bims-tremyl 2021-02-07 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2021–02–07
24 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Menin is necessary for long term maintenance of meningioma-1 driven leukemia.
Targeting DNA damage repair functions of two histone deacetylases, HDAC8 and SIRT6, sensitizes acute myeloid leukemia to NAMPT inhibition.
Autonomous TGFβ signaling induces phenotypic variation in human acute myeloid leukemia.
Multiplexed single-cell mass cytometry reveals distinct inhibitory effects on intracellular phosphoproteins by midostaurin in combination with chemotherapy in AML cells.
Forsaken Pharmaceutical: Glasdegib in Acute Myeloid Leukemia and Myeloid Diseases.
Selective recruitment of γδ T cells by a bispecific antibody for the treatment of acute myeloid leukemia.
Incorporation of Novel therapies for the treatment of acute myeloid leukemia: a perspective.
The transcriptional corepressor CBFA2T3 inhibits all-trans-retinoic acid-induced myeloid gene expression and differentiation in acute myeloid leukemia.
Convergent organization of aberrant MYB complex controls oncogenic gene expression in acute myeloid leukemia.
Concurrent inhibition of IDH and methyltransferase maximizes therapeutic efficacy in IDH mutant acute myeloid leukemia.
Make Your Cake and Eat It: Refueling of Immune Fitness in AML Post Allo-HCT Using Baking Soda.
CD123 Is Consistently Expressed on NPM1-Mutated AML Cells.
The complete story of less than complete responses: The evolution and application of acute myeloid leukemia clinical responses.
Biomarkers associated with blinatumomab outcomes in acute lymphoblastic leukemia.
Impact of measurable residual disease by decentralized flow cytometry: a PETHEMA real-world study in 1076 patients with acute myeloid leukemia.
Novel prognostic genes and subclasses of acute myeloid leukemia revealed by survival analysis of gene expression data.
Dose Optimization of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: A New Therapeutic Challenge.
Leukemia vaccine overcomes limitations of checkpoint blockade by evoking clonal T cell responses in a murine acute myeloid leukemia model.
A gene-environment-induced epigenetic program initiates tumorigenesis.
Near-infrared oxidative phosphorylation inhibitor integrates acute myeloid leukemia-targeted imaging and therapy.
Classification and Personalized Prognostic Assessment on the Basis of Clinical and Genomic Features in Myelodysplastic Syndromes.
An IDH1-vitamin C crosstalk drives human erythroid development by inhibiting pro-oxidant mitochondrial metabolism.
Targeting cereblon in AML.
Characteristics and outcome of patients with acute myeloid leukaemia and t(8;16)(p11;p13): results from an International Collaborative Study.

Leukemia. 2021 Feb 04.

Menin is necessary for long term maintenance of meningioma-1 driven leukemia.

Clara Libbrecht, Hongbo M Xie, Molly C Kingsley, Jessica N Haladyna, Simone S Riedel, Fatemeh Alikarami, Alexandra Lenard, Gerard M McGeehan, Patricia Ernst, Kathrin M Bernt.

Translocations of Meningioma-1 (MN1) occur in a subset of acute myeloid leukemias (AML) and result in high expression of MN1, either as a full-length protein, or as a fusion protein that includes most of the N-terminus of MN1. High levels of MN1 correlate with poor prognosis. When overexpressed in murine hematopoietic progenitors, MN1 causes an aggressive AML characterized by an aberrant myeloid precursor-like gene expression program that shares features of KMT2A-rearranged (KMT2A-r) leukemia, including high levels of Hoxa and Meis1 gene expression. Compounds that target a critical KMT2A-Menin interaction have proven effective in KMT2A-r leukemia. Here, we demonstrate that Menin (Men1) is also critical for the self-renewal of MN1-driven AML through the maintenance of a distinct gene expression program. Genetic inactivation of Men1 led to a decrease in the number of functional leukemia-initiating cells. Pharmacologic inhibition of the KMT2A-Menin interaction decreased colony-forming activity, induced differentiation programs in MN1-driven murine leukemia and decreased leukemic burden in a human AML xenograft carrying an MN1-ETV6 translocation. Collectively, these results nominate Menin inhibition as a promising therapeutic strategy in MN1-driven leukemia.

DOI: https://doi.org/10.1038/s41375-021-01146-z
Clin Cancer Res. 2021 Feb 04. pii: clincanres.3724.2020. [Epub ahead of print]

Targeting DNA damage repair functions of two histone deacetylases, HDAC8 and SIRT6, sensitizes acute myeloid leukemia to NAMPT inhibition.

Pu Zhang, Lindsey T Brinton, Katie Williams, Steven Sher, Shelley Orwick, Tzung-Huei Lai, Alice S Mims, Christopher C Coss, Samuel K Kulp, Youssef Youssef, Wing Keung Chan, Shaneice Mitchell, Allison Mustonen, Matthew Cannon, Hannah Phillips, Amy M Lehman, Tierney Kauffman, Larry Beaver, Daniel Canfield, Nicole R Grieselhuber, Lapo Alinari, Deepa Sampath, Pearlly Yan, John C Byrd, James S Blachly, Rosa Lapalombella.

PURPOSE: Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors are currently in development, but may be limited as a single agent therapy due to compound-specific toxicity and cancer metabolic plasticity allowing resistance development. To potentially lower the doses of NAMPT inhibitors required for therapeutic benefit against acute myeloid leukemia (AML), we performed a genome-wide CRISPRi screen to identify rational disease-specific partners for a novel NAMPT inhibitor, KPT-2974.
EXPERIMENTAL DESIGN: Cell lines and primary cells were analyzed for cell viability, self-renewal and responses at RNA and protein levels with loss-of-function approaches and pharmacologic treatments. In vivo efficacy of combination therapy was evaluated with a xenograft model.
RESULTS: We identified two histone deacetylases, HDAC8 and SIRT6, whose knockout conferred synthetic lethality with KPT-9274 in AML. Furthermore, HDAC8-specific inhibitor, PCI-34051, or clinical Class I HDAC inhibitor, AR-42, in combination with KPT-9274, synergistically decreased the survival of AML cells in a dose-dependent manner. AR-42/KPT-9274 co-treatment attenuated colony-forming potentials of patient cells while sparing healthy hematopoietic cells. Importantly, combined therapy demonstrated promising in vivo efficacy compared with KPT-9274 or AR-42 monotherapy. Mechanistically, genetic inhibition of SIRT6 potentiated the effect of KPT-9274 on PARP-1 suppression by abolishing mono-ADP ribosylation. AR-42/KPT-9274 co-treatment resulted in synergistic attenuation of homologous recombination (HR) and nonhomologous end joining (NHEJ) pathways in cell lines and leukemia initiating cells (LICs).
CONCLUSIONS: Our findings provide evidence that HDAC8 inhibition- or shSIRT6-induced DNA repair deficiencies are potently synergistic with NAMPT targeting, with minimal toxicity towards normal cells, providing a rationale for a novel-novel combination-based treatment for AML.

DOI: https://doi.org/10.1158/1078-0432.CCR-20-3724
Stem Cells. 2021 Feb 04.

Autonomous TGFβ signaling induces phenotypic variation in human acute myeloid leukemia.

Yasuhiro Shingai, Takafumi Yokota, Daisuke Okuzaki, Takao Sudo, Tomohiko Ishibashi, Yukiko Doi, Tomoaki Ueda, Takayuki Ozawa, Ritsuko Nakai, Akira Tanimura, Michiko Ichii, Hirohiko Shibayama, Yuzuru Kanakura, Naoki Hosen.

  Heterogeneity of leukemia stem cells (LSCs) is involved in their collective chemoresistance. To eradicate LSCs, it is necessary to understand the mechanisms underlying their heterogeneity. Here, we aimed to identify signals responsible for heterogeneity and variation of LSCs in human acute myeloid leukemia (AML). Monitoring expression levels of endothelial cell-selective adhesion molecule (ESAM), a hematopoietic stem cell-related marker, was useful to detect the plasticity of AML cells. While healthy human hematopoietic stem/progenitor cells robustly expressed ESAM, AML cells exhibited heterogeneous ESAM expression. Interestingly, ESAM- and ESAM+ leukemia cells obtained from AML patients were mutually interconvertible in culture. KG1a and CMK, human AML clones, also represented the heterogeneity in terms of ESAM expression. Single cell culture with ESAM- or ESAM+ AML clones recapitulated the phenotypic interconversion. The phenotypic alteration was regulated at the gene expression level, and RNA sequencing revealed activation of TGFβ signaling in these cells. AML cells secreted TGFβ1, which autonomously activated TGFβ pathway and induced their phenotypic variation. Surprisingly, TGFβ signaling blockade inhibited not only the variation but also the proliferation of AML cells. Therefore, autonomous activation of TGFβ signaling underlies the LSC heterogeneity, which may be a promising therapeutic target for AML. © AlphaMed Press 2021 SIGNIFICANCE STATEMENT: We have shown the autonomous TGFβ signaling as one of the molecular mechanisms underlying heterogeneity and variability of leukemia stem cells associated with human acute myeloid leukemia (AML). By monitoring the ESAM expression, we found that human AML cells were phenotypically heterogeneous and variable. ESAM- and ESAM+ AML cells were mutually convertible in culture. We determined that autocrine TGFβ signaling was involved in AML cell heterogeneity and variability. Inhibiting the TGFβ pathway not only suppressed ESAM variability, but also induced AML cell apoptosis. Thus, mechanisms promoting the heterogeneity and variability of LSCs can be therapeutic targets against intractable AML.

Keywords:  Acute myeloid leukemia; Autonomous signaling; Chemoresistance; Endothelial cell-selective adhesion molecule; Heterogeneity; Leukemia stem cells; Phenotypic variation; TGFβ

DOI:  https://doi.org/10.1002/stem.3348
Exp Hematol Oncol. 2021 Feb 02. 10(1): 7

Multiplexed single-cell mass cytometry reveals distinct inhibitory effects on intracellular phosphoproteins by midostaurin in combination with chemotherapy in AML cells.

Emma Rörby, Jörgen Adolfsson, Erik Hultin, Thomas Gustafsson, Kourosh Lotfi, Jörg Cammenga, Jan-Ingvar Jönsson.

   BACKGROUND: Fms-related tyrosine kinase 3 (FLT3) receptor serves as a prognostic marker and therapeutic target in acute myeloid leukemia (AML). Approximately one-third of AML patients carry mutation in FLT3, associated with unfavourable prognosis and high relapse rate. The multitargeted kinase inhibitor midostaurin (PKC412) in combination with standard chemotherapy (daunorubicin and cytarabine) was recently shown to increase overall survival of AML patients. For that reason, PKC412 has been approved for treatment of AML patients with FLT3-mutation. PKC412 synergizes with standard chemotherapy, but the mechanism involved is not fully understood and the risk of relapse is still highly problematic.
METHODS: By utilizing the unique nature of mass cytometry for single cell multiparameter analysis, we have explored the proteomic effect and intracellular signaling response in individual leukemic cells with internal tandem duplication of FLT3 (FLT3-ITD) after midostaurin treatment in combination with daunorubicin or cytarabine.
RESULTS: We have identified a synergistic inhibition of intracellular signaling proteins after PKC412 treatment in combination with daunorubicin. In contrast, cytarabine antagonized phosphorylation inhibition of PKC412. Moreover, we found elevated levels of FLT3 surface expression after cytarabine treatment. Interestingly, the surface localization of FLT3 receptor increased in vivo on the blast cell population of two AML patients during day 3 of induction therapy (daunorubicin; once/day from day 1-3 and cytarabine; twice/day from day 1-7). We found FLT3 receptor expression to correlate with intracellular cytarabine (AraC) response. AML cell line cultured with AraC with or without PKC412 had an antagonizing phosphorylation inhibition of pAKT (p = 0.042 and 0.0261, respectively) and pERK1/2 (0.0134 and 0.0096, respectively) in FLT3high compared to FLT3low expressing cell populations.
CONCLUSIONS: Our study provides insights into how conventional chemotherapy affects protein phosphorylation of vital signaling proteins in human leukemia cells. The results presented here support further investigation of novel strategies to treat FLT3-mutated AML patients with PKC412 in combination with chemotherapy agents and the potential development of novel treatment strategies.

Keywords:  Acute myeloid leukemia; Chemotherapy; FLT3; Intracellular therapy response; Mass cytometry; Midostaurin; Proteomics; Signaling proteins

DOI:  https://doi.org/10.1186/s40164-021-00201-w
Clin Lymphoma Myeloma Leuk. 2020 Dec 16. pii: S2152-2650(20)31013-2. [Epub ahead of print]

Forsaken Pharmaceutical: Glasdegib in Acute Myeloid Leukemia and Myeloid Diseases.

Jonathan Feld, Lewis R Silverman, Shyamala C Navada.

  Advancements in the understanding of the pathogenesis of acute myeloid leukemia (AML) have led to the introduction and approval of a number of novel drugs in AML. Glasdegib, an oral hedgehog pathway inhibitor, was approved in 2018 in combination with low-dose cytarabine for the treatment of newly diagnosed AML in patients unfit for intensive chemotherapy. In this review, we discuss the preclinical rationale for glasdegib, important clinical trials that led to glasdegib's approval, and future trials of glasdegib in AML and other myeloid diseases. Notably, 2 large randomized, placebo-controlled phase 3 trials (AML BRIGHT 1019) are currently recruiting patients with newly diagnosed AML to evaluate glasdegib in combination with intensive chemotherapy or azacitidine, depending on the patient's ability to tolerate induction chemotherapy. While glasdegib and low-dose cytarabine have been eclipsed by venetoclax and hypomethylating agent combinations for newly diagnosed AML in the United States, we discuss other areas where glasdegib may still have an opportunity to improve outcomes in this devastating disease.

Keywords:  Allogeneic stem cell transplant; Hedgehog pathway; Leukemia stem cells; Myelodysplastic syndromes; Myelofibrosis

DOI:  https://doi.org/10.1016/j.clml.2020.12.007
Leukemia. 2021 Feb 01.

Selective recruitment of γδ T cells by a bispecific antibody for the treatment of acute myeloid leukemia.

Rajkumar Ganesan, Vijaykumar Chennupati, Balaji Ramachandran, Michael Riis Hansen, Sanjaya Singh, Iqbal S Grewal.

Despite significant progress over the last few decades in the treatment of acute myeloid leukemia (AML), there still remains a major unmet medical need for this disease. Immunotherapy approaches for redirecting pan CD3+ T cells to target leukemia blasts have shown limited efficacy in clinical trials and often accompanied with severe toxicity in AML patients. We designed an alternative engager molecule (Anti-TRGV9/anti-CD123), a bispecific antibody that can simultaneously bind to the Vγ9 chain of the Vγ9Vδ2+ γδ T cell receptor and to AML target antigen, CD123, to selectively recruit Vγ9+ γδ T cells rather than pan T cells to target AML blasts. Our results suggest that prototypic bispecific antibodies (a) selectively activate Vγ9+ γδ T cells as judged by CD69 and CD25 surface expression, and intracellular Granzyme B expression, (b) selectively recruit Vγ9+ γδ T cells into cell-cell conjugate formation of γδ T cells with tumor cells indicating selective and effective engagement of effector and target tumor cells, and (c) mediate γδ T cell cytotoxicity (in vitro and in vivo) against tumor antigen-expressing cells. Collectively, these findings suggest that selectively redirecting Vγ9+ γδ T cells to target AML blasts has a potential for immunotherapy for AML patients and favors further exploration of this concept.

DOI: https://doi.org/10.1038/s41375-021-01122-7
Leuk Lymphoma. 2021 Feb 04. 1-26

Incorporation of Novel therapies for the treatment of acute myeloid leukemia: a perspective.

Julian A Waksal, Martin S Tallman.

  Acute myeloid leukemia (AML) is a heterogeneous group of diseases that poses an array of therapeutic challenges. For decades two chemotherapeutic agents, cytarabine and daunorubicin, remained the backbone of AML therapy protocols. However, since 2017 nine novel therapies have been approved for the management of AML. With the rapid expansion of therapeutic options, hematologists must adapt their practice to optimize the benefits of these novel therapy options and minimize treatment toxicity. Here, we discuss the novel therapies that have changed the standard of care in management of patients with AML. We summarize the pivotal clinical trials that lead to the approval of these agents, and ongoing trials evaluating additional potential indications. We discuss several promising therapy candidates and their corresponding clinical trials. We discuss therapeutic strategies to incorporate these therapies into practice and pose unanswered questions that have arisen along with the expansion of treatment options.

Keywords:  AML; acute myeloid leukemia; new treatments; novel; therapies; treatment

DOI:  https://doi.org/10.1080/10428194.2020.1842403
J Biol Chem. 2020 Jul 03. pii: S0021-9258(17)50314-2. [Epub ahead of print]295(27): 8887-8900

The transcriptional corepressor CBFA2T3 inhibits all-trans-retinoic acid-induced myeloid gene expression and differentiation in acute myeloid leukemia.

Nickolas Steinauer, Chun Guo, Jinsong Zhang.

  CBFA2/RUNX1 partner transcriptional co-repressor 3 (CBFA2T3, also known as MTG16 or ETO2) is a myeloid translocation gene family protein that functions as a master transcriptional corepressor in hematopoiesis. Recently, it has been shown that CBFA2T3 maintains leukemia stem cell gene expression and promotes relapse in acute myeloid leukemia (AML). However, a role for CBFA2T3 in myeloid differentiation of AML has not been reported. Here, we show that CBFA2T3 represses retinoic acid receptor (RAR) target gene expression and inhibits all-trans-retinoic acid (ATRA)-induced myeloid differentiation of AML cells. ChIP-Seq revealed that CBFA2T3 targets the RARα/RXRα cistrome in U937 AML cells, predominantly at myeloid-specific enhancers associated with terminal differentiation. CRISPR/Cas9-mediated abrogation of CBFA2T3 resulted in spontaneous and ATRA-induced activation of myeloid-specific genes in a manner correlated with myeloid differentiation. Importantly, these effects were reversed by CBFA2T3 re-expression. Mechanistic studies showed that CBFA2T3 inhibits RAR target gene transcription by acting at an early step to regulate histone acetyltransferase recruitment, histone acetylation, and chromatin accessibility at RARα target sites, independently of the downstream, RAR-mediated steps of transcription. Finally, we validated the inhibitory effect of CBFA2T3 on RAR in multiple AML subtypes and patient samples. To our knowledge, this is the first study to show that CBFA2T3 down-regulation is both necessary and sufficient for enhancing ATRA-induced myeloid gene expression and differentiation of AML cells. Our findings suggest that CBFA2T3 can serve as a potential target for enhancing AML responsiveness to ATRA differentiation therapies.

Keywords:  CBFA2/RUNX1 partner transcriptional co-repressor 3 (CBFA2T3); acute myeloid leukemia (AML); all-trans-retinoic acid (ATRA); cancer biology; cell differentiation; chromatin accessibility; chromatin immunoprecipitation (ChIP); chromatin regulation; epigenetics; gene transcription; histone acetylation; histone acetyltransferase; nuclear receptor; transcription corepressor; transcriptional corepressor

DOI:  https://doi.org/10.1074/jbc.RA120.013042
Elife. 2021 Feb 02. pii: e65905. [Epub ahead of print]10

Convergent organization of aberrant MYB complex controls oncogenic gene expression in acute myeloid leukemia.

Sumiko Takao, Lauren Forbes, Masahiro Uni, Shuyuan Cheng, Jose Mario Bello Pineda, Yusuke Tarumoto, Paolo Cifani, Gerard Minuesa, Celine Chen, Michael G Kharas, Robert K Bradley, Christopher R Vakoc, Richard P Koche, Alex Kentsis.

  Dysregulated gene expression contributes to most prevalent features in human cancers. Here, we show that most subtypes of acute myeloid leukemia (AML) depend on the aberrant assembly of MYB transcriptional co-activator complex. By rapid and selective peptidomimetic interference with the binding of CBP/P300 to MYB, but not CREB or MLL1, we find that the leukemic functions of MYB are mediated by CBP/P300 co-activation of a distinct set of transcription factor complexes. These MYB complexes assemble aberrantly with LYL1, E2A, C/EBP family members, LMO2 and SATB1. They are organized convergently in genetically diverse subtypes of AML, and are at least in part associated with inappropriate transcription factor co-expression. Peptidomimetic remodeling of oncogenic MYB complexes is accompanied by specific proteolysis and dynamic redistribution of CBP/P300 with alternative transcription factors such as RUNX1 to induce myeloid differentiation and apoptosis. Thus, aberrant assembly and sequestration of MYB:CBP/P300 complexes provide a unifying mechanism of oncogenic gene expression in AML. This work establishes a compelling strategy for their pharmacologic reprogramming and therapeutic targeting for diverse leukemias and possibly other human cancers caused by dysregulated gene control.

Keywords:  cancer biology; human

DOI:  https://doi.org/10.7554/eLife.65905
Haematologica. 2021 Feb 01. 106(2): 324-326

Concurrent inhibition of IDH and methyltransferase maximizes therapeutic efficacy in IDH mutant acute myeloid leukemia.

Zhihong Zeng, Marina Konopleva.

DOI: https://doi.org/10.3324/haematol.2020.266809
Immunometabolism. 2021 ;3(1): e210005

Make Your Cake and Eat It: Refueling of Immune Fitness in AML Post Allo-HCT Using Baking Soda.

Alex Tonks.

  Although there has been a recent renaissance in the availability of new therapeutic options for patients with acute myeloid leukemia (AML), survival rates remain low coupled with a high incidence of relapse. Enhancing T cell and immune function has become an effective therapeutic approach in hematological malignancies. However, AML cells can modulate the bone marrow microenvironment by changing extracellular nutrient and biochemical availability which can metabolically regulate immune function. Here we review the findings by Uhl et al. showing that T cell metabolism and function can be boosted by treatment with sodium bicarbonate to counteract the metabolic changes induced by lactic acid produced by leukemia cells.

Keywords:  AML; GvL; T cell; bicarbonate of soda; immunomodulation; metabolism

DOI:  https://doi.org/10.20900/immunometab20210005
Cancers (Basel). 2021 Jan 28. pii: 496. [Epub ahead of print]13(3):

CD123 Is Consistently Expressed on NPM1-Mutated AML Cells.

Vincenzo Maria Perriello, Ilaria Gionfriddo, Roberta Rossi, Francesca Milano, Federica Mezzasoma, Andrea Marra, Orietta Spinelli, Alessandro Rambaldi, Ombretta Annibali, Giuseppe Avvisati, Francesco Di Raimondo, Stefano Ascani, Brunangelo Falini, Maria Paola Martelli, Lorenzo Brunetti.

  NPM1-mutated (NPM1mut) acute myeloid leukemia (AML) comprises about 30% of newly diagnosed AML in adults. Despite notable advances in the treatment of this frequent AML subtype, about 50% of NPM1mut AML patients treated with conventional treatment die due to disease progression. CD123 has been identified as potential target for immunotherapy in AML, and several anti-CD123 therapeutic approaches have been developed for AML resistant to conventional therapies. As this antigen has been previously reported to be expressed by NPM1mut cells, we performed a deep flow cytometry analysis of CD123 expression in a large cohort of NPM1mut and wild-type samples, examining the whole blastic population, as well as CD34+CD38- leukemic cells. We demonstrate that CD123 is highly expressed on NPM1mut cells, with particularly high expression levels showed by CD34+CD38- leukemic cells. Additionally, CD123 expression was further enhanced by FLT3 mutations, which frequently co-occur with NPM1 mutations. Our results identify NPM1-mutated and particularly NPM1/FLT3 double-mutated AML as disease subsets that may benefit from anti-CD123 targeted therapies.

Keywords:  CD123; FLT3; NPM1; acute myeloid leukemia (AML); immunotherapy

DOI:  https://doi.org/10.3390/cancers13030496
Blood Rev. 2021 Jan 29. pii: S0268-960X(21)00012-6. [Epub ahead of print] 100806

The complete story of less than complete responses: The evolution and application of acute myeloid leukemia clinical responses.

Rory M Shallis, Daniel A Pollyea, Amer M Zeidan.

  Complete remission (CR) has long been the critical therapeutic response in acute myeloid leukemia (AML). However, "less than CR" responses have been and continue to be proposed to define clinically meaningful post-therapy outcomes. These responses include CR with incomplete recovery (CRi), CR with incomplete platelet recovery (CRp) and, most recently, CR with partial hematologic recovery (CRh), which has been introduced and subsequently used for regulatory approval. However, the clinical benefits associated with "less than CR" responses have primarily been evaluated in the context of intensive therapies. In an era with sophisticated measurable residual disease (MRD) assessments, including flow-based, cytogenetic and molecular techniques, and an increase in "targeted", non-intensive therapies, the clinical value of responses that are "less than CR" must be reevaluated. Improvements in the rate of CR has not always led to improvements in OS among older patients. As such, MRD techniques might help define a more stringent response criterion (MRD-negative CR) that might better correlate with OS and should be incorporated in future clinical trials. Here we discuss the evolution of CR and "less than CR" responses, data regarding their clinical benefits, and considerations relevant to response assessments with newer therapies.

Keywords:  AML; Acute myeloid leukemia; CRh; CRi; CRp; Incomplete; Partial; Remission; Response

DOI:  https://doi.org/10.1016/j.blre.2021.100806
Leukemia. 2021 Feb 04.

Biomarkers associated with blinatumomab outcomes in acute lymphoblastic leukemia.

Andrew H Wei, Josep-Maria Ribera, Richard A Larson, David Ritchie, Armin Ghobadi, Yuqi Chen, Abraham Anderson, Cedric E Dos Santos, Janet Franklin, Hagop Kantarjian.

This study aimed to identify biomarkers for clinical outcomes in a phase 3 clinical study of blinatumomab or chemotherapy in adults with Philadelphia chromosome-negative relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Patients were randomized 2:1 to receive blinatumomab, a BiTE® therapy, for 4 weeks (9 μg/day cycle 1 week 1, 28 μg/day thereafter) every 6 weeks, or chemotherapy. Baseline blood samples were evaluated to identify biomarkers prognostic (both treatment groups) or predictive (either treatment groups) for overall survival, event-free survival, hematologic remission, minimal residual disease (MRD) response, duration of response, or adverse events. Baseline values were balanced between treatment groups. Prognostic biomarkers were platelets, tumor burden, and percentage of T cells: each 1-log increase in platelets at baseline was prognostic for improved 6-month survival; lower tumor burden was prognostic for hematologic remission; and a higher percentage of CD3+ T-cells was prognostic for MRD response. Consistent with the BiTE mechanism of action, higher percentage of CD45+ CD3+ CD8+ T cells was associated with hematologic remission following blinatumomab. No examined biomarkers were significant for the risk of grade ≥3 adverse events. Incorporating baseline biomarkers into future studies may help to identify subgroups most likely to benefit from blinatumomab.

DOI: https://doi.org/10.1038/s41375-020-01089-x
Leukemia. 2021 Feb 01.

Impact of measurable residual disease by decentralized flow cytometry: a PETHEMA real-world study in 1076 patients with acute myeloid leukemia.

PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatías Malignas) cooperative study group

The role of decentralized assessment of measurable residual disease (MRD) for risk stratification in acute myeloid leukemia (AML) remains largely unknown, and so it does which methodological aspects are critical to empower the evaluation of MRD with prognostic significance, particularly if using multiparameter flow cytometry (MFC). We analyzed 1076 AML patients in first remission after induction chemotherapy, in whom MRD was evaluated by MFC in local laboratories of 60 Hospitals participating in the PETHEMA registry. We also conducted a survey on technical aspects of MRD testing to determine the impact of methodological heterogeneity in the prognostic value of MFC. Our results confirmed the recommended cutoff of 0.1% to discriminate patients with significantly different cumulative-incidence of relapse (-CIR- HR:0.71, P < 0.001) and overall survival (HR: 0.73, P = 0.001), but uncovered the limited prognostic value of MFC based MRD in multivariate and recursive partitioning models including other clinical, genetic and treatment related factors. Virtually all aspects related with methodological, interpretation, and reporting of MFC based MRD testing impacted in its ability to discriminate patients with different CIR. Thus, this study demonstrated that "real-world" assessment of MRD using MFC is prognostic in patients at first remission, and urges greater standardization for improved risk-stratification toward clinical decisions in AML.

DOI: https://doi.org/10.1038/s41375-021-01126-3
BMC Med Genomics. 2021 Feb 03. 14(1): 39

Novel prognostic genes and subclasses of acute myeloid leukemia revealed by survival analysis of gene expression data.

Yanli Lai, Guifang OuYang, Lixia Sheng, Yanli Zhang, Binbin Lai, Miao Zhou.

   BACKGROUND: Acute myeloid leukemia (AML) is biologically heterogeneous diseases with adverse prognosis. This study was conducted to find prognostic biomarkers that could effectively classify AML patients and provide guidance for treatment decision making.
METHODS: Weighted gene co-expression network analysis was applied to detect co-expression modules and analyze their relationship with clinicopathologic characteristics using RNA sequencing data from The Cancer Genome Atlas database. The associations of gene expression with patients' mortality were investigated by a variety of statistical methods and validated in an independent dataset of 405 AML patients. A risk score formula was created based on a linear combination of five gene expression levels.
RESULTS: The weighted gene co-expression network analysis detected 63 co-expression modules. The pink and darkred modules were negatively significantly correlated with overall survival of AML patients. High expression of FNDC3B, VSTM1 and CALR was associated with favourable overall survival, while high expression of PLA2G4A was associated with adverse overall survival. Hierarchical clustering analysis of FNDC3B, VSTM1, PLA2G4A, GOLGA3 and CALR uncovered four subgroups of AML patients. The cluster1 AML patients showed younger age, lower cytogenetics risk, higher frequency of NPM1 mutations and more favourable overall survival than cluster3 patients. The risk score was demonstrated to be an indicator of adverse prognosis in AML patients CONCLUSIONS: The FNDC3B, VSTM1, PLA2G4A, GOLGA3, CALR and risk score may serve as key prognostic biomarkers for the stratification and ultimately guide rational treatment of AML patients.

Keywords:  Acute myeloid leukemia; Overall survival; Risk score; The cancer genome atlas database; Weighted gene co-expression network analysis

DOI:  https://doi.org/10.1186/s12920-021-00888-0
J Clin Med. 2021 Feb 01. pii: 515. [Epub ahead of print]10(3):

Dose Optimization of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: A New Therapeutic Challenge.

Alessandra Iurlo, Daniele Cattaneo, Cristina Bucelli, Massimo Breccia.

  The chronic myeloid leukemia (CML) therapeutic landscape has dramatically changed with tyrosine kinase inhibitor (TKI) development, which allows a near-normal life expectancy. However, long-term TKI exposure has been associated with persistent adverse events (AEs) which negatively impact on quality of life (QoL) and have the potential to cause significant morbidity and mortality. In clinical practice, TKI dose reduction is usually considered to reduce AEs and improve QoL, but dose optimization could have also another aim, i.e., the achievement and maintenance of cytogenetic and molecular responses. While therapy cessation appeared as a safe option for about half of the patients achieving an optimal response, no systematic assessment of long-term TKI dose de-escalation has been made. The present review is focused on the most recent evidences for TKIs dose modifications in CML clinical studies and in the real-life setting. It will consider TKI dose modifications in newly diagnosed patients, dose reduction for AEs, or in deep molecular response, either as a prelude to treatment-free remission (TFR) or as continuous maintenance therapy in those patients not wishing to attempt TFR. In addition, it will focus on patients not achieving a molecular response deep enough to go to TFR, and for whom dose reduction could be an option to avoid AEs.

Keywords:  bosutinib; chronic myeloid leukemia; dasatinib; imatinib; nilotinib; ponatinib; prognosis; treatment de-escalation; treatment-free remission; tyrosine kinase inhibitor

DOI:  https://doi.org/10.3390/jcm10030515
Haematologica. 2021 Feb 04.

Leukemia vaccine overcomes limitations of checkpoint blockade by evoking clonal T cell responses in a murine acute myeloid leukemia model.

Dina Stroopinsky, Jessica Liegel, Manoj Bhasin, Giulia Cheloni, Beena Thomas, Swati Bhasin, Ruchit Panchal, Haider Ghiasuddin, Maryam Rahimian, Myrna Nahas, Shira Orr, Marzia Capelletti, Daniela Torres, Cansu Tacettin, Matthew Weinstock, Lina Bisharat, Adam Morin, Kathleen M Mahoney, Benjamin Ebert, Richard Stone, Donald Kufe, Gordon J Freeman, Jacalyn Rosenblatt, David Avigan.

We have developed a personalized vaccine whereby patient derived leukemia cells are fused to autologous dendritic cells, evoking a polyclonal T cell response against shared and neo-antigens. We postulated that the dendritic cell (DC)/AML fusion vaccine would demonstrate synergy with checkpoint blockade by expanding tumor antigen specific lymphocytes that would provide a critical substrate for checkpoint blockade mediated activation. Using an immunocompetent murine leukemia model, we examined the immunologic response and therapeutic efficacy of vaccination in conjunction with checkpoint blockade with respect to leukemia engraftment, disease burden, survival and the induction of tumor specific immunity. Mice treated with checkpoint blockade alone had rapid leukemia progression and demonstrated only a modest extension of survival. Vaccination with DC/AML fusions resulted in the expansion of tumor specific lymphocytes and disease eradication in a subset of animals, while the combination of vaccination and checkpoint blockade induced a fully protective tumor specific immune response in all treated animals. Vaccination followed by checkpoint blockade resulted in upregulation of genes regulating activation and proliferation in memory and effector T cells. Long term survivors exhibited increased T cell clonal diversity and were resistant to subsequent tumor challenge. The combined DC/AML fusion vaccine and checkpoint blockade treatment offers unique synergy inducing the durable activation of leukemia specific immunity, protection from lethal tumor challenge and the selective expansion of tumor reactive clones.

DOI: https://doi.org/10.3324/haematol.2020.259457
Nature. 2021 Feb 03.

A gene-environment-induced epigenetic program initiates tumorigenesis.

Direna Alonso-Curbelo, Yu-Jui Ho, Cassandra Burdziak, Jesper L V Maag, John P Morris, Rohit Chandwani, Hsuan-An Chen, Kaloyan M Tsanov, Francisco M Barriga, Wei Luan, Nilgun Tasdemir, Geulah Livshits, Elham Azizi, Jaeyoung Chun, John E Wilkinson, Linas Mazutis, Steven D Leach, Richard Koche, Dana Pe'er, Scott W Lowe.

Tissue damage increases the risk of cancer through poorly understood mechanisms1. In mouse models of pancreatic cancer, pancreatitis associated with tissue injury collaborates with activating mutations in the Kras oncogene to markedly accelerate the formation of early neoplastic lesions and, ultimately, adenocarcinoma2,3. Here, by integrating genomics, single-cell chromatin assays and spatiotemporally controlled functional perturbations in autochthonous mouse models, we show that the combination of Kras mutation and tissue damage promotes a unique chromatin state in the pancreatic epithelium that distinguishes neoplastic transformation from normal regeneration and is selected for throughout malignant evolution. This cancer-associated epigenetic state emerges within 48 hours of pancreatic injury, and involves an 'acinar-to-neoplasia' chromatin switch that contributes to the early dysregulation of genes that define human pancreatic cancer. Among the factors that are most rapidly activated after tissue damage in the pre-malignant pancreatic epithelium is the alarmin cytokine interleukin 33, which recapitulates the effects of injury in cooperating with mutant Kras to unleash the epigenetic remodelling program of early neoplasia and neoplastic transformation. Collectively, our study demonstrates how gene-environment interactions can rapidly produce gene-regulatory programs that dictate early neoplastic commitment, and provides a molecular framework for understanding the interplay between genetic and environmental cues in the initiation of cancer.

DOI: https://doi.org/10.1038/s41586-020-03147-x
Sci Adv. 2021 Jan;pii: eabb6104. [Epub ahead of print]7(1):

Near-infrared oxidative phosphorylation inhibitor integrates acute myeloid leukemia-targeted imaging and therapy.

Chi Zhang, Tao Liu, Peng Luo, Li Gao, Xingyun Liao, Le Ma, Zhongyong Jiang, Dengqun Liu, Zeyu Yang, Qingzhi Jiang, Yu Wang, Xu Tan, Shenglin Luo, Yang Wang, Chunmeng Shi.

Acute myeloid leukemia (AML) is a deadly hematological malignancy with frequent disease relapse. The biggest challenge for AML therapy is the lack of methods to target and kill the heterogeneous leukemia cells, which lead to disease relapse. Here, we describe a near-infrared (NIR) fluorescent dye, IR-26, which preferentially accumulates in the mitochondria of AML cells, depending on the hyperactive glycolysis of malignant cell, and simultaneously impairs oxidative phosphorylation (OXPHOS) to exert targeted therapeutic effects for AML cells. In particular, IR-26 also exhibits potential for real-time monitoring of AML cells with an in vivo flow cytometry (IVFC) system. Therefore, IR-26 represents a novel all-in-one agent for the integration of AML targeting, detection, and therapy, which may help to monitor disease progression and treatment responses, prevent unnecessary delays in administering upfront therapy, and improve therapeutic efficiency to the residual AML cells, which are responsible for disease relapse.

DOI: https://doi.org/10.1126/sciadv.abb6104
J Clin Oncol. 2021 Feb 04. JCO2001659

Classification and Personalized Prognostic Assessment on the Basis of Clinical and Genomic Features in Myelodysplastic Syndromes.

Matteo Bersanelli, Erica Travaglino, Manja Meggendorfer, Tommaso Matteuzzi, Claudia Sala, Ettore Mosca, Chiara Chiereghin, Noemi Di Nanni, Matteo Gnocchi, Matteo Zampini, Marianna Rossi, Giulia Maggioni, Alberto Termanini, Emanuele Angelucci, Massimo Bernardi, Lorenza Borin, Benedetto Bruno, Francesca Bonifazi, Valeria Santini, Andrea Bacigalupo, Maria Teresa Voso, Esther Oliva, Marta Riva, Marta Ubezio, Lucio Morabito, Alessia Campagna, Claudia Saitta, Victor Savevski, Enrico Giampieri, Daniel Remondini, Francesco Passamonti, Fabio Ciceri, Niccolò Bolli, Alessandro Rambaldi, Wolfgang Kern, Shahram Kordasti, Francesc Sole, Laura Palomo, Guillermo Sanz, Armando Santoro, Uwe Platzbecker, Pierre Fenaux, Luciano Milanesi, Torsten Haferlach, Gastone Castellani, Matteo G Della Porta.

PURPOSE: Recurrently mutated genes and chromosomal abnormalities have been identified in myelodysplastic syndromes (MDS). We aim to integrate these genomic features into disease classification and prognostication.
METHODS: We retrospectively enrolled 2,043 patients. Using Bayesian networks and Dirichlet processes, we combined mutations in 47 genes with cytogenetic abnormalities to identify genetic associations and subgroups. Random-effects Cox proportional hazards multistate modeling was used for developing prognostic models. An independent validation on 318 cases was performed.
RESULTS: We identify eight MDS groups (clusters) according to specific genomic features. In five groups, dominant genomic features include splicing gene mutations (SF3B1, SRSF2, and U2AF1) that occur early in disease history, determine specific phenotypes, and drive disease evolution. These groups display different prognosis (groups with SF3B1 mutations being associated with better survival). Specific co-mutation patterns account for clinical heterogeneity within SF3B1- and SRSF2-related MDS. MDS with complex karyotype and/or TP53 gene abnormalities and MDS with acute leukemia-like mutations show poorest prognosis. MDS with 5q deletion are clustered into two distinct groups according to the number of mutated genes and/or presence of TP53 mutations. By integrating 63 clinical and genomic variables, we define a novel prognostic model that generates personally tailored predictions of survival. The predicted and observed outcomes correlate well in internal cross-validation and in an independent external cohort. This model substantially improves predictive accuracy of currently available prognostic tools. We have created a Web portal that allows outcome predictions to be generated for user-defined constellations of genomic and clinical features.
CONCLUSION: Genomic landscape in MDS reveals distinct subgroups associated with specific clinical features and discrete patterns of evolution, providing a proof of concept for next-generation disease classification and prognosis.

DOI: https://doi.org/10.1200/JCO.20.01659
Cell Rep. 2021 Feb 02. pii: S2211-1247(21)00036-X. [Epub ahead of print]34(5): 108723

An IDH1-vitamin C crosstalk drives human erythroid development by inhibiting pro-oxidant mitochondrial metabolism.

Pedro Gonzalez-Menendez, Manuela Romano, Hongxia Yan, Ruhi Deshmukh, Julien Papoin, Leal Oburoglu, Marie Daumur, Anne-Sophie Dumé, Ira Phadke, Cédric Mongellaz, Xiaoli Qu, Phuong-Nhi Bories, Michaela Fontenay, Xiuli An, Valérie Dardalhon, Marc Sitbon, Valérie S Zimmermann, Patrick G Gallagher, Saverio Tardito, Lionel Blanc, Narla Mohandas, Naomi Taylor, Sandrina Kinet.

  The metabolic changes controlling the stepwise differentiation of hematopoietic stem and progenitor cells (HSPCs) to mature erythrocytes are poorly understood. Here, we show that HSPC development to an erythroid-committed proerythroblast results in augmented glutaminolysis, generating alpha-ketoglutarate (αKG) and driving mitochondrial oxidative phosphorylation (OXPHOS). However, sequential late-stage erythropoiesis is dependent on decreasing αKG-driven OXPHOS, and we find that isocitrate dehydrogenase 1 (IDH1) plays a central role in this process. IDH1 downregulation augments mitochondrial oxidation of αKG and inhibits reticulocyte generation. Furthermore, IDH1 knockdown results in the generation of multinucleated erythroblasts, a morphological abnormality characteristic of myelodysplastic syndrome and congenital dyserythropoietic anemia. We identify vitamin C homeostasis as a critical regulator of ineffective erythropoiesis; oxidized ascorbate increases mitochondrial superoxide and significantly exacerbates the abnormal erythroblast phenotype of IDH1-downregulated progenitors, whereas vitamin C, scavenging reactive oxygen species (ROS) and reprogramming mitochondrial metabolism, rescues erythropoiesis. Thus, an IDH1-vitamin C crosstalk controls terminal steps of human erythroid differentiation.

Keywords:  alpha-ketoglutarate; enucleation; erythropoiesis; hematopoietic stem and progenitor cell; human; isocitrate dehydrogenase; mitochondria; oxidative phosphorylation; redox stress; vitamin C

DOI:  https://doi.org/10.1016/j.celrep.2021.108723
Blood. 2021 Feb 04. 137(5): 584-586

Targeting cereblon in AML.

Steven Grant.

DOI: https://doi.org/10.1182/blood.2020009827
Br J Haematol. 2021 Feb 02.

Characteristics and outcome of patients with acute myeloid leukaemia and t(8;16)(p11;p13): results from an International Collaborative Study.

Sabine Kayser, Robert K Hills, Ralitsa Langova, Michael Kramer, Francesca Guijarro, Zuzana Sustkova, Elihu H Estey, Carole M Shaw, Zdeněk Ráčil, Jiri Mayer, Pavel Zak, Maria R Baer, Andrew M Brunner, Tomas Szotkowski, Petr Cetkovsky, David Grimwade, Roland B Walter, Alan K Burnett, Anthony D Ho, Gerhard Ehninger, Carsten Müller-Tidow, Uwe Platzbecker, Christian Thiede, Christoph Röllig, Angela Schulz, Gregor Warsow, Benedikt Brors, Jordi Esteve, Nigel H Russell, Richard F Schlenk, Mark J Levis.

  In acute myeloid leukaemia (AML) t(8;16)(p11;p13)/MYST3-CREBBP is a very rare abnormality. Previous small series suggested poor outcome. We report on 59 patients with t(8;16) within an international, collaborative study. Median age was 52 (range: 16-75) years. AML was de novo in 58%, therapy-related (t-AML) in 37% and secondary after myelodysplastic syndrome (s-AML) in 5%. Cytogenetics revealed a complex karyotype in 43%. Besides MYST3-CREBBP, whole-genome sequencing on a subset of 10 patients revealed recurrent mutations in ASXL1, BRD3, FLT3, MLH1, POLG, TP53, SAMD4B (n = 3, each), EYS, KRTAP9-1 SPTBN5 (n = 4, each), RUNX1 and TET2 (n = 2, each). Complete remission after intensive chemotherapy was achieved in 84%. Median follow-up was 5·48 years; five-year survival rate was 17%. Patients with s-/t-AML (P = 0·01) and those with complex karyotype (P = 0·04) had an inferior prognosis. Allogeneic haematopoietic cell transplantation (allo-HCT) was performed in 21 (36%) patients, including 15 in first complete remission (CR1). Allo-HCT in CR1 significantly improved survival (P = 0·04); multivariable analysis revealed that allo-HCT in CR1 was effective in de novo AML but not in patients with s-AML/t-AML and less in patients exhibiting a complex karyotype. In summary, outcomes of patients with t(8;16) are dismal with chemotherapy, and may be substantially improved with allo-HCT performed in CR1.

Keywords:  acute myeloid leukaemia; allogeneic haematopoietic cell transplantation; outcome; t(8;16)(p11;p13)/MYST3-CREBBP; whole-genome sequencing

DOI:  https://doi.org/10.1111/bjh.17336