form tetramers and exists as a hyperstable dimeric protein. Further, p53(A347D) cannot bind or transactivate the majority of canonical p53 target genes. Isogenic cell lines harboring either p53(A347D) or no p53 yield comparable tumorigenic properties, yet p53(A347D) displays remarkable neomorphic activities. Cells bearing p53(A347D) possess a distinct transcriptional profile and undergo metabolic reprogramming. Further, p53(A347D) induces striking mitochondrial network aberration and associates with mitochondria to drive apoptotic cell death upon topoisomerase II inhibition in the absence of transcription. Thus, dimer-forming p53 demonstrates both loss-of-function (LOF) and gain-of-function (GOF) properties compared with the wild-type form of the protein.
SIGNIFICANCE: A mutant p53 (A347D), which can only form dimers, is associated with increased cancer susceptibility in LFS individuals. We found that this mutant wields a double-edged sword, driving tumorigenesis through LOF while gaining enhanced apoptogenic activity as a new GOF, thereby yielding a potential vulnerability to select therapeutic approaches.

DOI: https://doi.org/10.1158/2159-8290.CD-22-0882
Sci Adv. 2023 Apr 21. 9(16): eade9746

Age-related loss of chromosome Y is associated with levels of sex hormone binding globulin and clonal hematopoiesis defined by TET2, TP53, and CBL mutations.

Ahmed A Z Dawoud, William J Tapper, Nicholas C P Cross.

Mosaic loss of the Y-chromosome (LOY) in peripheral blood leukocytes is the most common somatic alteration in men and linked to wide range of malignant and nonmalignant conditions. LOY is associated with age, smoking, and constitutional genetics. Here, we aimed to assess the relationships between LOY, serum biomarkers, and clonal hematopoiesis (CH). LOY in U.K. Biobank was strongly associated with levels of sex hormone binding globulin (SHBG), a key regulator of testosterone bioavailability. Mendelian randomization suggested a causal effect of SHBG on LOY but there was no evidence for an effect of LOY on SHBG. In contrast, age-related CH defined by somatic driver mutations was not associated with SHBG but was associated with LOY at clonal fractions above 30%. TET2, TP53, and CBL mutations were enriched in LOY cases, but JAK2 V617F was depleted. Our findings thus identify independent relationships between LOY, sex hormone levels, and CH.

DOI: https://doi.org/10.1126/sciadv.ade9746
Blood Adv. 2023 Apr 21. pii: bloodadvances.2023009960. [Epub ahead of print]

Intestinal permeability of stem cell transplant patients correlates with systemic acute phase responses and dysbiosis.

YunZu M Wang, Sheyar Abdullah, Nathan Luebbering, Lucille Langenberg, Alexandra Duell, Kelly Lake, Adam Lane, Brian Hils, Ormarie Vázquez Silva, Monica Trapp, Kodandaramireddy Nalapareddy, Jane Koo, Lee A Denson, Sonata Jodele, David B Haslam, William A Faubion, Stella M Davies, Pooja Khandelwal.

Intestinal permeability may correlate with adverse outcomes during hematopoietic stem cell transplantation (HSCT), but longitudinal quantification with traditional oral mannitol and lactulose is not feasible in HSCT recipients due to mucositis and diarrhea. A modified lactulose:rhamnose (LR) assay is validated in children with environmental enteritis. Our study objective was to quantify peri-HSCT intestinal permeability changes using the modified LR assay. The LR assay was administered pretransplant, Day+7 and +30 to 80 pediatric and young adult allogeneic HSCT patients. Lactulose and rhamnose were detected by urine mass spectrometry and expressed as an L:R ratio. Metagenomic shotgun sequencing of stool for microbiome analyses and ELISA analyses of plasma lipopolysaccharide binding protein (LBP), ST2, REG3α, claudin1, occludin, and intestinal alkaline phosphatase were performed at the same timepoints. L:R ratios were increased at Day+7 but returned to baseline at Day+30 in most patients (p=0.014). Conditioning regimen intensity did not affect the trajectory of L:R (p=0.39). Baseline L:R ratios did not vary by diagnosis. L:R correlated with LBP levels (r2= 0.208, p=0.0014). High L:R ratios were associated with lower microbiome diversity (p=0.035), loss of anaerobic organisms (p=0.020) and higher plasma LBP (p=0.0014). No adverse gastrointestinal effects occurred due to LR. Intestinal permeability as measured by L:R ratios after allogeneic HSCT correlates with intestinal dysbiosis and elevated plasma LBP. The lactulose/rhamnose assay is well-tolerated and may identify transplant recipients more likely to experience adverse outcomes.

DOI: https://doi.org/10.1182/bloodadvances.2023009960
Leukemia. 2023 Apr 14.

Health-related quality of life of patients with resistant/intolerant chronic phase chronic myeloid leukemia treated with asciminib or bosutinib in the phase 3 ASCEMBL trial.

Delphine Réa, Carla Boquimpani, Michael J Mauro, Yosuke Minami, Alex Allepuz, Vikalp Kumar Maheshwari, Denise D'Alessio, Ying Wu, Rachael Lawrance, Sarunas Narbutas, Giora Sharf, Andreas Hochhaus.

In ASCEMBL, an open-label, randomized Phase 3 study, asciminib demonstrated superior efficacy and better safety profile compared with bosutinib in patients with chronic myeloid leukemia in chronic phase (CML-CP) previously treated with ≥2 tyrosine kinase inhibitors. Health-related quality of life (HRQOL) reported by patients is key to understanding the benefit and impact of treatment on patients' lives, and is becoming increasingly important as the life expectancy of CML-CP patients increases and patients require long-term treatment. In ASCEMBL, patients completed questionnaires to assess CML symptoms and interference with daily life (M.D. Anderson Symptom Inventory - CML [MDASI-CML]), general HRQOL (five-level EQ-5D [EQ-5D-5L], Patient Global Impression of Change - CML [PGIC-CML]), and impact of CML on working life and activity (Work Productivity and Activity Impairment questionnaire - CML [WPAI-CML]). Patients' CML symptoms and HRQOL remained stable during 48 weeks of treatment with asciminib, with a general trend for decreased CML symptom severity, particularly for fatigue, and improvement in HRQOL. A clinically meaningful increase in diarrhea severity was observed in patients treated with bosutinib compared to asciminib. These data provide better understanding of the patient perspective and treatment impact on HRQOL in a later-line setting, where little information has been published to date.

DOI: https://doi.org/10.1038/s41375-023-01888-y
Blood. 2023 Apr 21. pii: blood.2023020435. [Epub ahead of print]

Alternative donor BMT with post-transplant cyclophosphamide as initial therapy for acquired severe aplastic anemia.

Amy DeZern, Marianna L Zahurak, Heather J Symons, Kenneth R Cooke, Carol Ann Huff, Tania Jain, Lode J Swinnen, Philip Hollingsworth Imus, Nina D Wagner-Johnston, Richard F Ambinder, Mark J Levis, Leo Luznik, Javier Bolaños-Meade, Ephraim J Fuchs, Richard J Jones, Robert A Brodsky.

Severe aplastic anemia (SAA) is a marrow failure disorder with high morbidity and mortality. It is treated with bone marrow transplantation (BMT) for those with fully matched donors or immunosuppressive therapy (IST) for those who lack such a donor, which is often the case for underrepresented minorities. We conducted a prospective phase II trial of reduced-intensity conditioning HLA-haplo BMT and post-transplantation cyclophosphamide (PTCy)-based graft-versus-host (GVHD) prophylaxis as initial therapy for patients with SAA. The median age was 25 (range 3-63) years and the median follow-up was 40.9 months (95% CI: 29.4, 55.7 mos). Over 35% of enrollment was from underrepresented racial/ethnic groups. The cumulative incidence of grade II-IV aGVHD at day 100 is 7% (95% CI: NA, 17%) and chronic GVHD at 2 years is 4% (95% CI: NA, 11%). The overall survival for 27 patients is 92% (95% CI: 83,100%) at one, two, and three years. The first 7 patients received lower dose total body irradiation (200 versus 400 cGY), but these patients were more likely to have graft failure, 3 of 7, compared to 0 out of 20 patients in the higher dose group (p=0.01, Fisher exact). HLA-haploidentical BMT with PTCy using 400cGY total body irradiation resulted in 100% overall survival with minimal GVHD in 20 consecutive patients. Not only does this approach avoid the ramifications of IST and its low failure-free survival, but also the use of haploidentical donors expands access to BMT across all populations. Clinical trial: NCT02833805.

DOI: https://doi.org/10.1182/blood.2023020435
Am J Hematol. 2023 Apr 21.

JAK2 inhibitor treatment of anemia in myelofibrosis.

Ayalew Tefferi, Alessandro M Vannucchi.

DOI: https://doi.org/10.1002/ajh.26934
Sci Adv. 2023 04 21. 9(16): eadf5330

RNA binding induces an allosteric switch in Cyp33 to repress MLL1-mediated transcription.

Markus Blatter, Charlotte Meylan, Antoine Cléry, Roberto Giambruno, Yaroslav Nikolaev, Michel Heidecker, Jessica Arvindbhai Solanki, Manuel O Diaz, Davide Gabellini, Frédéric H-T Allain.

Mixed-lineage leukemia 1 (MLL1) is a transcription activator of the HOX family, which binds to specific epigenetic marks on histone H3 through its third plant homeodomain (PHD3) domain. Through an unknown mechanism, MLL1 activity is repressed by cyclophilin 33 (Cyp33), which binds to MLL1 PHD3. We determined solution structures of Cyp33 RNA recognition motif (RRM) free, bound to RNA, to MLL1 PHD3, and to both MLL1 and the histone H3 lysine N6-trimethylated. We found that a conserved α helix, amino-terminal to the RRM domain, adopts three different positions facilitating a cascade of binding events. These conformational changes are triggered by Cyp33 RNA binding and ultimately lead to MLL1 release from the histone mark. Together, our mechanistic findings rationalize how Cyp33 binding to MLL1 can switch chromatin to a transcriptional repressive state triggered by RNA binding as a negative feedback loop.

DOI: https://doi.org/10.1126/sciadv.adf5330