bims-tremyl 2022-05-01 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2022–05–01
twenty papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Allogeneic TCRαβ deficient CAR T-cells targeting CD123 in acute myeloid leukemia.
Leukotrienes promote stem cell self-renewal and chemoresistance in acute myeloid leukemia.
Cystine uptake inhibition potentiates front-line therapies in acute myeloid leukemia.
Human acute myeloid leukemia stem cells: evolution of concept.
A phase 1b study of glasdegib + azacitidine in patients with untreated acute myeloid leukemia and higher-risk myelodysplastic syndromes.
Uptake of carbon nanodots into human AML cells in comparison to primary hematopoietic cells.
ILC1s control leukemia stem cell fate and limit development of AML.
Midostaurin plus intensive chemotherapy for younger and older Patients with AML and FLT3 internal tandem duplications.
Npm1 Haploinsufficiency in collaboration with MEIS1 is sufficient to induce AML in mice.
Using stroma-anchoring cytokines to augment ADCC: a phase 1 trial of F16IL2 and BI 836858 for posttransplant AML relapse.
Venetoclax combined with induction chemotherapy in patients with newly diagnosed acute myeloid leukaemia: a post-hoc, propensity score-matched, cohort study.
Harnessing the power of sphingolipids: Prospects for acute myeloid leukemia.
Mutant-SETBP1 activates transcription of Myc programs to accelerate CSF3R-driven myeloproliferative neoplasms.
Interleukin-4 treatment reduces leukemia burden in acute myeloid leukemia.
Suppression of MYC by PI3K/AKT/mTOR pathway inhibition in combination with all-trans retinoic acid treatment for therapeutic gain in acute myeloid leukaemia.
CD36-Mediated Fatty Acid Oxidation in Hematopoietic Stem Cells Is a Novel Mechanism of Emergency Hematopoiesis in Response to Infection.
IDH1 inhibitor-induced neutrophilic dermatosis in a patient with acute myeloid leukemia.
Association of Somatic Gene Mutations with Risk of Transformation into Acute Myeloid Leukemia in Patients with Myelodysplastic Syndrome: A Systematic Review and Meta-Analysis.
Hypoxic, glycolytic metabolism is a vulnerability of B-acute lymphoblastic leukemia-initiating cells.
Targeting CD123 in blastic plasmacytoid dendritic cell neoplasm using allogeneic anti-CD123 CAR T cells.

Nat Commun. 2022 Apr 28. 13(1): 2227

Allogeneic TCRαβ deficient CAR T-cells targeting CD123 in acute myeloid leukemia.

Mayumi Sugita, Roman Galetto, Hongliang Zong, Nathan Ewing-Crystal, Vicenta Trujillo-Alonso, Nuria Mencia-Trinchant, Winnie Yip, Stephanie Filipe, Celine Lebuhotel, Agnès Gouble, Duane C Hassane, Julianne Smith, Gail J Roboz, Monica L Guzman.

Acute myeloid leukemia (AML) is a disease with high incidence of relapse that is originated and maintained from leukemia stem cells (LSCs). Hematopoietic stem cells can be distinguished from LSCs by an array of cell surface antigens such as CD123, thus a candidate to eliminate LSCs using a variety of approaches, including CAR T cells. Here, we evaluate the potential of allogeneic gene-edited CAR T cells targeting CD123 to eliminate LSCs (UCART123). UCART123 cells are TCRαβneg T cells generated from healthy donors using TALEN® gene-editing technology, decreasing the likelihood of graft vs host disease. As safety feature, cells express RQR8 to allow elimination with Rituximab. UCART123 effectively eliminates AML cells in vitro and in vivo with significant benefits in overall survival of AML-patient derived xenograft mice. Furthermore, UCART123 preferentially target AML over normal cells with modest toxicity to normal hematopoietic stem/progenitor cells. Together these results suggest that UCART123 represents an off-the shelf therapeutic approach for AML.

DOI: https://doi.org/10.1038/s41467-022-29668-9
Leukemia. 2022 Apr 23.

Leukotrienes promote stem cell self-renewal and chemoresistance in acute myeloid leukemia.

Alec W Stranahan, Iryna Berezniuk, Sohini Chakraborty, Faye Feller, Mona Khalaj, Christopher Y Park.

Acute myeloid leukemia (AML) is characterized by poor clinical outcomes due to high rates of relapse following standard-of-care induction chemotherapy. While many pathogenic drivers have been described in AML, our understanding of the molecular mechanisms mediating chemotherapy resistance remains poor. Therefore, we sought to identify resistance genes to induction therapy in AML and elucidated ALOX5 as a novel mediator of resistance to anthracycline-based therapy. ALOX5 is transcriptionally upregulated in AML patient blasts in comparison to normal hematopoietic stem/progenitor cells (HSPCs) and ALOX5 mRNA, and protein expression is increased in response to induction therapy. In vitro, and in vivo genetic, and pharmacologic perturbation studies confirm that ALOX5 positively regulates the leukemogenic potential of AML LSCs, and its loss does not significantly affect the function of normal HSPCs. ALOX5 mediates resistance to daunorubicin (DNR) and promotes AML cell survival and maintenance through its leukotriene (LT) synthetic capacity, specifically via modulating the synthesis of LTB4 and its binding to LTB receptor (BLTR). Our study reveals a previously unrecognized role of LTs in AML pathogenesis and chemoresistance, whereby inhibition of ALOX5 mediated LTB4 synthesis and function could be combined with standard chemotherapy, to enhance the overall therapeutic efficacy in AML.

DOI: https://doi.org/10.1038/s41375-022-01579-0
Leukemia. 2022 Apr 26.

Cystine uptake inhibition potentiates front-line therapies in acute myeloid leukemia.

Bryann Pardieu, Justine Pasanisi, Frank Ling, Reinaldo Dal Bello, Justine Penneroux, Angela Su, Romane Joudinaud, Laureen Chat, Hsin Chieh Wu, Matthieu Duchmann, Gaetano Sodaro, Clémentine Chauvel, Florence A Castelli, Loic Vasseur, Kim Pacchiardi, Yannis Belloucif, Marie-Charlotte Laiguillon, Eshwar Meduri, Camille Vaganay, Gabriela Alexe, Jeannig Berrou, Chaima Benaksas, Antoine Forget, Thorsten Braun, Claude Gardin, Emmanuel Raffoux, Emmanuelle Clappier, Lionel Adès, Hugues de Thé, François Fenaille, Brian J Huntly, Kimberly Stegmaier, Hervé Dombret, Nina Fenouille, Camille Lobry, Alexandre Puissant, Raphael Itzykson.

By querying metabolic pathways associated with leukemic stemness and survival in multiple AML datasets, we nominated SLC7A11 encoding the xCT cystine importer as a putative AML dependency. Genetic and chemical inhibition of SLC7A11 impaired the viability and clonogenic capacity of AML cell lines in a cysteine-dependent manner. Sulfasalazine, a broadly available drug with xCT inhibitory activity, had anti-leukemic activity against primary AML samples in ex vivo cultures. Multiple metabolic pathways were impacted upon xCT inhibition, resulting in depletion of glutathione pools in leukemic cells and oxidative stress-dependent cell death, only in part through ferroptosis. Higher expression of cysteine metabolism genes and greater cystine dependency was noted in NPM1-mutated AMLs. Among eight anti-leukemic drugs, the anthracycline daunorubicin was identified as the top synergistic agent in combination with sulfasalazine in vitro. Addition of sulfasalazine at a clinically relevant concentration significantly augmented the anti-leukemic activity of a daunorubicin-cytarabine combination in a panel of 45 primary samples enriched in NPM1-mutated AML. These results were confirmed in vivo in a patient-derived xenograft model. Collectively, our results nominate cystine import as a druggable target in AML and raise the possibility to repurpose sulfasalazine for the treatment of AML, notably in combination with chemotherapy.

DOI: https://doi.org/10.1038/s41375-022-01573-6
Blood Res. 2022 Apr 30. 57(S1): 67-74

Human acute myeloid leukemia stem cells: evolution of concept.

Dong-Yeop Shin.

  The history of human acute myeloid leukemia stem cells (AMLSCs) began in a seminal study performed by Lapidot and Dick, proving that only CD34+CD38- human primary acute myeloid leukemia (AML) cells can repopulate in severe combined immunodeficient mice. The concept of leukemic stem cells (LSCs) has impeded a huge change in the treatment strategy against AML from killing proliferating leukemic cells to eradicating quiescent/dormant LSCs. As next-generation sequencing technologies have developed, multiple and recurrent genetic mutations have been discovered in large cohorts of patients with AML, and the updated understanding of leukemogenesis has improved the old concept of LSC to a revised version of a serial developmental model of LSC; that is, pre-LSCs are generated as seeds by the first hit on epigenetic regulators, and then, leukemia-initiating LSCs emerge from seeds by the second hits on genes involved in transcription and signaling. Dreams for universal and targetable AMLSC biomarker sparing healthy hematopoietic stem cells have weakened after the confrontation of significant heterogeneity of AMLSCs from genomic and immunophenotypic viewpoints. However, there is still hope for effective targets for AMLSCs since there is evidence that grouped gene signatures, such as 17-gene LSC score, and common epigenetic signatures, such as HOXA clusters, independent of various gene mutations, exist. Recently, the LSC niche in the bone marrow has been actively investigated and has expanded our knowledge of the physiology and vulnerability of AMLSCs. Presently, an applicable treatment that always works in AMLSCs is lacking. However, we will find a way, we always have.

Keywords:  Acute myeloid leukemia; Acute myeloid leukemia stem cell; Leukemic stem cell; Pre-leukemic stem cell

DOI:  https://doi.org/10.5045/br.2022.2021221
Ann Hematol. 2022 Apr 30.

A phase 1b study of glasdegib + azacitidine in patients with untreated acute myeloid leukemia and higher-risk myelodysplastic syndromes.

Mikkael A Sekeres, Michael Schuster, Magalie Joris, Jürgen Krauter, Johan Maertens, Dimitri Breems, Emmanuel Gyan, Tibor Kovacsovics, Amit Verma, Paresh Vyas, Eunice S Wang, Keith Ching, Thomas O'Brien, Corrado Gallo Stampino, Weidong Wendy Ma, Arthur Kudla, Geoffrey Chan, Amer M Zeidan.

  This phase 1b study evaluated glasdegib (100 mg once daily) + azacitidine in adults with newly diagnosed acute myeloid leukemia (AML), higher-risk myelodysplastic syndromes (MDS), or chronic myelomonocytic leukemia (CMML) who were ineligible for intensive chemotherapy. Of 72 patients enrolled, 12 were in a lead-in safety cohort (LIC) and 60 were in the AML and MDS (including CMML) expansion cohorts. In the LIC, the safety profile of glasdegib + azacitidine was determined to be consistent with those of glasdegib or azacitidine alone, with no evidence of drug-drug interaction. In the expansion cohort, the most frequently (≥ 10%) reported non-hematologic Grade ≥ 3 treatment-emergent adverse events were decreased appetite, electrocardiogram QT prolongation, and hypertension in the AML cohort and sepsis, diarrhea, hypotension, pneumonia, and hyperglycemia in the MDS cohort. Overall response rates in the AML and MDS cohorts were 30.0% and 33.3%, respectively; 47.4% and 46.7% of patients who were transfusion dependent at baseline achieved independence. Median overall survival (95% confidence interval) was 9.2 (6.2-14.0) months and 15.8 (9.3-21.9) months, respectively, and response was associated with molecular mutation clearance. Glasdegib + azacitidine in patients with newly diagnosed AML or MDS demonstrated an acceptable safety profile and preliminary evidence of clinical benefits.Trial registration: ClinicalTrials.gov NCT02367456.

Keywords:  Acute myeloid leukemia; Chronic myelomonocytic syndromes; Clinical trials; Glasdegib; Myelodysplastic syndromes

DOI:  https://doi.org/10.1007/s00277-022-04853-4
RSC Adv. 2021 Jul 27. 11(42): 26303-26310

Uptake of carbon nanodots into human AML cells in comparison to primary hematopoietic cells.

Cathrin Nollmann, Christian Wimmenauer, Stefan Fasbender, Saskia Mayer, Ron-Patrick Caddedu, Paul Jäger, Thomas Heinzel, Rainer Haas.

Carbon nanodots (CNDs) comprise a class of next generation nanomaterials with a wide variety of potential applications. Here, we report on their uptake into primary hematopoietic cells from three normal donors and malignant cells from five patients with de novo acute myeloid leukemia (AML). A significant CND uptake was observed in all cell types of the normal and leukemic cells. Still, the uptake was significantly smaller for the CD34+ and CD33+ myeloid subsets of the malignant cell population as compared to the normal blood-derived CD34+ and CD33+ cells. For the T and B lymphoid cell populations as defined by CD3 and CD19 within the leukemic and normal samples a similar uptake was observed. The CNDs accumulate preferentially in small clusters in the periphery of the nucleus as already shown in previous studies for CD34+ progenitor/stem cells and human breast cancer cells. This particular subcellular localization could be useful for targeting the lysosomal compartment, which plays a pivotal role in the context of autophagy associated survival of AML cells. Our results demonstrate the usability of CNDs beyond their application for in vitro and in vivo fluorescence labeling or drug delivery into normal and malignant cells.

DOI: https://doi.org/10.1039/d1ra05033h
Nat Immunol. 2022 Apr 29.

ILC1s control leukemia stem cell fate and limit development of AML.

Zhenlong Li, Rui Ma, Shoubao Ma, Lei Tian, Ting Lu, Jianying Zhang, Bethany L Mundy-Bosse, Bin Zhang, Guido Marcucci, Michael A Caligiuri, Jianhua Yu.

Type I innate lymphoid cells (ILC1s) are critical regulators of inflammation and immunity in mammalian tissues. However, their function in cancer is mostly undefined. Here, we show that a high density of ILC1s induces leukemia stem cell (LSC) apoptosis in mice. At a lower density, ILC1s prevent LSCs from differentiating into leukemia progenitors and promote their differentiation into non-leukemic cells, thus blocking the production of terminal myeloid blasts. All of these effects, which require ILC1s to produce interferon-γ after cell-cell contact with LSCs, converge to suppress leukemogenesis in vivo. Conversely, the antileukemia potential of ILC1s wanes when JAK-STAT or PI3K-AKT signaling is inhibited. The relevant antileukemic properties of ILC1s are also functional in healthy individuals and impaired in individuals with acute myeloid leukemia (AML). Collectively, these findings identify ILC1s as anticancer immune cells that might be suitable for AML immunotherapy and provide a potential strategy to treat AML and prevent relapse of the disease.

DOI: https://doi.org/10.1038/s41590-022-01198-y
Blood Adv. 2022 Apr 29. pii: bloodadvances.2022007223. [Epub ahead of print]

Midostaurin plus intensive chemotherapy for younger and older Patients with AML and FLT3 internal tandem duplications.

Hartmut Döhner, Daniela Weber, Julia Krzykalla, Walter Fiedler, Gerald Georg Wulf, Helmut R Salih, Michael Lübbert, Michael Kühn, Thomas Schroeder, Hans Salwender, Katharina S Götze, Jörg Westermann, Lars Fransecky, Karin Mayer, Bernd Hertenstein, Mark Ringhoffer, Hans-Joachim Tischler, Sigrid Machherndl-Spandl, Anika Schrade, Peter Paschka, Verena I Gaidzik, Frauke Theis, Felicitas R Thol, Michael Heuser, Richard F Schlenk, Lars Bullinger, Maral Saadati, Axel Benner, Richard A Larson, Richard M Stone, Konstanze Döhner, Arnold Ganser.

We conducted a single-arm phase-II trial (AMLSG 16-10) to evaluate midostaurin with intensive chemotherapy followed by allogeneic hematopoietic-cell transplantation (HCT) and a one-year midostaurin maintenance therapy in adult patients with acute myeloid leukemia (AML) and FLT3 internal tandem duplication (ITD). Patients 18-70 years of age with newly diagnosed FLT3-ITD-positive AML were eligible. Primary and key secondary endpoints were event-free (EFS) and overall survival (OS). Results were compared to a historical cohort of 415 patients treated on 5 prior AMLSG trials; statistical analysis was performed using a double-robust adjustment with propensity score weighting and covariate adjustment. Results were also compared to patients (18-59yrs) treated on the placebo arm of the CALGB 10603/RATIFY trial. The trial accrued 440 patients (18-60yrs, n=312; 61-70yrs, n=128). In multivariate analysis, EFS was significantly in favor of patients treated within the AMLSG 16-10 trial compared to the AMLSG control (HR 0.55; P<0.001); both in younger (HR 0.59; P<0.001) and older patients (HR 0.42; P<0.001). Multivariate analysis also showed a significant beneficial effect on OS compared to the AMLSG control (HR 0.57; P<0.001) as well as to the CALGB 10603/RATIFY trial (HR 0.71; p=0.005). The treatment effect of midostaurin remained significant in sensitivity analysis including allogeneic HCT as a time-dependent covariate. Addition of midostaurin to chemotherapy was safe in younger and older patients. In comparison to historical controls, the addition of midostaurin to intensive therapy led to a significant improvement in outcome in younger and older patients with AML and FLT3-ITD.

DOI: https://doi.org/10.1182/bloodadvances.2022007223
Blood Adv. 2022 Apr 25. pii: bloodadvances.2022007015. [Epub ahead of print]

Npm1 Haploinsufficiency in collaboration with MEIS1 is sufficient to induce AML in mice.

Andrew Muranyi, Tobias Ammer, Anna Kechter, Vijay P S Rawat, Amit U Sinha, Irene Gonzalez-Menendez, Leticia Quintanilla-Martinez, Anca Azoitei, Cagatay Günes, Annalisa Mupo, George S Vassiliou, Shiva Bamezai, Christian Buske.

NPM1 is among the most frequently mutated genes in acute myeloid leukemia (AML). Mutations in the NPM1 gene result in the increased export of NPM1 to the cytoplasm (NPM1c) and are associated with multiple transforming events including the aberrant upregulation of MEIS1 that maintains stem cell and cell cycle-associated pathways in NPM1c AML. However, another consequence of the NPM1c mutation is the inadequate levels of NPM1 wildtype in the nucleus and nucleolus, caused by loss of one wild-type allele in addition to enforced NPM1 nuclear export. The contribution of NPM1 haploinsufficiency independently of the NPM1 mutation to AML development and its relationship with MEIS1 function is poorly understood. Using mouse models, our study shows that NPM1 haploinsufficiency paired with MEIS1 overexpression is sufficient to induce a fully penetrant AML in mice which transcriptionally resembles human NPM1c AML. NPM1 haploinsufficiency alters MEIS1 binding occupancies such that it binds the promoter of the stem cell and cell cycle-associated oncogene, structural maintenance of chromosome protein 4 (SMC4) in NPM1 haploinsufficient AML cells but not in NPM1 wild type harboring Hoxa9/Meis1 transformed cells. SMC4 is higher expressed in haploinsufficient and NPM1c positive AML cells, which are more vulnerable to the disruption of the MEIS1-SMC4 axis compared to AML cells with non-mutated NPM1. Taken together, our study underlines that NPM1 haploinsufficiency on its own is a key factor of myeloid leukemogenesis and characterizes the MEIS1-SMC4 axis as a potential therapeutic target in this AML subtype.

DOI: https://doi.org/10.1182/bloodadvances.2022007015
Blood Adv. 2022 Apr 25. pii: bloodadvances.2021006909. [Epub ahead of print]

Using stroma-anchoring cytokines to augment ADCC: a phase 1 trial of F16IL2 and BI 836858 for posttransplant AML relapse.

Andrew F Berdel, Leo Ruhnke, Linus Angenendt, Martin Wermke, Christoph Röllig, Jan-Henrik Mikesch, Annika Scheller, Teresa Hemmerle, Mattia Matasci, Klaus Wethmar, Torsten Kessler, Mirjam Gerwing, Daniel Alexander Hescheler, Michael Schäfers, Wolfgang Hartmann, Bianca Altvater, Claudia Rossig, Martin Bornhäuser, Georg Lenz, Matthias Stelljes, Bjoern Rueter, Dario Neri, Wolfgang E Berdel, Christoph Schliemann.

Natural killer (NK) cells are key effectors in cancer immunosurveillance and posttransplant immunity, but deficiency of environmental signals and insufficient tumor recognition may limit their activity. We hypothesized that the antibody-mediated anchoring of interleukin-2 (IL-2) to a spliced isoform of the extracellular matrix (ECM) glycoprotein tenascin-C would potentiate NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) against leukemic blasts. In this novel-novel combination, dose-escalation phase 1 trial, we enrolled patients with posttransplant acute myeloid leukemia (AML) relapse to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of the antibody-cytokine fusion F16IL2 (10-20x106 IU IV, days 1, 8, 15, and 22 of 28-day cycles) in combination with the anti-CD33 antibody BI 836858 (10-40 mg IV, 2 days after each F16IL2 infusion). Among 15 patients (median [range] age, 50 [20-68] years) treated across 4 dose levels (DL), 6 (40%) had received 2 or 3 prior transplantations. The most frequent adverse events were pyrexia, chills and infusion-related reactions, which were manageable, transient and of grade ≤ 2. One dose-limiting toxicity occurred at each of DL 3 (pulmonary edema) and 4 (GVHD). Three objective responses were observed among 7 patients treated at the 2 higher DL, whereas no responses occurred at the 2 starting DL. Combination therapy stimulated the expansion and activation of NK cells, including those expressing the FcγRIIIA/CD16 receptor. ECM-targeted IL-2 combined with anti-CD33 immunotherapy represents an innovative approach associated with acceptable safety and encouraging biologic and clinical activity in posttransplant AML relapse. This trial was registered at EudraCT (2015-004763-37).

DOI: https://doi.org/10.1182/bloodadvances.2021006909
Lancet Haematol. 2022 May;pii: S2352-3026(22)00076-X. [Epub ahead of print]9(5): e350-e360

Venetoclax combined with induction chemotherapy in patients with newly diagnosed acute myeloid leukaemia: a post-hoc, propensity score-matched, cohort study.

Curtis A Lachowiez, Patrick K Reville, Hagop Kantarjian, Elias Jabbour, Gautam Borthakur, Naval Daver, Sanam Loghavi, Ken Furudate, Lianchun Xiao, Sherry Pierce, Nicholas J Short, Abhishek Maiti, Musa Yilmaz, Koji Sasaki, Koichi Takahashi, Marina Konopleva, Naveen Pemmaraju, Uday Popat, Elizabeth Shpall, Guillermo Garcia-Manero, Farhad Ravandi, Courtney D DiNardo, Tapan M Kadia.

BACKGROUND: Venetoclax combined with intensive chemotherapy has been shown to be safe with promising activity in fit patients with newly diagnosed acute myeloid leukaemia. The aim of this study was to compare the activity of venetoclax plus intensive chemotherapy with intensive chemotherapy alone.
METHODS: This was a post-hoc propensity score matched analysis of prospective clinical trials (NCT03214562, NCT02115295, and NCT01289457) in patients at The University of Texas MD Anderson Cancer Center, Texas, USA between March 29, 2010, and June 15, 2021. Eligible patients were aged 18 years and older, and had newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome, and were treated within trials incorporating purine analogues with an anthracycline and cytarabine either with venetoclax plus intensive chemotherapy or with intensive chemotherapy alone. Patients in the venetoclax plus intensive chemotherapy cohort were matched with patients in the intensive chemotherapy cohort. Morphological response and measurable residual disease (MRD) was assessed using bone marrow aspiration and biopsy and eight-colour multiparameter flow cytometry. The primary objectives were rate of MRD negative composite complete response and cumulative incidence of transition to allogeneic haematopoietic stem-cell transplantation (HSCT). All patients who had response within two treatment cycles (induction and re-induction) were included in the analyses. Secondary objectives included assessment of event-free and overall survival.
FINDINGS: The propensity matched cohort included 279 patients (median age 49 years [IQR 39-57]; 131 [47%] were men and 148 [53%] were women); 85 in the venetoclax plus intensive chemotherapy cohort and 194 in the intensive chemotherapy cohort. After a median follow up of 30 months (95% CI 26-36), 64 (86%) of 74 patients in the venetoclax plus intensive chemotherapy cohort had an MRD-negative composite complete response rate compared with 86 [61%] of 140 patients in the intensive chemotherapy cohort (odd ratio 3·2 [95% CI 1·5-6·7]; p=0·0028). The overall cumulative incidence of allogeneic HSCT in responding patients was higher with venetoclax plus intensive chemotherapy than intensive chemotherapy (79% [95% CI 67-88] vs 57% [49-65]; hazard ratio [HR] 1·52 [95% CI 1·11-2·08]; p=0·012). Venetoclax plus intensive chemotherapy improved event-free survival (median not reached [NR; 95% CI NR-NR] vs 14·3 months [10·7-33·5]; HR 0·57 [95% CI 0·34-0·95]; p=0·030), but overall survival did not significantly differ between the two cohorts (median NR [95% CI 24-NR] vs 32 months [19-NR]; HR 0·63 [95% CI 0·35-1·1], p=0·13).
INTERPRETATIONS: Venetoclax combined with intensive induction chemotherapy induced deep MRD-negative remissions, allowing transition to allogeneic HSCT in first remission, and improvement in event-free survival. These results highlight the incremental benefit of venetoclax added to intensive induction chemotherapy across European LeukemiaNet risk groups, and serve as a benchmark to inform enrolment on future confirmatory prospective clinical trials.
FUNDING: None.

DOI: https://doi.org/10.1016/S2352-3026(22)00076-X
Blood Rev. 2022 Apr 09. pii: S0268-960X(22)00024-8. [Epub ahead of print] 100950

Harnessing the power of sphingolipids: Prospects for acute myeloid leukemia.

Johnson Ung, Su-Fern Tan, Todd E Fox, Jeremy J P Shaw, Luke R Vass, Pedro Costa-Pinheiro, Francine E Garrett-Bakelman, Michael K Keng, Arati Sharma, David F Claxton, Ross L Levine, Martin S Tallman, Myles C Cabot, Mark Kester, David J Feith, Thomas P Loughran.

  Acute myeloid leukemia (AML) is an aggressive, heterogenous malignancy characterized by clonal expansion of bone marrow-derived myeloid progenitor cells. While our current understanding of the molecular and genomic landscape of AML has evolved dramatically and opened avenues for molecularly targeted therapeutics to improve upon standard intensive induction chemotherapy, curative treatments are elusive, particularly in older patients. Responses to current AML treatments are transient and incomplete, necessitating the development of novel treatment strategies to improve outcomes. To this end, harnessing the power of bioactive sphingolipids to treat cancer shows great promise. Sphingolipids are involved in many hallmarks of cancer of paramount importance in AML. Leukemic blast survival is influenced by cellular levels of ceramide, a bona fide pro-death molecule, and its conversion to signaling molecules such as sphingosine-1-phosphate and glycosphingolipids. Preclinical studies demonstrate the efficacy of therapeutics that target dysregulated sphingolipid metabolism as well as their combinatorial synergy with clinically-relevant therapeutics. Thus, increased understanding of sphingolipid dysregulation may be exploited to improve AML patient care and outcomes. This review summarizes the current knowledge of dysregulated sphingolipid metabolism in AML, evaluates how pro-survival sphingolipids promote AML pathogenesis, and discusses the therapeutic potential of targeting these dysregulated sphingolipid pathways.

Keywords:  Bcl-2; Ceramide; Mcl-1; Sphingolipid dysregulation; Sphingosine-1-phosphate; Therapeutics

DOI:  https://doi.org/10.1016/j.blre.2022.100950
Blood. 2022 Apr 28. pii: blood.2021014777. [Epub ahead of print]

Mutant-SETBP1 activates transcription of Myc programs to accelerate CSF3R-driven myeloproliferative neoplasms.

Sarah A Carratt, Garth L Kong, Brittany M Curtiss, Zachary Schonrock, Lauren Maloney, Breanna N Maniaci, Hunter Z Blaylock, Adrian Baris, Brian J Druker, Theodore P Braun, Julia E Maxson.

Colony stimulating factor 3 receptor (CSF3R) mutations lead to JAK pathway activation and are the molecular hallmark of chronic neutrophilic leukemia (CNL). Approximately half of CNL patients also have mutations in SET binding protein 1 (SETBP1). In this study, we developed models of SETBP1-mutant leukemia to understand the role that SETBP1 plays in CNL. SETBP1 mutations promote self-renewal of CSF3R-mutant hematopoietic progenitors in vitro and prevent cells from undergoing terminal differentiation. In vivo, SETBP1 mutations accelerate leukemia progression, leading to the rapid development of hepatosplenomegaly and granulocytosis. Through transcriptomic and epigenomic profiling, we found that SETBP1 enhances progenitor-associated programs-most strongly upregulating Myc and Myc target genes. This upregulation of Myc can be reversed by LSD1 inhibitors. In summary, we find that SETBP1 mutations promote aggressive hematopoietic cell expansion when expressed with mutant CSF3R through the upregulation of Myc-associated gene expression programs.

DOI: https://doi.org/10.1182/blood.2021014777
FASEB J. 2022 May;36(5): e22328

Interleukin-4 treatment reduces leukemia burden in acute myeloid leukemia.

Fenghua Qian, Brooke E Arner, Kathleen M Kelly, Charyguly Annageldiyev, Arati Sharma, David F Claxton, Robert F Paulson, K Sandeep Prabhu.

  Interleukin-4 (IL-4) is a signature cytokine pivotal in Type 2 helper T cell (Th2) immune response, particularly in allergy and hypersensitivity. Interestingly, IL-4 increases endogenous levels of prostaglandin D2 (PGD2 ) and its metabolites, Δ12 -prostaglandin J2 (Δ12 -PGJ2 ) and 15-deoxy-Δ12,14 -prostaglandin J2 (15d-PGJ2 ), collectively called cyclopentenone PGs (CyPGs). However, the therapeutic role of IL-4 in hematologic malignancies remains unclear. Here, we employed a murine model of acute myeloid leukemia (AML), where human MLL-AF9 fusion oncoprotein was expressed in hematopoietic progenitor cells, to test the effect of IL-4 treatment in vivo. Daily intraperitoneal treatment with IL-4 at 60 µg/kg/d significantly alleviated the severity of AML, as seen by decreased leukemia-initiating cells (LICs). The effect of IL-4 was mediated, in part, by the enhanced expression of hematopoietic- PGD2 synthase (H-PGDS) to effect endogenous production of CyPGs, through autocrine and paracrine signaling mechanisms. Similar results were seen with patient-derived AML cells cultured ex vivo with IL-4. Use of GW9662, a peroxisome proliferator-activated receptor gamma (PPARγ) antagonist, suggested endogenous CyPGs-PPARγ axis mediated p53-dependent apoptosis of LICs by IL-4. Taken together, our results reveal a beneficial role of IL-4 treatment in AML suggesting a potential therapeutic regimen worthy of clinical trials in patients with AML.

Keywords:  AML; H-PGDS; IL-4; PPARγ; prostaglandin

DOI:  https://doi.org/10.1096/fj.202200251R
Br J Haematol. 2022 Apr 25.

Suppression of MYC by PI3K/AKT/mTOR pathway inhibition in combination with all-trans retinoic acid treatment for therapeutic gain in acute myeloid leukaemia.

Sven Stengel, Kevin R Petrie, Yordan Sbirkov, Clara Stanko, Faezeh Ghazvini Zadegan, Veronica Gil, Rafał Skopek, Paweł Kamiński, Łukasz Szymański, Annamaria Brioli, Arthur Zelent, Tino Schenk.

  Aberrant activity of the phosphatidylinositol-3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR [PAM]) pathway, as well as suppressed retinoic acid signalling, contribute to enhanced proliferation and the differentiation blockade of immature myeloid cells in acute myeloid leukaemia (AML). Inhibition of the PAM pathway was shown to affect especially mixed-lineage leukaemia-rearranged AML. Here, we sought to test a combined strategy using small molecule inhibitors against members of the PAM signalling pathway in conjunction with all-trans retinoic acid (ATRA) to target a larger group of different AML subtypes. We find that ATRA treatment in combination with inhibition of PI3K (ZSTK474), mTOR (WYE132) or PI3K/mTOR (BEZ235, dactolisib) drastically reduces protein levels of the proto-oncogene MYC. In combination with BEZ235, ATRA treatment led to almost complete eradication of cellular MYC, G1 arrest, loss of clonal capacity and terminal granulocytic differentiation. We demonstrate that PAM inhibitor/ATRA treatment targets MYC via independent mechanisms. While inhibition of the PAM pathway causes MYC phosphorylation at threonine 58 via glycogen synthase kinase 3 beta and subsequent degradation, ATRA reduces its expression. Here, we present an approach using a combination of known drugs to synergistically reduce aberrant MYC levels, thereby effectively blocking proliferation and enabling differentiation in various AML subtypes.

Keywords:   MYC ; protein kinase B (AKT) ; BEZ235; acute myeloid leukaemia; all-trans retinoic acid; dactolisib; leukaemia; mammalian target of rapamycin; phosphatidylinositol-3 kinase; phosphatidylinositol-3 kinase/protein kinase B/mammalian target of rapamycin (PAM)

DOI:  https://doi.org/10.1111/bjh.18187
Immunometabolism. 2022 ;pii: e220008. [Epub ahead of print]4(2):

CD36-Mediated Fatty Acid Oxidation in Hematopoietic Stem Cells Is a Novel Mechanism of Emergency Hematopoiesis in Response to Infection.

Maria Maryanovich, Keisuke Ito.

  Hematopoietic homeostasis depends on the close regulation of hematopoietic stem cell (HSC) activity in the bone marrow. Quiescence and activation in response to stress, among other changes in state, are mediated by shifts in HSC metabolic activity. Although HSC steady-state metabolism is well established, the mechanisms driving HSC activation, proliferation, and differentiation in response to stress remain poorly understood. Here we discuss a study by Mistry et al. that describes a novel metabolic mechanism that fuels HSC activation and expansion. The authors show that to meet their metabolic needs in response to infection, hematopoietic stem and progenitor cells uptake free fatty acids from their microenvironment via CD36 to fuel fatty acid oxidation. These exciting findings suggest that in the context of infection, HSCs undergo a metabolic shift toward fatty acid metabolism that drives emergency hematopoiesis and raise questions about the role of the microenvironment in this process.

Keywords:  CD36; fatty-acid oxidation; hematopoiesis; hematopoietic stem cells; infection; oxidative phosphorylation

DOI:  https://doi.org/10.20900/immunometab20220008
Cancer Treat Res Commun. 2022 Apr 14. pii: S2468-2942(22)00050-8. [Epub ahead of print]31 100560

IDH1 inhibitor-induced neutrophilic dermatosis in a patient with acute myeloid leukemia.

Sydney Dunn-Valadez, Srilakshmi Bathini, Carly Elston, Sravanti Rangaraju, Antonio Di Stasi, Sarah Worth, Diana Morlote, Shuko Harada, Pankit Vachhani.

  Ivosidenib is an oral inhibitor of mutant Isocitrate dehydrogenase 1 (IDH1). It is approved for treatment of patients with relapsed or refractory IDH1-mutated acute myeloid leukemia (AML) and patients with newly diagnosed IDH1-mutated AML who are 75 years or older or those who are ineligible to receive intensive chemotherapy. While generally well tolerated, differentiation syndrome has been reported in 15-20% of patients. Here, we report a case of acute febrile neutrophilic dermatosis or Sweet's syndrome in conjunction with the use of ivosidenib for the treatment of relapsed AML. We discuss the clinical presentation of this rare entity, review relevant literature, and comment on its association with differentiation syndrome.

Keywords:  IDH1; Ivosidenib, Differentiation syndrome

DOI:  https://doi.org/10.1016/j.ctarc.2022.100560
Asian Pac J Cancer Prev. 2022 Apr 01. pii: 90083. [Epub ahead of print]23(4): 1107-1116

Association of Somatic Gene Mutations with Risk of Transformation into Acute Myeloid Leukemia in Patients with Myelodysplastic Syndrome: A Systematic Review and Meta-Analysis.

Noorwati Sutandyo, Resti Mulyasari, Agus Kosasih, Ikhwan Rinaldi, Melva Louisa, Andi Putra Kevinsyah, Kevin Winston.

   OBJECTIVES: we aim to conduct a systematic review and meta-analysis in population of adult MDS patients to elucidate the role of these genes in AML transformation risk.
MATERIALS AND METHODS: The protocol for this systematic review and meta-analysis was registered in the international prospective register of systematic reviews (PROSPERO) with ID number of CRD42020218581. Systematic literature search was conducted by all authors up to October 2021 on: (1) PubMed, (2) EBSCOhost, (3) Scopus, (4) JSTOR, and (5) grey literatures. Hand-searching for relevant articles was also conducted. The following keywords with their synonyms and combinations using Boolean operators were applied to all database: "myelodysplastic syndrome", SRSF2", "SF3B1", "U2AF1", "ASXL1", "DNMT3A", "TET2", "IDH1", "IDH2", "RUNX1", "acute myeloid leukemia progression", and "leukemia free survival". Outcome was measured using hazard ratio (HR).
RESULTS: We identified 14 articles to be used for this systematic review and meta-analysis. There was no statistically significant difference in AML transformation risk between U2AF1 mutant and U2AF1 wildtype MDS patients (HR: 1.41; 95% CI: 0.95-2.07, p=0.08, I2=0%). Pooled HR showed that patients with SRSF2 mutation had higher risk of AML transformation (HR 2.62; 95% CI: 1.54-4.45; p= .0004; I2= 55%). The pooled HR for SF3B1 was 0.48 (95% CI: 0.22-1.06, p=0.07, I2=55%). Mutations of TET2, ASXL1, and EZH2 were not associated with AML transformation. Meanwhile, DNMT3A mutations were associated with AML transformation with pooled HR of 2.73 (95% CI: 1.43-5.21; p= 0.08; I2: 67%). The pooled HR for IDH genes was smaller (HR: 2.92; 95%CI: 1.21-7.06; p=0.02; I2:65%). Patients with RUNX1 mutation were associated with AML transformation (HR: 1.85; 95%CI: 1.11-3.09; p=0.02; I2:38%).
CONCLUSION: Based from our analyses, MDS patients with mutations of SRSF2, DNMT3A, IDH, and RUNX1 have higher hazard ratio for AML transformation.

Keywords:  Mutation; Myelodysplastic syndrome; leukemia progression

DOI:  https://doi.org/10.31557/APJCP.2022.23.4.1107
Cell Rep. 2022 Apr 26. pii: S2211-1247(22)00516-2. [Epub ahead of print]39(4): 110752

Hypoxic, glycolytic metabolism is a vulnerability of B-acute lymphoblastic leukemia-initiating cells.

Vivian Morris, Dahai Wang, Zhiheng Li, William Marion, Travis Hughes, Patricia Sousa, Taku Harada, Shannan Ho Sui, Sergey Naumenko, Jérémie Kalfon, Prerana Sensharma, Marcelo Falchetti, Renan Vinicius da Silva, Tito Candelli, Pauline Schneider, Thanasis Margaritis, Frank C P Holstege, Yana Pikman, Marian Harris, Ronald W Stam, Stuart H Orkin, Angela N Koehler, Alex K Shalek, Trista E North, Maxim Pimkin, George Q Daley, Edroaldo Lummertz da Rocha, R Grant Rowe.

  High-risk forms of B-acute lymphoblastic leukemia (B-ALL) remain a therapeutic challenge. Leukemia-initiating cells (LICs) self-renew and spark relapse and therefore have been the subject of intensive investigation; however, the properties of LICs in high-risk B-ALL are not well understood. Here, we use single-cell transcriptomics and quantitative xenotransplantation to understand LICs in MLL-rearranged (MLL-r) B-ALL. Compared with reported LIC frequencies in acute myeloid leukemia (AML), engraftable LICs in MLL-r B-ALL are abundant. Although we find that multipotent, self-renewing LICs are enriched among phenotypically undifferentiated B-ALL cells, LICs with the capacity to replenish the leukemic cellular diversity can emerge from more mature fractions. While inhibiting oxidative phosphorylation blunts blast proliferation, this intervention promotes LIC emergence. Conversely, inhibiting hypoxia and glycolysis impairs MLL-r B-ALL LICs, providing a therapeutic benefit in xenotransplantation systems. These findings provide insight into the aggressive nature of MLL-r B-ALL and provide a rationale for therapeutic targeting of hypoxia and glycolysis.

Keywords:  CP: Cancer; CP: Metabolism; leukemia; metabolism; stem cell

DOI:  https://doi.org/10.1016/j.celrep.2022.110752
Nat Commun. 2022 Apr 28. 13(1): 2228

Targeting CD123 in blastic plasmacytoid dendritic cell neoplasm using allogeneic anti-CD123 CAR T cells.

Tianyu Cai, Agnès Gouble, Kathryn L Black, Anna Skwarska, Ammar S Naqvi, Deanne Taylor, Ming Zhao, Qi Yuan, Mayumi Sugita, Qi Zhang, Roman Galetto, Stéphanie Filipe, Antonio Cavazos, Lina Han, Vinitha Kuruvilla, Helen Ma, Connie Weng, Chang-Gong Liu, Xiuping Liu, Sergej Konoplev, Jun Gu, Guilin Tang, Xiaoping Su, Gheath Al-Atrash, Stefan Ciurea, Sattva S Neelapu, Andrew A Lane, Hagop Kantarjian, Monica L Guzman, Naveen Pemmaraju, Julianne Smith, Andrei Thomas-Tikhonenko, Marina Konopleva.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with poor outcomes with conventional therapy. Nearly 100% of BPDCNs overexpress interleukin 3 receptor subunit alpha (CD123). Given that CD123 is differentially expressed on the surface of BPDCN cells, it has emerged as an attractive therapeutic target. UCART123 is an investigational product consisting of allogeneic T cells expressing an anti-CD123 chimeric antigen receptor (CAR), edited with TALEN® nucleases. In this study, we examine the antitumor activity of UCART123 in preclinical models of BPDCN. We report that UCART123 have selective antitumor activity against CD123-positive primary BPDCN samples (while sparing normal hematopoietic progenitor cells) in the in vitro cytotoxicity and T cell degranulation assays; supported by the increased secretion of IFNγ by UCART123 cells when cultured in the presence of BPDCN cells. UCART123 eradicate BPDCN and result in long-term disease-free survival in a subset of primary patient-derived BPDCN xenograft mouse models. One potential challenge of CD123 targeting therapies is the loss of CD123 antigen through diverse genetic mechanisms, an event observed in one of three BPDCN PDX studied. In summary, these results provide a preclinical proof-of-principle that allogeneic UCART123 cells have potent anti-BPDCN activity.

DOI: https://doi.org/10.1038/s41467-022-29669-8