Arginine (R) at Position 595 in FLT3 Is Critical for Transforming Potential of FLT3-Length Mutations.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1598-1598
Author(s):  
Sridhar Vempati ◽  
Ruth Schwab ◽  
Theodora Malamoussi ◽  
Martin Dugas ◽  
Gudrun Mellert ◽  
...  
Keyword(s):  
Amino Acids ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Sequence Motif ◽  
Acute Leukemias ◽  
Activating Mutations ◽  
Juxtamembrane Region ◽  
Length Mutations ◽  
Tandem Duplications

Abstract Activating mutations in the juxtamembrane region of FMS-like tyrosine kinase-3 (FLT3-length mutations, FLT3-LM)-are found in 20–25% of patients with acute myeloid leukemia (AML). FLT3-LM consists of duplications and additional insertions that show a variable length and site of insertion. Although these different length mutations lead to constitutive activation of FLT3 and subsequent downstream signalling pathways, several questions still remain unanswered. Here, we focussed on the question whether a common sequence motif in the duplicated region can be identified in patients carrying FLT3-LM. To address this topic we sequenced the juxtamembrane region of FLT3 from 274 patients with acute leukemias. We found that the length of mutation (tandem duplications) varied from 2–42 amino acids with a median of 17 AA. Furthermore, the duplicated amino acids centered around the motif DFREYEY of FLT3. Since the length of the motif DFREYEY varied from patient to patient, we focussed our study on the frequency of single amino acids within the duplicated region. We found that arginine (R) 595 in the motif DFREYEY is duplicated in 77% of patients. Further studies showed that a single duplication of arginine at position 595 in FLT3 is able to confer factor independent growth to Ba/F3 cells. In vitro, deletion or substitution of duplicated R 595 in two FLT3-LMs with different lengths showed a 50% reduction in the factor independent growth when compared to undeleted/non-substituted FLT3-LMs. The reduced proliferative capacity of Ba/F3 cells expressing FLT3-LM with deletions of R-595 was associated with a reduction of STAT5 activation. Our data provide important insights into the molecular mechanisms of transformation by FLT3-LM and define duplicated R 595 as a critical mediator of the leukemic potential of these mutants.

Arginine 595 is duplicated in patients with acute leukemias carrying internal tandem duplications of FLT3 and modulates its transforming potential

Blood ◽  
2007 ◽  
Vol 110 (2) ◽  
pp. 686-694 ◽  
Author(s):  
Sridhar Vempati ◽  
Carola Reindl ◽  
Seshu Kumar Kaza ◽  
Ruth Kern ◽  
Theodora Malamoussi ◽  
...  
Keyword(s):  
Amino Acids ◽  
Molecular Mechanism ◽  
Positive Charge ◽  
Critical Role ◽  
Heterogeneous Group ◽  
Wild Type ◽  
Acute Leukemias ◽  
Juxtamembrane Region ◽  
Tandem Duplications

Abstract FLT3–internal tandem duplications (FLT3-ITDs) comprise a heterogeneous group of mutations in patients with acute leukemias that are prognostically important. To characterize the mechanism of transformation by FLT3-ITDs, we sequenced the juxtamembrane region (JM) of FLT3 from 284 patients with acute leukemias. The length of FLT3-ITDs varied from 2 to 42 amino acids (AAs) with a median of 17 AAs. The analysis of duplicated AAs showed that in the majority of patients, the duplications localize between AAs 591 to 599 (YVDFREYEY). Arginine 595 (R595) within this region is duplicated in 77% of patients. Single duplication of R595 in FLT3 conferred factor-independent growth to Ba/F3 cells and activated STAT5. Moreover, deletion or substitution of the duplicated R595 in 2 FLT3-ITD constructs as well as the deletion of wild-type R595 in FLT3-ITD substantially reduced the transforming potential and STAT5 activation, pointing to a critical role of the positive charge of R595 in stabilizing the active confirmation of FLT3-ITDs. Deletion of R595 in FLT3-WT nearly abrogated the ligand-dependent activation of FLT3-WT. Our data provide important insights into the molecular mechanism of transformation by FLT3-ITDs and show that duplication of R595 is important for the leukemic potential of FLT3-ITDs.

scholarly journals WTIP upregulates FOXO3a and induces apoptosis through PUMA in acute myeloid leukemia

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Yunqi Zhu ◽  
Xiangmin Tong ◽  
Ying Wang ◽  
Xiaoya Lu
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tumor Suppressor ◽  
Transcriptional Activation ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Hematologic Malignancy ◽  
Apoptotic Pathway ◽  
Acute Myeloid

AbstractAcute myeloid leukemia (AML) is an aggressive and heterogeneous clonal hematologic malignancy for which novel therapeutic targets and strategies are required. Emerging evidence suggests that WTIP is a candidate tumor suppressor. However, the molecular mechanisms of WTIP in leukemogenesis have not been explored. Here, we report that WTIP expression is significantly reduced both in AML cell lines and clinical specimens compared with normal controls, and low levels of WTIP correlate with decreased overall survival in AML patients. Overexpression of WTIP inhibits cell proliferation and induces apoptosis both in vitro and in vivo. Mechanistic studies reveal that the apoptotic function of WTIP is mediated by upregulation and nuclear translocation of FOXO3a, a member of Forkhead box O (FOXO) transcription factors involved in tumor suppression. We further demonstrate that WTIP interacts with FOXO3a and transcriptionally activates FOXO3a. Upon transcriptional activation of FOXO3a, its downstream target PUMA is increased, leading to activation of the intrinsic apoptotic pathway. Collectively, our results suggest that WTIP is a tumor suppressor and a potential target for therapeutic intervention in AML.

scholarly journals Molecular Mechanisms Underlying the Positive Stringent Response of the Bacillus subtilis ilv-leu Operon, Involved in the Biosynthesis of Branched-Chain Amino Acids

2008 ◽  
Vol 190 (18) ◽  
pp. 6134-6147 ◽  
Author(s):  
Shigeo Tojo ◽  
Takenori Satomura ◽  
Kanako Kumamoto ◽  
Kazutake Hirooka ◽  
Yasutaro Fujita
Keyword(s):  
Amino Acids ◽  
Bacillus Subtilis ◽  
Transcription Initiation ◽  
Molecular Mechanisms ◽  
Stringent Response ◽  
Branched Chain Amino Acids ◽  
Base Substitution ◽  
Branched Chain

ABSTRACT Branched-chain amino acids are the most abundant amino acids in proteins. The Bacillus subtilis ilv-leu operon is involved in the biosynthesis of branched-chain amino acids. This operon exhibits a RelA-dependent positive stringent response to amino acid starvation. We investigated this positive stringent response upon lysine starvation as well as decoyinine treatment. Deletion analysis involving various lacZ fusions revealed two molecular mechanisms underlying the positive stringent response of ilv-leu, i.e., CodY-dependent and -independent mechanisms. The former is most likely triggered by the decrease in the in vivo concentration of GTP upon lysine starvation, GTP being a corepressor of the CodY protein. So, the GTP decrease derepressed ilv-leu expression through detachment of the CodY protein from its cis elements upstream of the ilv-leu promoter. By means of base substitution and in vitro transcription analyses, the latter (CodY-independent) mechanism was found to comprise the modulation of the transcription initiation frequency, which likely depends on fluctuation of the in vivo RNA polymerase substrate concentrations after stringent treatment, and to involve at least the base species of adenine at the 5′ end of the ilv-leu transcript. As discussed, this mechanism is presumably distinct from that for B. subtilis rrn operons, which involves changes in the in vivo concentration of the initiating GTP.

scholarly journals Negatively charged amino acids in the stalk region of membrane proteins reduce ectodomain shedding

2020 ◽  
Vol 295 (35) ◽  
pp. 12343-12352 ◽  
Author(s):  
Ryo Iwagishi ◽  
Rika Tanaka ◽  
Munenosuke Seto ◽  
Tomoyo Takagi ◽  
Naoko Norioka ◽  
...  
Keyword(s):  
Amino Acids ◽  
Membrane Proteins ◽  
Molecular Mechanisms ◽  
Alternative Exon ◽  
Ectodomain Shedding ◽  
Post Translational Modification ◽  
Charged Amino Acids ◽  
Juxtamembrane Region ◽  
Protein Variants ◽  
Variant Protein

Ectodomain shedding is a post-translational modification mechanism by which the entire extracellular domain of membrane proteins is liberated through juxtamembrane processing. Because shedding rapidly and irreversibly alters the characteristics of cells, this process is properly regulated. However, the molecular mechanisms governing the propensity of membrane proteins to shedding are largely unknown. Here, we present evidence that negatively charged amino acids within the stalk region, an unstructured juxtamembrane region at which shedding occurs, contribute to shedding susceptibility. We show that two activated leukocyte cell adhesion molecule (ALCAM) protein variants produced by alternative splicing have different susceptibilities to ADAM metallopeptidase domain 17 (ADAM17)-mediated shedding. Of note, the inclusion of a stalk region encoded by a 39-bp-long alternative exon conferred shedding resistance. We found that this alternative exon encodes a large proportion of negatively charged amino acids, which we demonstrate are indispensable for conferring the shedding resistance. We also show that the introduction of negatively charged amino acids into the stalk region of shedding-susceptible ALCAM variant protein attenuates its shedding. Furthermore, we observed that negatively charged amino acids residing in the stalk region of Erb-B2 receptor tyrosine kinase 4 (ERBB4) are indispensable for its shedding resistance. Collectively, our results indicate that negatively charged amino acids within the stalk region interfere with the shedding of multiple membrane proteins. We conclude that the composition of the stalk region determines the shedding susceptibility of membrane proteins.

Bioactive Compounds from Seaweed with Anti-Leukemic Activity: A Mini-Review on Carotenoids and Phlorotannins

2020 ◽  
Vol 20 (1) ◽  
pp. 39-53 ◽  
Author(s):  
Tânia P. Almeida ◽  
Alice A. Ramos ◽  
Joana Ferreira ◽  
Amaya Azqueta ◽  
Eduardo Rocha
Keyword(s):  
Drug Resistance ◽  
Bioactive Compounds ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
First Line ◽  
In Vivo Models ◽  
Few Data

: Chronic Myeloid Leukemia (CML) represents 15-20% of all new cases of leukemia and is characterized by an uncontrolled proliferation of abnormal myeloid cells. Currently, the first-line of treatment involves Tyrosine Kinase Inhibitors (TKIs), which specifically inhibits the activity of the fusion protein BCR-ABL. However, resistance, mainly due to mutations, can occur. In the attempt to find more effective and less toxic therapies, several approaches are taken into consideration such as research of new anti-leukemic drugs and “combination chemotherapy” where different drugs that act by different mechanisms are used. Here, we reviewed the molecular mechanisms of CML, the main mechanisms of drug resistance and current strategies to enhance the therapeutic effect of TKIs in CML. Despite major advances in CML treatment, new, more potent anticancer drugs and with fewer side effects are needed. Marine organisms, and particularly seaweed, have a high diversity of bioactive compounds with some of them having anticancer activity in several in vitro and in vivo models. The state-of-art suggests that their use during cancer treatment may improve the outcome. We reviewed here the yet few data supporting anti-leukemic activity of some carotenoids and phlorotannins in some leukemia models. Also, strategies to overcome drug resistance are discussed, particularly the combination of conventional drugs with natural compounds.

Imatinib targets other than bcr/abl and their clinical relevance in myeloid disorders

Blood ◽  
2004 ◽  
Vol 104 (7) ◽  
pp. 1931-1939 ◽  
Author(s):  
Animesh Pardanani ◽  
Ayalew Tefferi
Keyword(s):  
Tyrosine Kinases ◽  
Myeloid Leukemia ◽  
Growth Factor Receptor ◽  
Myeloproliferative Disorders ◽  
Hematologic Malignancies ◽  
Myeloid Metaplasia ◽  
Activating Mutations ◽  
Myelofibrosis With Myeloid Metaplasia

Abstract Imatinib mesylate is a small molecule drug that in vitro inhibits the Abelson (Abl), Arg (abl-related gene), stem cell factor receptor (Kit), and platelet-derived growth factor receptor A and B (PDGFRA and PDGFRB) tyrosine kinases. The drug has acquired therapeutic relevance because of similar inhibitory activity against certain activating mutations of these molecular targets. The archetypical disease in this regard is chronic myeloid leukemia, where abl is constitutively activated by fusion with the bcr gene (bcr/abl). Similarly, the drug has now been shown to display equally impressive therapeutic activity in eosinophilia-associated chronic myeloproliferative disorders that are characterized by activating mutations of either the PDGFRB or the PDGFRA gene. The former usually results from translocations involving chromosome 5q31-33, and the latter usually results from an interstitial deletion involving chromosome 4q12 (FIP1L1-PDGFRA). In contrast, imatinib is ineffective, in vitro and in vivo, against the mastocytosis-associated c-kit D816V mutation. However, wild-type and other c-kit mutations might be vulnerable to the drug, as has been the case in gastrointestinal stomal cell tumors. Imatinib is considered investigational for the treatment of hematologic malignancies without a defined molecular drug target, such as polycythemia vera, myelofibrosis with myeloid metaplasia, and acute myeloid leukemia.

scholarly journals Manipulation of dietary amino acids prevents and reverses obesity in mice through multiple mechanisms that modulate energy homeostasis

2020 ◽  
Author(s):  
Ada Admin ◽  
Chiara Ruocco ◽  
Maurizio Ragni ◽  
Fabio Rossi ◽  
Pierluigi Carullo ◽  
...  
Keyword(s):  
Amino Acids ◽  
Energy Metabolism ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Uncoupling Protein ◽  
Essential Amino Acids ◽  
Brown Fat ◽  
Acid Oxidation ◽  
White Fat

Reduced activation of energy metabolism increases adiposity in humans and other mammals. Thus, exploring dietary and molecular mechanisms able to improve energy metabolism is of paramount medical importance, as such mechanisms can be leveraged as a therapy for obesity and related disorders. Here, <a>we show that a designer protein-deprived diet enriched in free essential amino acids can i) promote the brown fat thermogenic program and fatty acid oxidation, ii) stimulate uncoupling protein 1 (UCP1)-independent respiration in subcutaneous white fat, iii) change the gut microbiota composition, and iv) prevent and reverse obesity and dysregulated glucose homeostasis in multiple mouse models, prolonging the healthy lifespan. </a>These effects are independent of unbalanced amino acid ratio, energy consumption, and intestinal calorie absorption. A brown fat-specific activation of the mechanistic target of rapamycin complex 1 seems involved in the diet-induced beneficial effects, as also strengthened by <i>in vitro</i> experiments. Hence, our results suggest that brown and white fat may be targets of specific amino acids to control UCP1-dependent and -independent thermogenesis, thereby contributing to the improvement of metabolic health.

Mutations of the Catalytic Subunit of Class IA PI3K Are Constitutively Active and Confer Factor-Independent Growth to Early Hematopoietic Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1455-1455
Author(s):  
Stefan Horn ◽  
James McCubrey ◽  
Carol Stocking ◽  
Lorenz Truemper ◽  
Jorg Basecke
Keyword(s):  
Hot Spot ◽  
Hematopoietic Cells ◽  
Specific Inhibitor ◽  
Kinase Domain ◽  
Catalytic Subunit ◽  
Dependent Manner ◽  
Acute Leukemias ◽  
Activating Mutations ◽  
Exon 9

Abstract Background: Activating mutations of the catalytic subunit of class IA phosphoinositide 3-kinase alpha (PIK3CA) are clustered in small hot-spot regions of the PIK3CA gene, including exon 9 within the helical domain and exon 11 within the kinase domain. They have been linked to several human neoplasias, including colorectal, breast and hepatocellular cancers. In acute leukemias, PIK3CA mutations have not been investigated in larger chorts and so far only been observed in a few patients. Since the PI3K/Akt/GSK3beta pathway is an important signaling cascade of receptor tyrosine kinases (e.g. Flt3R, Kit) which are frequently activated in acute leukemias we investigated the functional activity of PIK3CA mutants. Materials and methods: We transfected early hematopoietic cells (Ba/F3 cell line) with PI3KCA exon 9 and 11 mutations and investigated the cells in an in vitro factor-independent growth assay and pharmacologic inhibition experiments. Results: We demonstrate that mutations in the helical or kinase domain of PIK3CA lead to the constitutive activation of PI3Kalpha in Ba/F3 cells, inducing factor-independent growth of the IL3-dependent cells. The frequency of IL3-independent Ba/F3 cells after tranfection with exon 9 and 11 PIK3CA mutants was equivalent to the frequency confered by PIK3CA mutants containing the membrane localization signal of either src or ras. Proliferation and survival of the cells were inhibited by the PI3K inhibitors LY294002 and Quercitin or an inhibitor of the PI3K downstream target Akt. Inhibition occurred in a dose- and time-dependent manner and could be reverted by addition of IL-3. One of the major targets of PI3K/Akt signaling is GSK3beta which becomes inactivated after Akt-mediated phosphorylation. By using a GSK3beta-specific inhibitor or LiCl we could show that the inactivation of GSK3beta alone did not result in factor-independent growth of Ba/F3 cells. However, GSK3beta inhibition led to a delay in the induction of cell death after IL3-withdrawal. Conclusion: Activating mutations of PIK3CA, associated with several human neoplasias and acute leukemia are functionally active in hematopoietic cells, confer factor independency and respond to PI3K/Akt inhibition.

A Novel Class of Activating Mutations in NOTCH1 in T-ALL.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 694-694 ◽  
Author(s):  
Maria Luisa Sulis ◽  
Odette Williams ◽  
Valeria Tosello ◽  
Sasikala Pallippukam ◽  
Teresa Palomero ◽  
...  
Keyword(s):  
Amino Acids ◽  
T Cell ◽  
Mutant Allele ◽  
Gamma Secretase ◽  
Activating Mutations ◽  
Notch1 Signaling ◽  
Juxtamembrane Region ◽  
Human T Cell ◽  
Fold Activation ◽  
Notch1 Receptor

Abstract Aberrant activation of NOTCH1 signaling induces transformation of T-cell progenitors and plays a prominent role in the pathogenesis of over 50% of human T-cell acute lymphoblastic leukemias (T-ALL), which harbor activating mutations in the heterodimerization (HD) and PEST domains of NOTCH1. Here we report a new class of activating mutations in NOTCH1 in human T-ALL. These so called JuxtaMembrane Expansion (JME) mutants consist of internal tandem duplications of exon 28 and adjacent intronic sequences in the NOTCH1 gene, which result in expansions of the extracellular juxtamembrane region of the NOTCH1 receptor. Western blot analysis of T-ALL cell lines lacking known NOTCH1 mutations demonstrated high levels of activated NOTCH1 protein in Jurkat T-ALL cells, suggesting the presence of an as yet unidentified activating NOTCH1 mutation in this cell line. Sequence analysis of Jurkat NOTCH1 transcripts revealed an internal tandem duplication in exon 28 of NOTCH1, resulting in the insertion of 17 amino acids at position 1740 in the extracelullar juxtamembrane region of the receptor. Subsequent PCR amplification of NOTCH1 exon 28 sequences from 194 primary T-ALL lymphoblast samples identified seven additional in frame insertion mutations ranging from 11 to 36 amino acids in length, all of which were located in the vicinity of codon 1740 in the extracelullar juxtamembrane region of the NOTCH1 receptor. Luciferase assays showed that expression of the NOTCH1 Jurkat JME17 mutant allele induced over 200 fold activation of a NOTCH1 reporter construct compared to controls. Activation of NOTCH1 signaling requires proteolytic cleavage of the receptor, first by an ADAM metalloprotease (S2 clevage) and subsequently by the gamma-secretase complex. NOTCH1 signaling induced by the Jurkat JME17 mutant was completely abrogated by incubation with CompE, a highly active gamma-secretase inhibitor. Consistently, treatment of Jurkat T-ALL cells with CompE resulted in rapid clearance of activated NOTCH1 protein and in marked downregulation of NOTCH1 target genes such as HES1 and DELTEX1. Interestingly, and in contrast with previously described HD mutations, JME NOTCH1 alleles retain an intact HD domain and a protected canonical S2 metalloprotease cleavage site. Thus, we hypothesized that activation of NOTCH1 by JME mutations could be mediated by aberrant metalloprotease cleavage at ectopic S2 sites within the JME insertion sequence. However, mutation of the canonical S2 cleavage abrogated the function of the NOTCH1 Jurkat JME17 mutant allele. Furthermore, analysis of artificially generated JME insertions containing sequences unrelated to the leukemia-derived JME alleles, showed that activation of NOTCH1 by JME mutations depends primarily on the length of the inserted peptides and not on their specific amino acid sequences. Thus, shorter insertions of 5 to 13 amino acids in length induced moderate (5–10 fold) activation of the NOTCH1 receptor, while insertions of 14 amino acids or longer induced marked (>70 fold) increases in NOTCH1 signaling. Overall, these results provide further insight in the mechanisms that control the activation of the NOTCH1 receptor in T-ALL.

Hoxa9/Meis1 Mediate Leukemic Programming through Microrna-155

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 884-884
Author(s):  
Edith Schneider ◽  
Anna Staffas ◽  
Milijana Mirkovic-Hoesle ◽  
Bernhard Gentner ◽  
Jens Ruschmann ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Colony Formation ◽  
Healthy Donor ◽  
Molecular Mechanisms ◽  
Acute Leukemias ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Donor Bone Marrow

Abstract Synergistic deregulation of HOXA9 and the HOX-gene cofactor MEIS1 is a commonly observed phenomenon in acute myeloid leukemia (AML). The leukemogenic potential of aberrant Hoxa9 and Meis1 expression has been shown in several AML models. However, the molecular mechanisms behind Hoxa9- and Meis1-induced leukemogenesis are still not well understood. In order to identify functionally relevant Meis1-induced microRNAs (miRNA), we profiled the global miRNA expression using a Hoxa9-Meis1 murine AML progression model. This two-step model allowed us to quantify miRNAs at a pre-leukemic stage through the overexpression of the proto-oncogene Hoxa9 (Hoxa9/ctrl), as well as after full leukemic transformation through co-overexpression of Hoxa9 and Meis1 (Hoxa9/Meis1). The pre-leukemic stage is characterized by in vitro immortalization without in vivo engraftment, whereas the transplanted leukemic cells induce full-blown AML in vivo. MiR-155 turned out to be one of the most significant differentially expressed miRNA species and its upregulation was independently validated in Hoxa9/Meis1 cells by qRT-PCR. Subsequent analysis of various AML subtypes (CN-AML, t(11q23), t(8;21), t(15;17), n=38) showed significantly elevated levels of miR-155 in CN-AML with NPM1mut (n=10, p<0.01) and AML with t(11q23) (n=8, p<0.05) compared to healthy donor bone marrow (MNC). These results are in line with overexpression of HOXA9 (CN-AML NPM1mut: p<0.05, t(11q23): p<0.05) and MEIS1 (CN-AML NPM1mut: p<0.01, t(11q23): p<0.05) in these AML samples compared to healthy donor bone marrow cells (MNC). Expression analysis of miR-155 in healthy murine bone marrow (mbm) cells revealed miR-155 enrichment in hematopoietic stem- and progenitor cells compared to mature myeloid cells (p<0.05), mirroring a similar expression pattern as observed for Meis1. Therefore, to dissect the leukemic potential of miR-155 to program mbm, 5-FU-stimulated mbm cells were retrovirally transduced with miR-155, leading to significantly increased proliferation in vitro (p<0.05). This finding suggests enhancement of self-renewal on the stem-/progenitor cell level by miR-155. Furthermore, mbm cells overexpressing Hoxa9 together with miR-155 (Hoxa9/miR-155) significantly increased colony formation (p<0.05) in a methylcellulose assay. In turn, absence of miR-155 (miR-155-/- mbm) significantly reduced colony formation in conjunction with Hoxa9 (p<0.05) and MLL-AF9 (p=0.05), a known positive regulator of Hoxa9 and Meis1. These findings suggest a role for miR-155 in both proliferation and self-renewal indicating that the oncogenic program of Hoxa9/Meis1 relies on the presence of miR-155. The leukemic potency of Hoxa9/miR-155 was further investigated in a murine transplantation model in vivo. Transplantation of mbm co-overexpressing Hoxa9/miR-155 led to significantly increased engraftment levels already after four weeks (wks) (57.8%±31.3, n=16) compared to Hoxa9/ctrl (11.7%±19.3%, p<0.0001, n=17), but less than with Hoxa9/Meis1 (74.5%±20.3%, p<0.01, n=14). In contrast to Hoxa9/ctrl (22±7 wks), mice that received Hoxa9/miR-155 mbm cells had a significantly accelerated onset of a myeloproliferative disease (MPD)-like leukemia within 11 wks (11±6 wks, p<0.0001), but still a less aggressive course of disease compared to mice transplanted with Hoxa9/Meis1 (5±1 wks, p<0.0001). This result is striking considering the aggressive nature of the Hoxa9/Meis1 AML model and given how little is known about its central mechanisms. It also highlights the relevant contribution of miR-155 to the leukemic programming induced by Hoxa9/Meis1 and provides a further rational to target miR-155 in AML. Considering the central role of the Hoxa9/Meis1 in both myeloid and lymphoid acute leukemias, we demonstrate for the first time the leukemogenic relevance of a miRNA within this transcriptional axis. Disclosures No relevant conflicts of interest to declare.

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