scholarly journals WDR26 and MTF2 are therapeutic targets in multiple myeloma

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Fumou Sun ◽  
Yan Cheng ◽  
Jesse D. Riordan ◽  
Adam Dupuy ◽  
Wendy Dubois ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cell ◽  
Insertional Mutagenesis ◽  
Leukemia Virus ◽  
Genetically Engineered ◽  
Cancer Genes ◽  
Phd Finger ◽  
Treatment And Prevention ◽  
Genetically Engineered Mouse Model ◽  
Human Multiple Myeloma

AbstractUnbiased genetic forward screening using retroviral insertional mutagenesis in a genetically engineered mouse model of human multiple myeloma may further our understanding of the genetic pathways that govern neoplastic plasma cell development. To evaluate this hypothesis, we performed a tumor induction study in MYC-transgenic mice infected as neonates with the Moloney-derived murine leukemia virus, MOL4070LTR. Next-generation DNA sequencing of proviral genomic integration sites yielded rank-ordered candidate tumor progression genes that accelerated plasma cell neoplasia in mice. Rigorous clinical and biological validation of these genes led to the discovery of two novel myeloma genes: WDR26 (WD repeat-containing protein 26) and MTF2 (metal response element binding transcription factor 2). WDR26, a core component of the carboxy-terminal to LisH (CTLH) complex, is overexpressed or mutated in solid cancers. MTF2, an ancillary subunit of the polycomb repressive complex 2 (PRC2), is a close functional relative of PHD finger protein 19 (PHF19) which is currently emerging as an important driver of myeloma. These findings underline the utility of genetic forward screens in mice for uncovering novel blood cancer genes and suggest that WDR26-CTLH and MTF2-PRC2 are promising molecular targets for new approaches to myeloma treatment and prevention.

scholarly journals Laboratory Mice – A Driving Force in Immunopathology and Immunotherapy Studies of Human Multiple Myeloma

2021 ◽  
Vol 12 ◽  
Author(s):  
Michael Pisano ◽  
Yan Cheng ◽  
Fumou Sun ◽  
Binod Dhakal ◽  
Anita D’Souza ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Mouse Models ◽  
Plasma Cell ◽  
Plasma Cells ◽  
De Novo ◽  
Human Cancer ◽  
Tumor Development ◽  
Adaptive Immune Response ◽  
Genetically Engineered

Mouse models of human cancer provide an important research tool for elucidating the natural history of neoplastic growth and developing new treatment and prevention approaches. This is particularly true for multiple myeloma (MM), a common and largely incurable neoplasm of post-germinal center, immunoglobulin-producing B lymphocytes, called plasma cells, that reside in the hematopoietic bone marrow (BM) and cause osteolytic lesions and kidney failure among other forms of end-organ damage. The most widely used mouse models used to aid drug and immunotherapy development rely on in vivo propagation of human myeloma cells in immunodeficient hosts (xenografting) or myeloma-like mouse plasma cells in immunocompetent hosts (autografting). Both strategies have made and continue to make valuable contributions to preclinical myeloma, including immune research, yet are ill-suited for studies on tumor development (oncogenesis). Genetically engineered mouse models (GEMMs), such as the widely known Vκ*MYC, may overcome this shortcoming because plasma cell tumors (PCTs) develop de novo (spontaneously) in a highly predictable fashion and accurately recapitulate many hallmarks of human myeloma. Moreover, PCTs arise in an intact organism able to mount a complete innate and adaptive immune response and tumor development reproduces the natural course of human myelomagenesis, beginning with monoclonal gammopathy of undetermined significance (MGUS), progressing to smoldering myeloma (SMM), and eventually transitioning to frank neoplasia. Here we review the utility of transplantation-based and transgenic mouse models of human MM for research on immunopathology and -therapy of plasma cell malignancies, discuss strengths and weaknesses of different experimental approaches, and outline opportunities for closing knowledge gaps, improving the outcome of patients with myeloma, and working towards a cure.

scholarly journals Elimination of clonogenic stem cells from human multiple myeloma cell lines by a plasma cell-reactive monoclonal antibody and complement

Blood ◽  
1987 ◽  
Vol 70 (5) ◽  
pp. 1482-1489 ◽  
Author(s):  
AW Tong ◽  
JC Lee ◽  
JW Fay ◽  
MJ Stone
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Monoclonal Antibody ◽  
Bone Marrow ◽  
Cell Lines ◽  
Plasma Cell ◽  
Colony Formation ◽  
Human Multiple Myeloma ◽  
Rpmi 8226 ◽  
Marrow Cells

Abstract The monoclonal antibody (MoAb) MM4 reacts with human multiple myeloma (MM) cell lines and bone marrow from patients with plasma cell dyscrasias but not with normal peripheral blood or bone marrow cells. Treatment with MM4 and rabbit complement (C') was cytotoxic to the plasma cell-derived cell lines GM 1312, RPMI 8226, and ARH-77, as demonstrated by chromium release microcytotoxicity and trypan blue exclusion assays. The same treatment eliminated greater than 99% of clonogenic myeloma stem cell colony formation of these cell lines, with less than 20% inhibition of normal human bone marrow pleuripotent progenitor colony formation in vitro. As an experimental model to explore the efficacy of MM4 + C' in purging MM-involved bone marrow, normal marrow cells were mixed with RPMI 8226 or GM 1312 cells in the ratio of 90:10 or 50:50 (marrow:myeloma cells). Colony growth assays indicated that MM4 + C' eliminated at least 2 logs of clonogenic myeloma stem cells in both 90:10 and 50:50 preparations, while sparing the majority of normal marrow progenitors (inhibition of CFU-C:10% to 13%; BFU-E:0%). The selectivity of MM4-mediated cytotoxicity may be useful for eliminating myeloma clonogenic stem cells from bone marrow of patients with multiple myeloma.

A Trangenic Mouse Model of Plasma Cell Malignancy Shows Cytogenetic and Gene Expression Profiles Similar to Human Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 619-619
Author(s):  
Kristin Boylan ◽  
Mary A. Kvitrud ◽  
Brian G. Van Ness
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Chromosomal Abnormalities ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Rt Pcr ◽  
Mouse Tumors ◽  
Human Multiple Myeloma

Abstract Multiple myeloma is an incurable plasma cell malignancy for which existing animal models are limited. Human plasma cell tumors are genetically diverse, with no single chromosomal abnormality defining the disease, however, dysregulation of the genes c-myc and bcl-xl are both commonly observed. We have previously shown that targeted expression of c-myc and bcl-xl transgenes in mouse plasma cells produces malignancy which displays features of human myeloma such as localization of tumor cells to the bone marrow and lytic bone lesions. Tumors are also present at extramedullary sites (Cheung et al., J. Clin. Invest.113: 1763, 2004). Tumors rapidly develop (median 16 weeks) in 100% of mice, and can be adoptively transferred to syngeneic controls using as few as 1 million tumor cells to produce tumors in as few as 10 days. Adoptive transfer of similar cell numbers from younger double transgenic mice, without evidence of malignancy, results in increased tumor latency (>8 weeks) or the absence of tumor formation, suggesting that an accumulation of genetic changes is required for tumor development. In order to understand the specific genetic alterations required for tumor progression and for localization of tumors to the bone marrow vs extramedullary sites, we have undertaken a detailed analysis of plasma cell tumors in myc/bcl-xl mice and have begun to compare them with human multiple myeloma. Analysis of cell surface markers shows the majority of tumors have a plasmablast phenotype, expressing CD138+, B220+, CD38+, and CD19+. This result is confirmed by RT-PCR for B cell and plasma cell specific markers Pax5, Xbp1 and Blimp1, which can be detected in tumor samples. In addition, transcripts for Mip1α, EZH2, and Dusp6, genes shown to be upregulated in human myeloma, can also be detected in the mouse myc/bcl-xl tumors. Spectral karyotype analysis of metaphase chromosomes from primary tumor cell cultures demonstrates that a variety of chromosomal abnormalities are present in mouse tumors, including trisomies and translocations, similar to what is observed in human myeloma. The most frequently aberrant chromosomes are 12 and 16, followed by chromosomes 1 and 4. Interestingly, two common sites for translocations were identified; 12F which corresponds to the mouse immunoglobulin heavy chain locus, and 4D, which corresponds to a genomic region containing genes for plasma cell tumor susceptibility (Bliskovsky et al., PNAS100:14982, 2003). Further characterization of these translocations are being done to identify the precise breakpoints involved, and analysis of gene expression by RT-PCR and microarray analysis will be correlated to specific chromosomal abnormalities. Additionally, global gene expression profiles from myc/bcl-xl tumor cell cultures have been compared to existing profiles of human myeloma (Zhan et al., Blood99: 1745, 2002). Our preliminary comparison of gene expression profiles from myc/bcl-xl tumors to human myeloma tumors with high myc expression show the mouse tumors are more similar to human tumors than to normal plasma cells. These data suggest the myc/bcl-xl mouse tumors are similar to a subset of human myelomas, and will provide insight into the specific genes and pathways underlying human disease.

scholarly journals Drug response in a genetically engineered mouse model of multiple myeloma is predictive of clinical efficacy

Blood ◽  
2012 ◽  
Vol 120 (2) ◽  
pp. 376-385 ◽  
Author(s):  
Marta Chesi ◽  
Geoffrey M. Matthews ◽  
Victoria M. Garbitt ◽  
Stephen E. Palmer ◽  
Jake Shortt ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Predictive Value ◽  
Histone Deacetylase Inhibitors ◽  
Single Agent ◽  
Genetically Engineered ◽  
Attrition Rate ◽  
Clinical Activity ◽  
Genetically Engineered Mouse Model ◽  
End Stage

Abstract The attrition rate for anticancer drugs entering clinical trials is unacceptably high. For multiple myeloma (MM), we postulate that this is because of preclinical models that overemphasize the antiproliferative activity of drugs, and clinical trials performed in refractory end-stage patients. We validate the Vk*MYC transgenic mouse as a faithful model to predict single-agent drug activity in MM with a positive predictive value of 67% (4 of 6) for clinical activity, and a negative predictive value of 86% (6 of 7) for clinical inactivity. We identify 4 novel agents that should be prioritized for evaluation in clinical trials. Transplantation of Vk*MYC tumor cells into congenic mice selected for a more aggressive disease that models end-stage drug-resistant MM and responds only to combinations of drugs with single-agent activity in untreated Vk*MYC MM. We predict that combinations of standard agents, histone deacetylase inhibitors, bromodomain inhibitors, and hypoxia-activated prodrugs will demonstrate efficacy in the treatment of relapsed MM.

The Mutational Profile of Plasma Cell Disorders

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. SCI-14-SCI-14
Author(s):  
Andy Futreal
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cell ◽  
Conflicts Of Interest ◽  
Massively Parallel Sequencing ◽  
Prognostic Significance ◽  
Mapk Signaling ◽  
Good Prognosis ◽  
Cancer Genes ◽  
Hematologic Cancer ◽  
Genomic Complexity

Abstract Multiple myeloma is a plasma cell malignancy that is the second most common hematologic cancer. The genetics of the disease have been previously characterized by two major subtypes involving recurrent translocations of the immunoglobulin heavy chain, c-MAF, cyclin D (CCND1) and FGFR3/MMSET oncogenes, and the hyperdiploid group with multiple recurrent trisomies. Further, there are characterized cytogenetic/ploidy subsets that appear to carry prognostic significance. Specifically, gains of chromosomes 5, 9, 11, 15, and 19 confer a good prognosis whilst gain of 1q plus deletions of 1p, 12p, 14q, 16q, and 22q confer a poor prognosis. More recently the application of massively parallel sequencing has revealed further insights into the genetic architecture of multiple myeloma. Work from several groups has identified the contribution of mutations in genes involved in non-canonical NF-kB signaling, MAPK signaling and histone methylation, as well as infrequent mutation of cancer genes implicated in other tumor types and novel genes. These data will be presented to give an overall update on the current state of multiple myeloma genetics and our current level of insight in the genomic complexity that characterizes this disease. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Anti-CD40 antibody binding modulates human multiple myeloma clonogenicity in vitro

Blood ◽  
1994 ◽  
Vol 84 (9) ◽  
pp. 3026-3033 ◽  
Author(s):  
AW Tong ◽  
BQ Zhang ◽  
G Mues ◽  
M Solano ◽  
T Hanson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cell ◽  
Cell Lineage ◽  
Myeloma Cell ◽  
Plasma Cell Dyscrasia ◽  
Primary Amyloidosis ◽  
Human B Cells ◽  
Human Multiple Myeloma ◽  
Rpmi 8226

Abstract Ligand binding of the B-cell lineage antigen CD40 enhances growth and interleukin-6 (IL-6) secretion in human B cells (the CD40/IL-6 loop). IL-6 has an autocrine and paracrine role in human multiple myeloma (MM) cell growth. With the use of the CD40 monoclonal antibody (MoAb) G28–5, we examined CD40 expression and the effect of CD40 binding on MM clonogenic colony (MCC) formation to characterize the IL-6/CD40 loop activity in MM. CD40 was expressed on plasmacytoid cells in 21 of 28 plasma cell dyscrasia (PCD) bone marrow (BM) biopsies tested (10 of 14 MM, 2 of 2 Waldenstrom's macroglobulinemia [WM], 2 of 2 plasma cell leukemia [PCL], 6 of 8 monoclonal gammopathy of undetermined significance [MGUS], and 1 of 2 primary amyloidosis [AL]). G28–5 binding increased MCCs by 35% to 150% in 11 of 17 CD40+ PCD BM cultures, but did not affect MCC formation in CD40- specimens or normal BM colony forming units (CFU-GEMM, CFU-GM, BFU-E). Responsive cultures originated from BM of patients with MM (2 of 5 cases tested), WM (2 of 2), PCL (2 of 2), and MGUS (5 of 6). CD40-responsiveness was not significantly inhibited by the presence of an anti-IL-6 MoAb (2 of 2 MGUS cultures tested), and did not correlate with the capacity to respond to IL-6 stimulation (n = 17, P > .05) or a detectable level of endogenous IL-6 (n = 15, P > .05). Additional studies were performed with PCD cell lines to characterize the interrelationship of CD40 activation and IL-6 production. Fifty percent to greater than 95% of cells from the RPMI 8226 and ARH77 lines expressed CD40, whereas 6% of U266 cells were CD40+. For RPMI 8226, ARH-77, and U266 cells, the increased MCC formation after anti-CD40 stimulation was not affected by the presence of an anti-IL-6 neutralizing MoAb and was not accompanied by detectable IL-6 secretion. There was no apparent increase in IL-6 mRNA transcription following G28–5 treatment of U266 or RPMI 8226 cells. Our observations indicate that CD40 is expressed in a subset of human myeloma cells present in various PCDs. Cell-line studies suggest that the CD40+ myeloma cell may regulate MM clonogenic colony formation without activating the IL-6 pathway.

scholarly journals Disrupting Ectopic Super-Enhancers to Treat Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1593-1593
Author(s):  
Seth Welsh ◽  
Daniel Riggs ◽  
Erin Meermeier ◽  
Chang-Xin Shi ◽  
Victoria Garbitt ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Transcription Factor ◽  
Mouse Model ◽  
Therapeutic Response ◽  
Genetically Engineered ◽  
Therapeutic Window ◽  
Super Enhancer ◽  
Genetically Engineered Mouse Model

Abstract Multiple myeloma (MM) is an incurable form of plasma cell cancer in which primary and secondary chromosomal translocations routinely juxtapose oncogenes to plasma cell-specific super-enhancers. Coincidentally, drugs which target super-enhancers have had success clinically. For example, immunomodulatory imide drugs (IMiDs) degrade super-enhancer-binding pioneer factors IKAROS and AIOLOS, while glucocorticoids (Dexamethasone) and proteasome inhibitors (Bortezomib) have the ability to transrepress or block the processing of super-enhancer-forming NF-κB proteins, respectively. Currently, alternative enhancer-targeting drugs are also in clinical development, like p300 inhibitors which target the acetyl-binding bromodomains and/or histone acetyl transferase activity of the chromatin-regulating coactivator homologs CBP and EP300. Despite showing therapeutic promise, our understanding of how these drugs function, alone or together, remains incomplete. Case in point, we find that IMiD-induced degradation of its target proteins IKAROS and AIOLOS does not guarantee a therapeutic response in vitro, and patients successfully treated with IMiDs eventually relapse; meanwhile, coactivator-targeting therapies like p300 inhibitors are often too toxic in vivo, and lack a therapeutic window. To improve the outcomes of MM patients we need to understand the heterogeneous genetics and transcription-factor milieus of the myeloma enhancer landscape, as well as how to increase the precision of enhancer-disrupting drugs. To accomplish this, our lab utilizes more than 60 human myeloma cell lines that have been extensively characterized at the genetic, proteomic, and drug-therapeutic-response levels. Additionally, we have generated a highly-predictive immunocompetent mouse model (Vk*MYC hCRBN+) that develops human-like MM and is sensitive to both IMiDs and a new class of therapeutics termed "degronimids" (normal mice do not respond to IMiDs or degronimids). Our central hypothesis is that combining a broad coactivator-targeting drug (e.g., the p300 inhibitor GNE-781), with a MM-specific transcription factor-targeting drug (e.g., IMiDs) restricts toxicities to myeloma cells and thus improves the therapeutic window. Currently, we are testing a variety of coactivator-targeting compounds alongside traditional IMiD therapies and other preclinical transcription factor-targeting drugs both in vivo and in vitro. We show that Vk*MYC hCRBN+ mice are exquisitely sensitive to GNE-781, requiring one fourth of the dose needed to treat other cancers and therefore avoiding the neutropenia and thrombocytopenia seen at higher doses. Second, we show that although IMiDs and GNE-781 induce an effective but transient response in vivo as single agents, the combination of the two drugs proved curative, with a progressive deepening of the anti-tumor response occurring even after therapy is discontinued. Ongoing experiments aim to determine how this drug combination, and other coactivator + transcription factor-targeting combinations, permanently disrupt myeloma-specific super-enhancers. Disclosures Neri: BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Bahlis: Sanofi: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genentech: Consultancy. Boise: AstraZeneca: Honoraria, Research Funding; AbbVie/Genentech: Membership on an entity's Board of Directors or advisory committees. Chesi: Abcuro: Patents & Royalties: Genetically engineered mouse model of myeloma; Pi Therapeutics: Patents & Royalties: Genetically engineered mouse model of myeloma; Pfizer: Consultancy; Novartis: Consultancy, Patents & Royalties: human CRBN transgenic mouse; Palleon Pharmaceuticals: Patents & Royalties: Genetically engineered mouse model of myeloma.

scholarly journals Elimination of clonogenic stem cells from human multiple myeloma cell lines by a plasma cell-reactive monoclonal antibody and complement

Blood ◽  
1987 ◽  
Vol 70 (5) ◽  
pp. 1482-1489
Author(s):  
AW Tong ◽  
JC Lee ◽  
JW Fay ◽  
MJ Stone
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Monoclonal Antibody ◽  
Bone Marrow ◽  
Cell Lines ◽  
Plasma Cell ◽  
Colony Formation ◽  
Human Multiple Myeloma ◽  
Rpmi 8226 ◽  
Marrow Cells

The monoclonal antibody (MoAb) MM4 reacts with human multiple myeloma (MM) cell lines and bone marrow from patients with plasma cell dyscrasias but not with normal peripheral blood or bone marrow cells. Treatment with MM4 and rabbit complement (C') was cytotoxic to the plasma cell-derived cell lines GM 1312, RPMI 8226, and ARH-77, as demonstrated by chromium release microcytotoxicity and trypan blue exclusion assays. The same treatment eliminated greater than 99% of clonogenic myeloma stem cell colony formation of these cell lines, with less than 20% inhibition of normal human bone marrow pleuripotent progenitor colony formation in vitro. As an experimental model to explore the efficacy of MM4 + C' in purging MM-involved bone marrow, normal marrow cells were mixed with RPMI 8226 or GM 1312 cells in the ratio of 90:10 or 50:50 (marrow:myeloma cells). Colony growth assays indicated that MM4 + C' eliminated at least 2 logs of clonogenic myeloma stem cells in both 90:10 and 50:50 preparations, while sparing the majority of normal marrow progenitors (inhibition of CFU-C:10% to 13%; BFU-E:0%). The selectivity of MM4-mediated cytotoxicity may be useful for eliminating myeloma clonogenic stem cells from bone marrow of patients with multiple myeloma.

scholarly journals Clonal competition with alternating dominance in multiple myeloma

Blood ◽  
2012 ◽  
Vol 120 (5) ◽  
pp. 1067-1076 ◽  
Author(s):  
Jonathan J. Keats ◽  
Marta Chesi ◽  
Jan B. Egan ◽  
Victoria M. Garbitt ◽  
Stephen E. Palmer ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
High Risk Patient ◽  
Genomic Analysis ◽  
Genetically Engineered ◽  
Disease Course ◽  
Genetically Engineered Mouse Model ◽  
Risk Patients ◽  
Changes Over Time ◽  
Over Time

Abstract Emerging evidence indicates that tumors can follow several evolutionary paths over a patient's disease course. With the use of serial genomic analysis of samples collected at different points during the disease course of 28 patients with multiple myeloma, we found that the genomes of standard-risk patients show few changes over time, whereas those of cytogenetically high-risk patients show significantly more changes over time. The results indicate the existence of 3 temporal tumor types, which can either be genetically stable, linearly evolving, or heterogeneous clonal mixtures with shifting predominant clones. A detailed analysis of one high-risk patient sampled at 7 time points over the entire disease course identified 2 competing subclones that alternate in a back and forth manner for dominance with therapy until one clone underwent a dramatic linear evolution. With the use of the Vk*MYC genetically engineered mouse model of myeloma we modeled this competition between subclones for predominance occurring spontaneously and with therapeutic selection.

scholarly journals An insertional mutagenesis screen identifies genes that cooperate with Mll-AF9 in a murine leukemogenesis model

Blood ◽  
2012 ◽  
Vol 119 (19) ◽  
pp. 4512-4523 ◽  
Author(s):  
Rachel J. Bergerson ◽  
Lara S. Collier ◽  
Aaron L. Sarver ◽  
Raha A. Been ◽  
Sanne Lugthart ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Insertional Mutagenesis ◽  
Leukemia Virus ◽  
Cancer Genes ◽  
Lymphoid Leukemia ◽  
Long Latency ◽  
Elevated Expression ◽  
Murine Leukemia

Abstract Patients with a t(9;11) translocation (MLL-AF9) develop acute myeloid leukemia (AML), and while in mice the expression of this fusion oncogene also results in the development of myeloid leukemia, it is with long latency. To identify mutations that cooperate with Mll-AF9, we infected neonatal wild-type (WT) or Mll-AF9 mice with a murine leukemia virus (MuLV). MuLV-infected Mll-AF9 mice succumbed to disease significantly faster than controls presenting predominantly with myeloid leukemia while infected WT animals developed predominantly lymphoid leukemia. We identified 88 candidate cancer genes near common sites of proviral insertion. Analysis of transcript levels revealed significantly elevated expression of Mn1, and a trend toward increased expression of Bcl11a and Fosb in Mll-AF9 murine leukemia samples with proviral insertions proximal to these genes. Accordingly, FOSB and BCL11A were also overexpressed in human AML harboring MLL gene translocations. FOSB was revealed to be essential for growth in mouse and human myeloid leukemia cells using shRNA lentiviral vectors in vitro. Importantly, MN1 cooperated with Mll-AF9 in leukemogenesis in an in vivo BM viral transduction and transplantation assay. Together, our data identified genes that define transcription factor networks and important genetic pathways acting during progression of leukemia induced by MLL fusion oncogenes.

Sign in / Sign up

Export Citation Format

Share Document