bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2020‒11‒08
twenty-two papers selected by
Paolo Gallipoli
Barts Cancer Institute, Queen Mary University of London


  1. Leukemia. 2020 Nov 02.
    Namburi S, Broxmeyer HE, Hong CS, Whiteside TL, Boyiadzis M.
      Mechanisms by which acute myeloid leukemia (AML) interferes with normal hematopoiesis are under intense investigation. Emerging evidence suggests that exosomes produced by leukemia blasts suppress hematopoiesis. Exosomes isolated from AML patients' plasma at diagnosis significantly and dose-dependently suppressed colony formation of normal hematopoietic progenitor cells (HPC). Levels of HPC suppression mediated by exosomes of AML patients who achieved complete remission (CR) were significantly decreased compared to those observed at AML diagnosis. Exosomes from plasma of patients who had achieved CR but with incomplete cell count recovery (CRi) after chemotherapy suppressed in vitro colony formation as effectively as did exosomes obtained at AML diagnosis. Dipeptidylpeptidase4 (DPP4/CD26), a serine protease that cleaves select penultimate amino acids of various proteins, has been previously implicated in the regulation of hematopoiesis. DPP4 was carried by exosomes from AML plasma or leukemia cell lines. Leukemia exosomes which suppressed HSC colony formation had markedly higher DPP4 functional activity than that detected in the exosomes of normal donors. Pharmacological inhibition of DPP4 activity in AML exosomes reversed the effects of exosome-mediated myelosuppression. Reversing the negative effects of exosomes on AML hematopoiesis, and thus improving cell count recovery, might emerge as a new therapeutic approach to AML.
    DOI:  https://doi.org/10.1038/s41375-020-01047-7
  2. Leukemia. 2020 Nov 04.
    Rummelt C, Gorantla SP, Meggendorfer M, Charlet A, Endres C, Döhner K, Heidel FH, Fischer T, Haferlach T, Duyster J, von Bubnoff N.
      An important limitation of FLT3 tyrosine kinase inhibitors (TKIs) in FLT3-ITD positive AML is the development of resistance. To better understand resistance to FLT3 inhibition, we examined FLT3-ITD positive cell lines which had acquired resistance to midostaurin or sorafenib. In 6 out of 23 TKI resistant cell lines we were able to detect a JAK1 V658F mutation, a mutation that led to reactivation of the CSF2RB-STAT5 pathway. Knockdown of JAK1, or treatment with a JAK inhibitor, resensitized cells to FLT3 inhibition. Out of 136 patients with FLT3-ITD mutated AML and exposed to FLT3 inhibitor, we found seven different JAK family mutations in six of the cases (4.4%), including five bona fide, activating mutations. Except for one patient, the JAK mutations occurred de novo (n = 4) or displayed increasing variant allele frequency after exposure to FLT3 TKI (n = 1). In vitro each of the five activating variants were found to induce resistance to FLT3-ITD inhibition, which was then overcome by dual FLT3/JAK inhibition. In conclusion, our data characterize a novel mechanism of resistance to FLT3-ITD inhibition and may offer a potential therapy, using dual JAK and FLT3 inhibition.
    DOI:  https://doi.org/10.1038/s41375-020-01077-1
  3. Cell Death Dis. 2020 Nov 06. 11(11): 956
    Polak A, Bialopiotrowicz E, Krzymieniewska B, Wozniak J, Stojak M, Cybulska M, Kaniuga E, Mikula M, Jablonska E, Gorniak P, Noyszewska-Kania M, Szydlowski M, Piechna K, Piwocka K, Bugajski L, Lech-Maranda E, Barankiewicz J, Kolkowska-Lesniak A, Patkowska E, Glodkowska-Mrowka E, Baran N, Juszczynski P.
      Spleen tyrosine kinase (SYK) is an important oncogene and signaling mediator activated by cell surface receptors crucial for acute myeloid leukemia (AML) maintenance and progression. Genetic or pharmacologic inhibition of SYK in AML cells leads to increased differentiation, reduced proliferation, and cellular apoptosis. Herein, we addressed the consequences of SYK inhibition to leukemia stem-cell (LSC) function and assessed SYK-associated pathways in AML cell biology. Using gain-of-function MEK kinase mutant and constitutively active STAT5A, we demonstrate that R406, the active metabolite of a small-molecule SYK inhibitor fostamatinib, induces differentiation and blocks clonogenic potential of AML cells through the MEK/ERK1/2 pathway and STAT5A transcription factor, respectively. Pharmacological inhibition of SYK with R406 reduced LSC compartment defined as CD34+CD38-CD123+ and CD34+CD38-CD25+ in vitro, and decreased viability of LSCs identified by a low abundance of reactive oxygen species. Primary leukemic blasts treated ex vivo with R406 exhibited lower engraftment potential when xenotransplanted to immunodeficient NSG/J mice. Mechanistically, these effects are mediated by disturbed mitochondrial biogenesis and suppression of oxidative metabolism (OXPHOS) in LSCs. These mechanisms appear to be partially dependent on inhibition of STAT5 and its target gene MYC, a well-defined inducer of mitochondrial biogenesis. In addition, inhibition of SYK increases the sensitivity of LSCs to cytarabine (AraC), a standard of AML induction therapy. Taken together, our findings indicate that SYK fosters OXPHOS and participates in metabolic reprogramming of AML LSCs in a mechanism that at least partially involves STAT5, and that SYK inhibition targets LSCs in AML. Since active SYK is expressed in a majority of AML patients and confers inferior prognosis, the combination of SYK inhibitors with standard chemotherapeutics such as AraC constitutes a new therapeutic modality that should be evaluated in future clinical trials.
    DOI:  https://doi.org/10.1038/s41419-020-03156-8
  4. Blood Adv. 2020 Nov 10. 4(21): 5402-5413
    Ho JM, Dobson SM, Voisin V, McLeod J, Kennedy JA, Mitchell A, Jin L, Eppert K, Bader G, Minden MD, Dick JE, Wang JCY.
      The leukemia stem cell (LSC) populations of acute myeloid leukemia (AML) exhibit phenotypic, genetic, and functional heterogeneity that contribute to therapy failure and relapse. Progress toward understanding the mechanistic basis for therapy resistance in LSCs has been hampered by difficulties in isolating cell fractions that enrich for the entire heterogeneous population of LSCs within individual AML samples. We previously reported that CD200 gene expression is upregulated in LSC-containing AML fractions. Here, we show that CD200 is present on a greater proportion of CD45dim blasts compared with more differentiated CD45high cells in AML patient samples. In 75% (49 of 65) of AML cases we examined, CD200 was expressed on ≥10% of CD45dim blasts; of these, CD200 identified LSCs within the blast population in 9 of 10 (90%) samples tested in xenotransplantation assays. CD200+ LSCs could be isolated from CD200+ normal HSCs with the use of additional markers. Notably, CD200 expression captured both CD34- and CD34+ LSCs within individual AML samples. Analysis of highly purified CD200+ LSC-containing fractions from NPM1-mutated AMLs, which are commonly CD34-, exhibited an enrichment of primitive gene expression signatures compared with unfractionated cells. Overall, our findings support CD200 as a novel LSC marker that is able to capture the entire LSC compartment from AML patient samples, including those with NPM1 mutation.
    DOI:  https://doi.org/10.1182/bloodadvances.2020001802
  5. Blood Adv. 2020 Nov 10. 4(21): 5393-5401
    Stengel A, Shahswar R, Haferlach T, Walter W, Hutter S, Meggendorfer M, Kern W, Haferlach C.
      Fusion transcripts are frequent genetic abnormalities in myeloid malignancies and are often the basis for risk stratification, minimal residual disease (MRD) monitoring, and targeted therapy. We comprehensively analyzed the fusion transcript landscape in 572 acute myeloid leukemia (AML) and 630 myelodysplastic syndrome (MDS) patients by whole transcriptome sequencing (WTS). Totally, 274 fusion events (131 unique fusions) were identified in 210/572 AML patients (37%). In 16/630 MDS patients, 16 fusion events (15 unique fusions) were detected (3%). In AML, 141 cases comprised entity-defining rearrangements (51% of all detected fusions) and 21 (8%) additional well-known fusions, all detected by WTS (control group). In MDS, only 1 fusion was described previously (NRIP1-MECOM, n = 2). Interestingly, a high number of so-far unreported fusions were found (41% [112/274] in AML, 88% [14/16] in MDS), all validated by cytogenetic and/or whole genome sequencing data. With 1 exception (CTDSP1-CFLAR, n = 2), all novel fusions were observed in 1 patient each. In AML, cases with novel fusions showed concomitantly a high frequency of TP53 mutations (67%) and of a complex karyotype (71%), which was also observed in MDS, but less pronounced (TP53, 26%; complex karyotype, 21%). A functional annotation of genes involved in novel fusions revealed many functional relevant genes (eg, transcription factors; n = 28 in AML, n = 2 in MDS) or enzymes (n = 42 in AML, n = 9 in MDS). Taken together, new genomic alterations leading to fusion transcripts were much more common in AML than in MDS. Any novel fusions might be of use for developing markers (eg, for MRD monitoring), particularly in cases without an entity-defining abnormality.
    DOI:  https://doi.org/10.1182/bloodadvances.2020003007
  6. Sci Rep. 2020 Nov 04. 10(1): 19037
    Wang J, Dao FT, Yang L, Qin YZ.
      Recurrent genetic mutations occur in acute myeloid leukemia (AML) and have been incorporated into risk stratification to predict the prognoses of AML patients. The bone marrow microenvironment plays a critical role in the development and progression of AML. However, the characteristics of the genetic mutation-associated microenvironment have not been comprehensively identified to date. In this study, we obtained the gene expression profiles of 173 AML patients from The Cancer Genome Atlas (TCGA) database and calculated their immune and stromal scores by applying the ESTIMATE algorithm. Immune scores were significantly associated with OS and cytogenetic risk. Next, we categorized the intermediate and poor cytogenetic risk patients into individual-mutation and wild-type groups according to RUNX1, ASXL1, TP53, FLT3-ITD, NPM1 and biallelic CEBPA mutation status. The relationships between the immune microenvironment and each genetic mutation were investigated by identifying differentially expressed genes (DEGs) and conducting functional enrichment analyses of them. Significant immune- and stromal-relevant DEGs associated with each mutation were identified, and most of the DEGs (from the FLT3-ITD, NPM1 and biallelic CEBPA mutation groups) were validated in the GSE14468 cohort downloaded from the Gene Expression Omnibus (GEO) database. In summary, we identified key immune- and stromal-relevant gene signatures associated with genetic mutations in AML, which may provide new biomarkers for risk stratification and personalized immunotherapy.
    DOI:  https://doi.org/10.1038/s41598-020-76048-8
  7. Haematologica. 2020 Nov 05. Online ahead of print 0
    Li J, Whelan S, Kotturi MF, Meyran D, D'Souza C, Hansen K, Liang S, Hunter J, Trapani JA, Neeson PJ.
      This study explored the novel immune checkpoint poliovirus receptor-related immunoglobulin domain-containing (PVRIG) in acute myeloid leukemia (AML). We showed that AML patient blasts consistently expressed the PVRIG ligand (poliovirus receptor-related 2, PVRL2). Furthermore, PVRIG blockade significantly enhanced NK cell killing of PVRL2+, poliovirus receptor (PVR)lo AML cell lines, and significantly increased NK cell activation and degranulation in the context of patient primary AML blasts. However, in AML patient bone marrow, NK cell PVRIG expression levels were not increased. To understand how PVRIG blockade might potentially be exploited therapeutically, we investigated the biology of PVRIG and revealed that NK cell activation resulted in reduced PVRIG expression on the cell surface. This occurred whether NK cells were activated by tumour cell recognition, cytokines (IL-2 and IL-12) or activating receptor stimulation (CD16 and NKp46). PVRIG was present at higher levels in the cytoplasm than on the cell surface, particularly on CD56bright NK cells, which further increased cytoplasmic PVRIG levels following IL-2 and IL-12 activation. PVRIG was continually transported to the cell surface via the endoplasmic reticulum (ER) and Golgi in both unstimulated and activated NK cells. Taken together, our findings suggest that anti- PVRIG blocking antibody functions by binding to surface-bound PVRIG, which undergoes rapid turnover in both unstimulated and activated NK cells. We conclude that the PVRIGPVRL2 immune checkpoint axis can feasibly be targeted with PVRIG blocking antibody for NK-mediated immunotherapy of PVRL2+ AML.
    DOI:  https://doi.org/10.3324/haematol.2020.258574
  8. Leuk Lymphoma. 2020 Nov 03. 1-10
    Buschner G, Feuerecker B, Spinner S, Seidl C, Essler M.
      Acute myeloid leukemia (AML) is a malignant disease of the bone marrow, comprising various subtypes. We have investigated seven different AML cell lines that showed different sensitivities toward the inducer of apoptosis ABT-737, with IC50 concentrations ranging from 9.9 nM to 1.8 µM. Besides, the AML cell lines revealed distinct differences in 18F-FDG uptake ranging from 4.1 to 11.0%. Moreover, the Pearson coefficient (0.363) suggests a moderate correlation between 18F-FDG uptake and the IC50 values of ABT-737. Differentiation of the AML cell lines NB-4 and AML-193 with all-trans-retinoic-acid (ATRA) induced a significant increase in sensitivity towards ABT-737 along with a reduced uptake of 18F-FDG. Therefore, 18F-FDG uptake could be predictive on sensitivity to treatment with ABT-737. Furthermore, because differentiation treatment of AML cells using ATRA reduced 18F-FDG uptake and increased sensitivity towards ABT-737, a combined treatment regimen with ATRA and ABT-737 might be a promising therapeutic option in the future.
    Keywords:   18F-FDG; ABT-737; Cancer metabolism; acute myeloid leukemia; all trans retinoic acid (ATRA); apoptosis
    DOI:  https://doi.org/10.1080/10428194.2020.1839648
  9. Cancers (Basel). 2020 Nov 01. pii: E3225. [Epub ahead of print]12(11):
    Stanchina M, Soong D, Zheng-Lin B, Watts JM, Taylor J.
      Acute myeloid leukemia (AML) is a genetically heterogeneous malignancy comprised of various cytogenetic and molecular abnormalities that has notoriously been difficult to treat with an overall poor prognosis. For decades, treatment options were limited to either intensive chemotherapy with anthracycline and cytarabine-based regimens (7 + 3) or lower intensity regimens including hypomethylating agents or low dose cytarabine, followed by either allogeneic stem cell transplant or consolidation chemotherapy. Fortunately, with the influx of rapidly evolving molecular technologies and new genetic understanding, the treatment landscape for AML has dramatically changed. Advances in the formulation and delivery of 7 + 3 with liposomal cytarabine and daunorubicin (Vyxeos) have improved overall survival in secondary AML. Increased understanding of the genetic underpinnings of AML has led to targeting actionable mutations such as FLT3, IDH1/2 and TP53, and BCL2 or hedgehog pathways in more frail populations. Antibody drug conjugates have resurfaced in the AML landscape and there have been numerous advances utilizing immunotherapies including immune checkpoint inhibitors, antibody-drug conjugates, bispecific T cell engager antibodies, chimeric antigen receptor (CAR)-T therapy and the development of AML vaccines. While there are dozens of ongoing studies and new drugs in the pipeline, this paper serves as a review of the advances achieved in the treatment of AML in the last several years and the most promising future avenues of advancement.
    Keywords:  BCL2; CD123; CD33; CD47; FLT3; IDH1/2; anti-body drug conjugate; hedgehog; immunotherapy; novel therapeutics AML
    DOI:  https://doi.org/10.3390/cancers12113225
  10. Cancer Discov. 2020 Nov 06.
      Acute myeloid leukemia often had few clones, mostly with multiple epigenetic regulator mutations.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-163
  11. Leuk Lymphoma. 2020 Nov 02. 1-10
    Megías-Vericat JE, Martínez-Cuadrón D, Herrero MJ, Rodríguez-Veiga R, Solana-Altabella A, Boluda B, Ballesta-López O, Cano I, Acuña-Cruz E, Cervera J, Poveda JL, Sanz M, Aliño SF, Montesinos P.
      Anthracycline uptake could be affected by influx and efflux transporters in acute myeloid leukemia (AML). Combinations of single-nucleotide polymorphisms (SNPs) of wild-type genotype of influx transporters (SLC22A16, SLCO1B1) and homozygous variant genotypes of ABC polymorphisms (ABCB1, ABCC1, ABCC2, ABCG2) were evaluated in 225 adult de novo AML patients. No differences in complete remission were reported, but higher induction death was observed with combinations of SLCO1B1 rs4149056 and ABCB1 (triple variant haplotype, rs1128503), previously associated with ABCB1 and SLCO1B1 SNPs. Several combinations of SLCO1B1 and SLC22A16 with ABCB1 SNPs were associated with higher toxicities, including nephrotoxicity and hepatotoxicity, neutropenia, previously related to ABCB1, and a novel correlation with mucositis. Combination of SLC22A16 rs714368 and ABCG2 rs2231142 was related to cardiac toxicity, reproducing previous correlations with ABCG2. This study shows the impact of transporter polymorphisms in AML chemotherapy safety. Further prospective studies with larger populations are needed to validate these associations.
    Keywords:   ABCB1 ; SLCO1B1 ; SNP-SNP combination; anthracyclines; idarubicin; polymorphism
    DOI:  https://doi.org/10.1080/10428194.2020.1839650
  12. Mol Cancer Ther. 2020 Nov 06. pii: molcanther.0115.2020. [Epub ahead of print]
    Khan I, Eklund EA, Gartel AL.
      Acute myeloid leukemia (AML) is characterized by impaired myeloid lineage differentiation, uncontrolled proliferation and inhibition of pro-apoptotic pathways. In spite of a relatively homogenous clinical disease presentation, risk of long-term survival in AML varies from 20-80% depending on molecular disease characteristics. In recognition of the molecular heterogeneity of AML, the European Leukemia Net (ELN) and WHO classification systems now incorporate cytogenetics and increasing numbers of gene mutations into AML prognostication. Several of the genomic AML subsets are characterized by unique transcription factor alterations which are highlighted in this review. There are many mechanisms of transcriptional deregulation in leukemia. We broadly classify transcription factors based on mechanisms of transcriptional deregulation including direct involvement of transcription factors in recurrent translocations, loss of function mutations, and intracellular relocalization. Transcription factors, due to their pleiotropic effects have been attractive but elusive targets. Indirect targeting approaches include inhibition of upstream kinases such as TAK1 for suppression of NFκB signaling and downstream effectors such as FGF signaling in HOXA-upregulated leukemia. Other strategies include targeting scaffolding proteins like BrD4 in the case of MYC or coactivators such as menin to suppress HOX expression; disrupting critical protein interactions in the case of β-catenin: TCF/LEF , and preventing transcription factor binding to DNA as in the case of PU.1 or FOXM1. We comprehensively describe the mechanism of deregulation of transcription factors in genomic subsets of AML, consequent pathway addictions and potential therapeutic strategies.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-20-0115
  13. Clin Cancer Res. 2020 Nov 04. pii: clincanres.1346.2020. [Epub ahead of print]
    Ramsey HE, Greenwood DL, Zhang S, Childress MA, Arrate MP, Gorska AE, Fuller LD, Zhao Y, Stengel KR, Fischer MA, Stubbs MC, Liu P, Boyd KL, Rathmell JC, Hiebert SW, Savona MR.
      PURPOSE: The BCL2 inhibitor, venetoclax (VEN), has transformed clinical care in acute myeloid leukemia (AML). However, subsets of patients do not respond or eventually acquire resistance. VEN-based regimens can potentially lead to marrow suppression. Bromodomain and extra-terminal inhibitors (BETi) are potential treatments for AML, as regulators of critical AML oncogenes. We tested the efficacy of novel BET inhibitor INCB054329, and its synergy with VEN to reduce AML without induction of hematopoietic toxicity.EXPERIMENTAL DESIGN: INCB054329 efficacy was assessed by changes in cell cycle and apoptosis in treated AML cell lines. In vivo efficacy was assessed by tumor reduction in MV-4-11 cell line derived xenografts. Precision run-on and sequencing (PRO-Seq) evaluated effects of INCB054329. Synergy between low dose BETi and VEN was assessed in cell lines and patient samples while efficacy and toxicity was assessed in patient derived xenograft (PDX) models.
    RESULTS: INCB054329 induced dose-dependent apoptosis and quiescence in AML cell lines. PRO-Seq analysis evaluated the effects of INCB054329 on transcription and confirmed reduced transcriptional elongation of key oncogenes, MYC and BCL2, and genes involved in the cell cycle and metabolism. Combinations of BETi and VEN led to reduced cell viability in cell lines and patient samples. Low dose combinations of INCB054329 and VEN in cell line and PDX models reduced AML burden, regardless of the sensitivity to monotherapy without development of toxicity.
    CONCLUSIONS: Our findings suggest low dose combinations of VEN and BETi may be more efficacious for AML patients than either monotherapy, potentially providing a longer, more tolerable dosing regimen.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-1346
  14. Clin Cancer Res. 2020 Nov 04. pii: clincanres.2149.2020. [Epub ahead of print]
    Han YC, Kahler J, Piche-Nicholas N, Hu W, Thibault S, Jiang F, Leal M, Katragadda M, Maderna A, Dushin RG, Prashad N, Charati MB, Clark T, Tumey LN, Tan X, Giannakou A, Rosfjord E, Gerber HP, Tchistiakova L, Loganzo F, O'Donnell CJ, Sapra P.
      PURPOSE: Mortality due to acute myeloid leukemia (AML) remains high, and the management of relapsed or refractory AML continues to be therapeutically challenging. The reapproval of MYLOTARG, an anti-CD33-calicheamicin antibody-drug conjugate (ADC), has provided a proof-of-concept for an ADC-based therapeutic for AML. Several other ADCs have since entered clinical development of AML but have met with limited success. We sought to develop a next-generation ADC for AML with a wide therapeutic index that overcomes the shortcomings of previous generations of ADCs.EXPERIMENTAL DESIGN: We compared the therapeutic index of our novel CD33-targeted ADC platform to other currently available CD33-targeted ADCs in preclinical models of AML. Next, using this next-generation ADC platform, we performed a head-to-head comparison of two attractive AML antigens: CD33 and CD123.
    RESULTS: Our novel ADC platform offered improved safety and therapeutic index when compared to certain currently available ADC platforms in preclinical models of AML. Differentiation between the CD33- and CD123- targeted ADC was observed in safety studies conducted in cynomolgus monkeys. The CD33-targeted ADC produced severe hematological toxicity, whereas minimal hematological toxicity was observed with the CD123-targeted ADC at the same doses and exposures. The improved toxicity profile of an ADC targeting CD123 over CD33 was consistent with the more restricted expression of CD123 in normal tissues.
    CONCLUSIONS: We optimized all components of ADC design (i.e., leukemia antigen, antibody, and linker-payload) to develop an ADC that has the potential to translate into an effective new therapy against AML.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-2149
  15. Leukemia. 2020 Nov 06.
    Sportoletti P, Sorcini D, Guzman AG, Reyes JM, Stella A, Marra A, Sartori S, Brunetti L, Rossi R, Papa BD, Adamo FM, Pianigiani G, Betti C, Scialdone A, Guarente V, Spinozzi G, Tini V, Martelli MP, Goodell MA, Falini B.
      Recurrent loss-of-function mutations of BCL6 co-repressor (BCOR) gene are found in about 4% of AML patients with normal karyotype and are associated with DNMT3a mutations and poor prognosis. Therefore, new anti-leukemia treatments and mouse models are needed for this combinatorial AML genotype. For this purpose, we first generated a Bcor-/- knockout mouse model characterized by impaired erythroid development (macrocytosis and anemia) and enhanced thrombopoiesis, which are both features of myelodysplasia/myeloproliferative neoplasms. We then created and characterized double Bcor-/-/Dnmt3a-/- knockout mice. Interestingly, these animals developed a fully penetrant acute erythroid leukemia (AEL) characterized by leukocytosis secondary to the expansion of blasts expressing c-Kit+ and the erythroid marker Ter119, macrocytic anemia and progressive reduction of the thrombocytosis associated with loss of Bcor alone. Transcriptomic analysis of double knockout bone marrow progenitors revealed that aberrant erythroid skewing was induced by epigenetic changes affecting specific transcriptional factors (GATA1-2) and cell-cycle regulators (Mdm2, Tp53). These findings prompted us to investigate the efficacy of demethylating agents in AEL, with significant impact on progressive leukemic burden and mice overall survival. Information gained from our model expands the knowledge on the biology of AEL and may help designing new rational treatments for patients suffering from this high-risk leukemia.
    DOI:  https://doi.org/10.1038/s41375-020-01075-3
  16. Life Sci Alliance. 2021 Jan;pii: e202000709. [Epub ahead of print]4(1):
    Wesolowski R, Kowenz-Leutz E, Zimmermann K, Dörr D, Hofstätter M, Slany RK, Mildner A, Leutz A.
      Chromosomal rearrangements of the mixed-lineage leukemia gene MLL1 are the hallmark of infant acute leukemia. The granulocyte-macrophage progenitor state forms the epigenetic basis for myelomonocytic leukemia stemness and transformation by MLL-type oncoproteins. Previously, it was shown that the establishment of murine myelomonocytic MLL-ENL transformation, but not its maintenance, depends on the transcription factor C/EBPα, suggesting an epigenetic hit-and-run mechanism of MLL-driven oncogenesis. Here, we demonstrate that compound deletion of Cebpa/Cebpb almost entirely abrogated the growth and survival of MLL-ENL-transformed cells. Rare, slow-growing, and apoptosis-prone MLL-ENL-transformed escapees were recovered from compound Cebpa/Cebpb deletions. The escapees were uniformly characterized by high expression of the resident Cebpe gene, suggesting inferior functional compensation of C/EBPα/C/EBPβ deficiency by C/EBPε. Complementation was augmented by ectopic C/EBPβ expression and downstream activation of IGF1 that enhanced growth. Cebpe gene inactivation was accomplished only in the presence of complementing C/EBPβ, but not in its absence, confirming the Cebpe dependency of the Cebpa/Cebpb double knockouts. Our data show that MLL-transformed myeloid cells are dependent on C/EBPs during the initiation and maintenance of transformation.
    DOI:  https://doi.org/10.26508/lsa.202000709
  17. Exp Hematol. 2020 Nov 02. pii: S0301-472X(20)30618-4. [Epub ahead of print]
    Chin PS, Assi SA, Ptasinska A, Imperato MR, Cockerill PN, Bonifer C.
      Acute myeloid leukemia development occurs in a step-wise fashion whereby an original driver mutation is followed by additional mutations. The first type of mutations tends to be in genes encoding members of the epigenetic/transcription regulatory machinery (i.e. RUNX1, DNMT3A, TET2), while the secondary mutations often involve genes encoding members of signalling pathways that cause uncontrolled growth of such cells such as the growth factor receptors c-KIT of FLT3. Patients usually present with both types of mutations, but it is currently unclear how both mutational events shape the epigenome in developing AML cells. To this end we generated an in vitro model of t(8;21) AML by expressing its driver oncoprotein RUNX1-ETO with or without a mutated (N822K) KIT protein. The expression of N822K-c-KIT strongly increases the self-renewal capacity of RUNX1-ETO expressing cells. Global analysis of gene expression changes and alterations in the epigenome show that N822K-c-KIT expression profoundly influences the open chromatin landscape and transcription factor binding. However, our experiments also show that double mutant cells still differ from their patient derived counterparts, highlighting the importance of studying patient cells to obtain a true picture of how gene regulatory networks have been reprogrammed during tumourigenesis.
    Keywords:  N822K c-KIT; RUNX1/ETO; chromatin landscape; t(8;21) AML; transcription factor
    DOI:  https://doi.org/10.1016/j.exphem.2020.10.005
  18. Leuk Lymphoma. 2020 Nov 02. 1-24
    Gaut D, Mead M.
      Allogeneic hematopoietic stem cell transplantation (alloHCT) results in improved outcomes for acute myeloid leukemia (AML) patients compared to consolidation chemotherapy in transplant-eligible patients with adverse-risk disease. Despite achieving a complete remission (CR) to initial therapy, defined as <5% bone marrow blasts with recovery of peripheral blood elements, a large number of patients suffer disease relapse following alloHCT. There is a growing focus on minimal or measurable residual disease (MRD) in patients with AML, variably defined using multiparametric flow cytometry and nucleic acid sequencing techniques, to detect levels of disease not included in current CR terminology. MRD has emerged as an important prognostic tool in AML and may improve risk stratification, further refine selection of post-remission treatment, and provide an opportunity for therapeutic intervention. Herein, we review MRD detection methods, timing of measurement, prognostic implications, and MRD-directed therapy in AML patients undergoing alloHCT.
    Keywords:  Acute myeloid leukemia; allogeneic stem cell transplantation; measurable residual disease; overall survival; targeted therapy
    DOI:  https://doi.org/10.1080/10428194.2020.1827251