CD24High / FLJ/P1Low Expression Correlates with Bad Prognosis and Shorter Survival in Adult ALL.

Abstract Leukemia is a neoplastic proliferation of cells of hematopoietic origin that arises following somatic mutation in a single hematopoietic stem cell, the progeny of which forms a clone of leukemia cells. Genetic alterations leading to leukemia transformation of a cell are often associated with major alterations of chromosomes that can be detected by studying cells of the leukemic clone in mitosis. One of these alterations is a chromosomal translocation that is often used to identify genes potentially involved in other type of rearrangements such as deletions. Abnormalities of chromosome band 13q14 occur in hematologic malignancies of all lineages and at all stages of differentiation. Unlike other chromosomal translocations, which are usually specific for a given lineage, the chromosomal translocation t(12;13)(p12;q14) has been observed in both B-cell and T-cell precursor acute lymphoblastic leukemia (ALL), in differentiated and undifferentiated acute myeloid leukemia (AML) and in chronic myeloid leukemia at progression to blast crisis (CML-BC). Recently, we have shown the presence of a myeloid- and lymphoid-specific breakpoint cluster regions within chromosome band 13q14 in acute leukemia (Genes Chromosome Cancer 25:222–229,1999). In addition, a new cell line has been established from one of the lymphoid cases, MUTZ5, that carries a single t(12;13) translocation (Leukemia 15:1471–1474, 2001). The molecular characterization of this translocation led to the identification of a new gene, FLJ13639, that is disrupted and lost in the MUTZ5 cell line. This gene shares homologies with the large family of short-chain dehydrogenase reductase (SDR). Furthermore, three transcripts and proteins were found to be differentially expressed for this gene, where P1 is potentially the active form of dehydrogenase, while P2 and P3 are lacking the co-activator site. We report here that one of the consequences of the loss of FLJ13639 is the over-expression of CD24 that appears to provide leukemia cells with a proliferation and invasiveness advantage, as well as a certain degree of chemoresistance. FLJ13639 is a new mitochondrial protein that seems to be important for the respiration and apoptosis processes. In addition, semi-quantitative RT-PCR for CD24 and FLJ13639/P1 was performed in a series of cell lines as well as 29 adult ALL samples at diagnosis. Fifty percent of the samples showed a CD24High / FLJ/P1Low profile whereas the remaining samples showed either a balanced expression or a CD24Low / FLJ/P1High profile. These preliminary data on patient samples indicated a correlation between survival and CD24High / FLJ/P1Low expression profile (p=0.04). The current median time survival for the CD24High / FLJ/P1Low group is 9 months whereas the CD24Low / FLJ/P1High group is 28 months. Therefore, this appears to be a new potential prognostic marker for adult ALL. Figure Figure

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FLJ/P1 Is a New Mitochondrial Dehydrogenase Important in Respiration and Apoptosis.

Blood ◽

10.1182/blood.v108.11.4292.4292 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4292-4292

Author(s):

Lionel J. Coignet ◽

Timothy Johnson ◽

Alain Nganga ◽

Pushpankur Ghoshal ◽

Christiane Houde ◽

...

Keyword(s):

Cell Line ◽

Myeloid Leukemia ◽

Expression Profiles ◽

Lymphoblastic Leukemia ◽

Active Form ◽

Chromosomal Translocation ◽

Genetic Alterations ◽

Leukemia Cells ◽

Chromosome Band ◽

Hematopoietic Stem

Abstract Leukemia is a neoplastic proliferation of cells of hematopoietic origin that arises following somatic mutation in a single hematopoietic stem cell, the progeny of which forms a clone of leukemia cells. Genetic alterations leading to leukemia transformation of a cell are often associated with major alterations of chromosomes that can be detected by studying cells of the leukemic clone in mitosis. One of these alterations is a chromosomal translocation that is often used to identify genes potentially involved in other type of rearrangements such as deletions. Abnormalities of chromosome band 13q14 occur in hematologic malignancies of all lineages and at all stages of differentiation. Unlike other chromosomal translocations, which are usually specific for a given lineage, the chromosomal translocation t(12;13)(p12;q14) has been observed in both B-cell and T-cell precursor acute lymphoblastic leukemia (ALL), in differentiated and undifferentiated acute myeloid leukemia (AML) and in chronic myeloid leukemia at progression to blast crisis (CML-BC). Recently, we have shown the presence of a myeloid- and lymphoid-specific breakpoint cluster regions within chromosome band 13q14 in acute leukemia (Genes Chromosome Cancer 25:222-229,1999). In addition, a new cell line has been established from one of the lymphoid cases, MUTZ5, that carries a single t(12;13) translocation (Leukemia15:1471-1474, 2001). The molecular characterization of this translocation led to the identification of a new gene, FLJ13639, that is disrupted and lost in the MUTZ5 cell line. This gene shares homologies with the large family of short-chain dehydrogenase reductase (SDR). Furthermore, three transcripts and proteins were found to be differentially expressed for this gene, where P1 is potentially the active form of dehydrogenase, while P2 and P3 are lacking the co-activator site. We previously reported that one of the consequences of the loss of FLJ13639 is the over-expression of CD24 that appears to provide leukemia cells with a proliferation and invasiveness advantage, as well as a certain degree of chemoresistance. In addition, data on patient samples indicated a correlation between survival and CD24High/FLJ/P1Low expression profile (Blood 106 (11), Nov 2005). We show that FLJ/P1 is a new mitochondrial protein that is important for the respiration and apoptosis processes. Restoration of the FLJ/P1 function induced CD24 down-regulation, decreased invasive potential as assessed by Matrigel assay and decreased chemoresistance. FLJ/P1 function restoration might represent a new potential therapy, that could, when combined with the assessment of FLJ/P1-CD234 expression profiles, allow the future development of personalized treatment.

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Sensitization of Leukemic Cells for Glucocorticoids by Inhibition of NFκB Activity.

Blood ◽

10.1182/blood.v104.11.3395.3395 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3395-3395 ◽

Cited By ~ 1

Author(s):

Jacqueline Cloos ◽

Josefien Vink ◽

Marjolein van Miltenburg ◽

Ruud Oerlemans ◽

Joost van der Heijden ◽

...

Keyword(s):

Protein Expression ◽

Myeloid Leukemia ◽

Lymphoblastic Leukemia ◽

Active Form ◽

26S Proteasome ◽

Leukemic Cells ◽

Leukemia Cells ◽

Mrna Levels ◽

U937 Cells ◽

Acute Leukemias

Abstract Based on their immunosuppressive and cytotoxic effects, glucocorticoids (GCs) find widespread use as immune-modulatory agents and in (childhood) leukemia, lymphomas and myelomas. Unfortunately, resistance to GCs is a major adverse prognostic factor and occurs in about 20% in newly diagnosed childhood acute lymphoblastic leukemia (ALL) and in more than 50% in relapsed ALL, while acute myeloid leukemia (AML) is largely unresponsive to GCs. In addition, adult AML is more often GC resistant compared to childhood AML. Recently, we observed (van der Heijden et al, Ann Rheum Dis 63: 131-137,2004) that prolonged exposure of human CEM-C7 T cell leukemia cells to the anti-rheumatic drug sulfasalazine (SSZ) sensitized these primary sensitive cells even further for GCs. SSZ is an inhibitor of activation of NFκB that is often therapeutically used in combination with methotrexate and prednisone. Following these observations, two human myeloid leukemia cell lines (THP-1 and U937) with inherent resistance to GCs (IC50 for prednisolone > 250 μM, IC50 dexamethasone > 25 μM) were exposed to SSZ to establish whether this would provoke GC sensitization. Indeed, prolonged SSZ exposure sensitized both myeloid leukemia cells for prednisolone (IC50 < 1 μM) and dexamethasone (IC50 < 0.05 μM). In order to elicit the mechanistic basis for the GC sensitizing effect of SSZ expression levels of Glucocorticoid Receptor α (GRα), NFκB p65 and Inhibitor of NFκB (IκBα) were analyzed. In contrast to GC-sensitive CEM-C7 cells, parental THP-1 and U937 cells had no detectable and constitutive expression of GRα and NFκB p65 protein, even though mRNA levels for both parameters were readily detectable. In SSZ-exposed THP-1 and U937 cells protein expression of NFκB p65 was markedly increased although it does not represent the active form of NFκB since protein expression of IκB increased concomitantly. Consistent with the sensitization for GCs in SSZ-exposed THP-1 and U937 cells was a marked increase in GRα protein expression, suggesting that GRα is post-transcriptionally prevented from degradation. In line with this concept is that co-incubation with a 26S proteasome inhibitor Bortezomib further enhanced (5-fold) GC sensitivity in SSZ-exposed THP-1 and U937 cells. Collectively, this study reveals that SSZ-exposure impairs activation of NFκB and facilitates stabilization of GRα protein, conditions which confer GC-sensitization in leukemic cells with primary resistance to GCs. In conclusion, modulation of GC resistance in acute leukemias by NFκB inhibitors is a novel, clinically attractive approach that warrants further preclinical and subsequent clinical investigations.

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Establishment and characteristics of a T-cell acute lymphoblastic leukemia cell line, JK-T1, with a chromosomal translocation between 8q24 and 14q13

Cancer Genetics and Cytogenetics ◽

10.1016/0165-4608(92)90329-7 ◽

1992 ◽

Vol 64 (1) ◽

pp. 86-90 ◽

Cited By ~ 6

Author(s):

Mitsuyoshi Urashima ◽

Hideaki Iyori ◽

Kouji Fujisawa ◽

Yasutaka Hoshi ◽

Jun-ichi Akatsuka ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Cell Line ◽

Lymphoblastic Leukemia ◽

Leukemia Cell ◽

Chromosomal Translocation ◽

Leukemia Cell Line ◽

Cell Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia Cell Line

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A Novel, Myeloid Transcription Factor, C/EBPε, Is Upregulated During Granulocytic, But Not Monocytic, Differentiation

Blood ◽

10.1182/blood.v90.7.2591.2591_2591_2600 ◽

1997 ◽

Vol 90 (7) ◽

pp. 2591-2600 ◽

Cited By ~ 9

Author(s):

Roberta Morosetti ◽

Dorothy J. Park ◽

Alexey M. Chumakov ◽

Isabelle Grillier ◽

Masaaki Shiohara ◽

...

Keyword(s):

Stem Cells ◽

Transcription Factor ◽

Hematopoietic Stem Cells ◽

Cell Line ◽

Cell Lines ◽

Myeloid Leukemia ◽

Leukemia Cell ◽

Rt Pcr ◽

Hematopoietic Stem ◽

Nb4 Cells

Human C/EBPε is a newly cloned CCAAT/enhancer-binding transcription factor. Initial studies indicated it may be an important regulator of human myelopoiesis. To elucidate the range of expression of C/EBPε, we used reverse transcription-polymerase chain reaction (RT-PCR) analysis and examined its expression in 28 hematopoietic and 14 nonhematopoietic cell lines, 16 fresh myeloid leukemia samples, and normal human hematopoietic stem cells and their mature progeny. Prominent expression of C/EBPε mRNA occurred in the late myeloblastic and promyelocytic cell lines (NB4, HL60, GFD8), the myelomonoblastic cell lines (U937 and THP-1), the early myeloblast cell lines (ML1, KCL22, MDS92), and the T-cell lymphoblastic leukemia cell lines CEM and HSB-2. For the acute promyelocytic leukemia cell line NB4, C/EBPε was the only C/EBP family member that was easily detected by RT-PCR. No C/EBPε mRNA was found in erythroid, megakaryocyte, basophil, B lymphoid, or nonhematopoietic cell lines. Most acute myeloid leukemia samples (11 of 12) from patients expressed C/EBPε. Northern blot and RT-PCR analyses showed that C/EBPε mRNA decreased when the HL60 and KG-1 myeloblast cell lines were induced to differentiate toward macrophages. Similarly, Western blot analysis showed that expression of C/EBPε protein was either unchanged or decreased slightly as the promyelocytic cell line NB4 differentiated down the macrophage-like pathway after treatment with a potent vitamin D3 analog (KH1060). In contrast, C/EBPε protein levels increased dramatically as NB4 cells were induced to differentiate down the granulocytic pathway after exposure to 9-cis retinoic acid. Furthermore, very early, normal hematopoietic stem cells (CD34+/CD38−), purified from humans had very weak expression of C/EBPε mRNA, but levels increased as these cells differentiated towards granulocytes. Likewise, purified granulocytes appeared to express higher levels of C/EBPε mRNA than purified macrophages. Addition of phosphothiolated antisense, but not sense oligonucleotides to C/EBPε, decreased clonal growth of HL-60 and NB4 cells by about 50% compared with control cultures. Taken together, our results indicate that expression of C/EBPε is restricted to hematopoietic tissues, especially myeloid cells as they differentiate towards granulocytes and inhibition of its expression in HL-60 and NB4 myeloblasts and promyelocytes decreased their proliferative capacity. Therefore, this transcriptional factor may play an important role in the process of normal myeloid development.

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HRX involvement in de novo and secondary leukemias with diverse chromosome 11q23 abnormalities [see comments]

Blood ◽

10.1182/blood.v81.12.3197.3197 ◽

1993 ◽

Vol 81 (12) ◽

pp. 3197-3203 ◽

Cited By ~ 113

Author(s):

SP Hunger ◽

DC Tkachuk ◽

MD Amylon ◽

MP Link ◽

AJ Carroll ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Topoisomerase Ii ◽

De Novo ◽

Lymphoblastic Leukemia ◽

Myelogenous Leukemia ◽

Chromosome Band ◽

11Q23 Abnormalities ◽

Acute Myeloid ◽

Secondary Leukemias

Abstract Chromosome band 11q23 is a site of recurrent translocations and interstitial deletions in human leukemias. Recent studies have shown that the 11q23 gene HRX is fused to heterologous genes from chromosomes 4 or 19 after t(4;11)(q21;q23) and t(11;19)(q23;p13) translocations to create fusion genes encoding proteins with structural features of chimeric transcription factors. In this report, we show structural alterations of HRX by conventional Southern blot analyses in 26 of 27 de novo leukemias with cytogenetically diverse 11q23 abnormalities. The sole case that lacked HRX rearrangements was a t(11;17)-acute myeloid leukemia with French-American-British M3-like morphology. We also analyzed 10 secondary leukemias that arose after therapy with topoisomerase II inhibitors and found HRX rearrangements in 7 of 7 with 11q23 translocations, and in 2 of 2 with unsuccessful karyotypes. In total, we observed HRX rearrangements in 35 leukemias involving at least nine distinct donor loci (1q32, 4q21, 6q27, 7p15, 9p21–24, 15q15, 16p13, and two 19p13 sites). All breakpoints localized to an 8-kb region that encompassed exons 5–11 of HRX, suggesting that fusion proteins containing similar portions of HRX may be consistently created in leukemias with 11q23 abnormalities. We conclude that alteration of HRX is a recurrent pathogenetic event in leukemias with 11q23 aberrations involving many potential partners in a variety of settings including acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia in blast crisis, and topoisomerase II inhibitor- induced secondary leukemias of both the myeloid and lymphoid lineages.

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SETDB1 mediated histone H3 lysine 9 methylation suppresses MLL-fusion target expression and leukemic transformation

Haematologica ◽

10.3324/haematol.2019.223883 ◽

2019 ◽

Vol 105 (9) ◽

pp. 2273-2285 ◽

Cited By ~ 4

Author(s):

James Ropa ◽

Nirmalya Saha ◽

Hsiangyu Hu ◽

Luke F. Peterson ◽

Moshe Talpaz ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Target Genes ◽

Critical Role ◽

High Expression ◽

Leukemia Cells ◽

Biological Impact ◽

Hematopoietic Stem ◽

Acute Myeloid

Epigenetic regulators play a critical role in normal and malignant hematopoiesis. Deregulation, including epigenetic deregulation, of the HOXA gene cluster drives transformation of about 50% of acute myeloid leukemia. We recently showed that the Histone 3 Lysine 9 methyltransferase SETDB1 negatively regulates the expression of the pro-leukemic genes Hoxa9 and its cofactor Meis1 through deposition of promoter H3K9 trimethylation in MLL-AF9 leukemia cells. Here, we investigated the biological impact of altered SETDB1 expression and changes in H3K9 methylation on acute myeloid leukemia. We demonstrate that SETDB1 expression is correlated to disease status and overall survival in acute myeloid leukemia patients. We recapitulated these findings in mice, where high expression of SETDB1 delayed MLL-AF9 mediated disease progression by promoting differentiation of leukemia cells. We also explored the biological impact of treating normal and malignant hematopoietic cells with an H3K9 methyltransferase inhibitor, UNC0638. While myeloid leukemia cells demonstrate cytotoxicity to UNC0638 treatment, normal bone marrow cells exhibit an expansion of cKit+ hematopoietic stem and progenitor cells. Consistent with these data, we show that bone marrow treated with UNC0638 is more amenable to transformation by MLL-AF9. Next generation sequencing of leukemia cells shows that high expression of SETDB1 induces repressive changes to the promoter epigenome and downregulation of genes linked with acute myeloid leukemia, including Dock1 and the MLL-AF9 target genes Hoxa9, Six1, and others. These data reveal novel targets of SETDB1 in leukemia that point to a role for SETDB1 in negatively regulating pro-leukemic target genes and suppressing acute myeloid leukemia.

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Distinct association of RUNX family expression with genetic alterations and clinical outcome in acute myeloid leukemia

Cancer Biomarkers ◽

10.3233/cbm-200016 ◽

2020 ◽

Vol 29 (3) ◽

pp. 387-397

Author(s):

Yangli Zhao ◽

Tingjuan Zhang ◽

Yangjing Zhao ◽

Jingdong Zhou

Keyword(s):

Acute Myeloid Leukemia ◽

Clinical Outcome ◽

Myeloid Leukemia ◽

Disease Free Survival ◽

Genetic Alterations ◽

Differentially Expressed ◽

Aberrant Expression ◽

Hematopoietic Stem ◽

Frequent Event ◽

Acute Myeloid

BACKGROUND: The runt-related transcription factor family (RUNXs) including RUNX1, RUNX2, and RUNX3 are key transcriptional regulators in normal hematopoiesis. RUNXs dysregulations caused by aberrant expression or mutation are frequently seen in various human cancers especially in acute myeloid leukemia (AML). OBJECTIVE: We systemically analyzed the expression of RUNXs and their relationship with clinic-pathological features and prognosis in AML patients. METHODS: Expression of RUNXs was analyzed between AML patients and normal controls from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) projects. Correlations between RUNXs expression and clinical features together with survival were further analyzed. RESULTS: All RUNXs expression in AML patients was significantly increased as compared with controls. RUNXs expression was found to be significantly associated with genetic abnormalities such as RUNX1 mutation, t(8;21) and inv(16)/t(16;16). By Kaplan-Meier analysis, only RUNX3 overexpression was associated with shorter overall survival (OS) and disease-free survival (DFS) among non-M3 AML patients. Notably, in high RUNX3 expression groups, patients received hematopoietic stem cell transplantation (HSCT) had markedly better OS and DFS than patients without HSCT among both all AML and non-M3 AML. In low RUNX3 expression groups, there were no significant differences in OS and DFS between HSCT and non-HSCT groups among both all AML and non-M3 AML. In addition, a total of 835 differentially expressed genes and 69 differentially expressed microRNAs were identified to be correlated with RUNX3 expression in AML. CONCLUSION: RUNXs overexpression was a frequent event in AML, and was closely associated with diverse genetic alterations. Moreover, RUNX3 expression may be associated with clinical outcome, and helpful for guiding treatment choice between HSCT and chemotherapy in AML.

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A novel nutritional index “simplified CONUT” and the disease risk index independently stratify prognosis of elderly patients with acute myeloid leukemia

Scientific Reports ◽

10.1038/s41598-020-76250-8 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Hajime Senjo ◽

Masahiro Onozawa ◽

Daisuke Hidaka ◽

Shota Yokoyama ◽

Satoshi Yamamoto ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Nutritional Status ◽

Risk Stratification ◽

Elderly Patients ◽

Myeloid Leukemia ◽

The Elderly ◽

Genetic Alterations ◽

Newly Diagnosed ◽

Hematopoietic Stem ◽

Acute Myeloid

Abstract Elderly patients aged 65 or older with acute myeloid leukemia (AML) have poor prognosis. The risk stratification based on genetic alteration has been proposed in national comprehensive cancer network (NCCN) guideline but its efficacy was not well verified especially in real world elderly patients. The nutritional status assessment using controlling nutritional status (CONUT) score is a prognostic biomarker in elderly patients with solid tumors but was not examined in elderly AML patients. We performed prospective analysis of genetic alterations of 174 patients aged 65 or older with newly diagnosed AML treated without hematopoietic stem cell transplantation (HSCT) and developed simplified CONUT (sCONUT) score by eliminating total lymphocyte count from the items to adapt AML patients. In this cohort, both the NCCN 2017 risk group and sCONUT score successfully stratified the overall survival (OS) of the elderly patients. A multivariable analysis demonstrated that adverse group in NCCN 2017 and high sCONUT score were independently associated with poor 2-year OS. Both risk stratification based on NCCN 2017 and sCONUT score predict prognosis in the elderly patients with newly diagnosed AML.

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Fine-tuning patient-derived xenograft models for precision medicine approaches in leukemia

Journal of Investigative Medicine ◽

10.1136/jim-2016-000076 ◽

2016 ◽

Vol 64 (3) ◽

pp. 740-744 ◽

Cited By ~ 8

Author(s):

Olivia L Francis ◽

Terry-Ann M Milford ◽

Cornelia Beldiman ◽

Kimberly J Payne

Keyword(s):

Precision Medicine ◽

Lymphoblastic Leukemia ◽

Genetic Alterations ◽

Fine Tuning ◽

Leukemia Cells ◽

Human Leukemia ◽

Preclinical Models ◽

Species Activity ◽

Pdx Models

Many leukemias are characterized by well-known mutations that drive oncogenesis. Mice engineered with these mutations provide a foundation for understanding leukemogenesis and identifying therapies. However, data from whole genome studies provide evidence that malignancies are characterized by multiple genetic alterations that vary between patients, as well as inherited genetic variation that can also contribute to oncogenesis. Improved outcomes will require precision medicine approaches–targeted therapies tailored to malignancies in each patient. Preclinical models that reflect the range of mutations and the genetic background present in patient populations are required to develop and test the combinations of therapies that will be used to provide precision medicine therapeutic strategies. Patient-derived xenografts (PDX) produced by transplanting leukemia cells from patients into immune deficient mice provide preclinical models where disease mechanisms and therapeutic efficacy can be studied in vivo in context of the genetic variability present in patient tumors. PDX models are possible because many elements in the bone marrow microenvironment show cross-species activity between mice and humans. However, several cytokines likely to impact leukemia cells are species-specific with limited activity on transplanted human leukemia cells. In this review we discuss the importance of PDX models for developing precision medicine approaches to leukemia treatment. We illustrate how PDX models can be optimized to overcome a lack of cross-species cytokine activity by reviewing a recent strategy developed for use with a high-risk form of B-cell acute lymphoblastic leukemia (B-ALL) that is characterized by overexpression of CRLF2, a receptor component for the cytokine, TSLP.

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