The CADM1 tumor suppressor gene is a major candidate gene in MDS with deletion of the long arm of chromosome 11.

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis leading to peripheral cytopenias and in a substantial proportion of cases to acute myeloid leukemia. The deletion of the long arm of chromosome 11, del(11q), is a rare but recurrent clonal event in MDS. Here, we detail the largest series of 113 cases of MDS and myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) harboring a del(11q) analyzed at clinical, cytological, cytogenetic, and molecular levels. Female predominance, a survival prognosis similar to other MDS, a low monocyte count, and dysmegakaryopoiesis were the specific clinical and cytological features of del(11q) MDS. In most cases, del(11q) was isolated, primary and interstitial encompassing the 11q22-23 region containing ATM, KMT2A, and CBL genes. The common deleted region at 11q23.2 is centered on an intergenic region between CADM1 (also known as Tumor Suppressor in Lung Cancer 1) and NXPE2. CADM1 was expressed in all myeloid cells analyzed in contrast to NXPE2. At the functional level, the deletion of Cadm1 in murine Lineage-Sca1+Kit+ cells modifies the lymphoid-to-myeloid ratio in bone marrow, although not altering their multilineage hematopoietic reconstitution potential after syngenic transplantation. Together with the frequent simultaneous deletions of KMT2A, ATM, and CBL and mutations of ASXL1, SF3B1, and CBL, we show that CADM1 may be important in the physiopathology of the del(11q) MDS, extending its role as tumor-suppressor gene from solid tumors to hematopoietic malignancies

Sumoylation Inhibits the Growth Suppressive Properties of Ikaros.

The Ikaros transcription factor is a tumor suppressor that is also important for lymphocyte development. How post-translational modifications influence Ikaros function remains partially understood. We show that Ikaros undergoes sumoylation in developing T cells that correspond to mono-, bi- or poly-sumoylation by SUMO1 and/or SUMO2/3 on three lysine residues (K58, K240 and K425). Sumoylation occurs in the nucleus and requires DNA binding by Ikaros. Sumoylated Ikaros is less effective than unsumoylated forms at inhibiting the expansion of murine leukemic cells, and Ikaros sumoylation is abundant in human B-cell acute lymphoblastic leukemic cells, but not in healthy peripheral blood leukocytes. Our results suggest that sumoylation may be important in modulating the tumor suppressor function of Ikaros

Large deletions of the 5' region of IKZF1 lead to haploinsufficiency in B-cell precursor acute lymphoblastic leukaemia

No abstract availabl

Sumoylation of Ikaros in B-ALL cells.

<p><b>(A)</b> Detection of Ikaros proteins by western blot in whole cell extracts from human peripheral blood mononuclear cells (PBMC), primary leukemic cells from a B-ALL patient, and the ACC42, RS4;11 and Tom-1 B-ALL cell lines. <b>(B)</b> Detection of Ikaros sumoylation in whole cell extracts from B-ALL patient #H4524 and the cell line ACC42. Protein extracts were immunoprecipitated with an anti-Ikaros antibody, and probed with an anti-Ikaros antibody, or with a mix of anti-SUMO1 and anti-SUMO2/3 antibodies. Open arrowheads point to the Ik1 and Ik2 isoforms; asterisks to IgGs. Note that a sumoylated protein comigrates with Ik1, presumably corresponding to sumoylated Ik2.</p

Impact of Ikaros mutations on sumoylation.

<p><b>(A)</b> Schematic representation of Ik1-ER deletion mutants. (<b>B</b>) Modification pattern of Ik1-ER deletion mutants. ILC87 cells expressing Ik1-ER or deletion mutants were treated and lysed as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0157767#pone.0157767.g001" target="_blank">Fig 1D</a>. Nuclear extracts were immunoprecipitated with an anti-ER antibody, separated by SDS-PAGE (6%) and analyzed with anti-Ikaros antibodies against C-terminal or N-terminal epitopes. (<b>C</b>) Nuclear extracts from 50x10⁶ ILC87 cells expressing Ik1-ER or the indicated point mutants were immunoprecipitated with an anti-ER antibody, separated on a NuPAGE Novex 3–8% Tris-Acetate gel and analyzed with an anti-Ikaros antibody. The pattern of the various modified proteins is schematized on the right and the corresponding modifications indicated. In (B) and (C), arrowheads point to unmodified proteins.</p

Azacitidine Plus Venetoclax for the Treatment of Relapsed and Newly Diagnosed Acute Myeloid Leukemia Patients

International audienceVenetoclax (VEN) belongs the BH3-mimetic class that selectively targets BCL-2, activating apoptosis. The combination of VEN and azacitidine (AZA) has changed the paradigm of treatment of newly diagnosed (ND) acute myeloid leukemia (AML) patients ineligible for intensive chemotherapy. There is scarce evidence for the use of VEN–AZA for relapsed or refractory (R/R) AML. We compared the outcome of 39 R/R AML and 38 ND AML patients treated between 01/20 and 12/21. The median age was 69 (22–86) and 73 (61–81) in the R/R and ND groups, respectively. Adverse cytogenetics were found in 36% of patients in the R/R group and 59% of patients in the ND group. Overall response rate was 37% in R/R AML, including 13% CR, 8% CRi, 3% PR and 13% MLFS, and 58% in the ND AML, including 32% CR, 13% CRi and 13% MLFS. Adverse cytogenetics was associated with treatment failure in the R/R group (Relative Risk = 0.13, p = 0.005). Median overall survival (OS) was 5.9 months in the R/R group and 9.4 months in the ND group. Median OS was 2.2 months in the adverse cytogenetics group versus 8.7 months in the intermediate cytogenetics group in the R/R group (p = 0.02). Median leukemia-free survival was not different between the two groups (9.4 months and 10.3 months), indicating that VEN–AZA can be an efficient salvage treatment for selected R/R AML patients. In conclusion, VEN–AZA is a promising treatment for ND AML and for selected R/R AML patients

Genetic characterization of B-cell prolymphocytic leukemia: a prognostic model involving and MYC and TP53

B-cell prolymphocytic leukemia (B-PLL) is a rare hematological disorder whose underlying oncogenic mechanisms are poorly understood. Our cytogenetic and molecular assessment of 34 patients with B-PLL revealed several disease-specific features and potential therapeutic targets. The karyotype was complex ({greater than or equal to}3 abnormalities) in 73% of the patients and highly complex (5 abnormalities) in 45%. The most frequent chromosomal aberrations were translocations involving [t()] (62%), deletion (del)17p (38%), trisomy (tri)18 (30%), del13q (29%), tri3 (24%), tri12 (24%), and del8p (23%). Twenty-six of the 34 patients (76%) exhibit aberration, resulting from mutually exclusive translocations or gains. Whole-exome sequencing revealed frequent mutations in , , , , , , , , and The majority of B-PLL used the or subgroups (89%), and displayed significantly mutated genes (79%). We identified three distinct cytogenetic risk groups: low-risk (no aberration), intermediate-risk ( aberration but no del17p), and high-risk ( aberration and del17p) (p=.0006). drug response profiling revealed that the combination of a B-cell receptor or BCL2 inhibitor with OTX015 (a bromodomain and extra-terminal motif (BET) inhibitor targeting ) was associated with significantly lower viability of B-PLL cells harboring a t(). We conclude that cytogenetic analysis is a useful diagnostic and prognostic tool in B-PLL. Targeting may be a useful treatment option in this disease

Sumoylation limits the growth-inhibitory effects of Ikaros.

<p><b>(A)</b> Western blot showing similar level of Ik1-ER and Ik-TM-ER proteins in nuclear extracts of ILC87-Ik1-ER and ILC87-Ik-TM-ER cells treated with EtOH or 4OHT. <b>(B)</b> Scatter plots showing the distributions of the fold changes (4OHT- vs EtOH-treated cells, expressed as log2 values) in the 2 independent analyses performed with ILC87-Ik1-ER cells (top panel), or between representative analyses performed with ILC87-Ik1-ER and ILC87-Ik-TM-ER cells (bottom panel). The red diagonal highlights the theoritical position for probe sets with similar fold-changes. <b>(C)</b> RT-qPCR analysis of repression of the <i>Mpzl2</i> and <i>Scn4b</i> genes in ILC87-Ik1-ER and ILC87-Ik-TM-ER cells treated with 4OHT for 24h, in 2 independent experiments (duplicate measurements in each case). <b>(D-F)</b> Competitive growth inhibition assay. <b>(D)</b> Experimental setup: ILC87 cells transduced with IK1-ER or Ik-TM-ER (GFP⁺) were mixed at a 1:1 ratio with ILC87 cells (or ILC87 cells mock-transduced with an empty Mig-NGFR retrovirus) and cultured for 6 days in the presence of EtOH or 4OHT. <b>(E)</b> Proportion of GFP⁺ cells in living cells of EtOH and 4OHT-treated ILC87-Ik1-ER and ILC87-Ik-TM-ER cells in a representative experiment. <b>(F)</b> Growth inhibition over time by Ik1-ER and Ik-TM-ER (ratio of GFP⁺ cells in 4OHT-treated over EtOH-treated samples; average of 4 experiments). Statistical significance was evaluated with a Student's t-test.</p

Isolated isochromosomes i(X)(p10) and idic(X)(q13) are associated with myeloid malignancies and dysplastic features

International audienc