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Dive into the research topics where Seyedmehdi Shojaee is active.

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Featured researches published by Seyedmehdi Shojaee.


Nature | 2011

BCL6 enables Ph + acute lymphoblastic leukaemia cells to survive BCR–ABL1 kinase inhibition

Cihangir Duy; Christian Hurtz; Seyedmehdi Shojaee; Leandro Cerchietti; Huimin Geng; Srividya Swaminathan; Lars Klemm; Soo-Mi Kweon; Rahul Nahar; Melanie Braig; Eugene Park; Yong-Mi Kim; Wolf-Karsten Hofmann; Sebastian Herzog; Hassan Jumaa; H. Phillip Koeffler; J. Jessica Yu; Nora Heisterkamp; Thomas G. Graeber; Hong L Wu; B. Hilda Ye; Ari Melnick; Markus Müschen

Tyrosine kinase inhibitors (TKIs) are widely used to treat patients with leukaemia driven by BCR–ABL1 (ref. 1) and other oncogenic tyrosine kinases. Recent efforts have focused on developing more potent TKIs that also inhibit mutant tyrosine kinases. However, even effective TKIs typically fail to eradicate leukaemia-initiating cells (LICs), which often cause recurrence of leukaemia after initially successful treatment. Here we report the discovery of a novel mechanism of drug resistance, which is based on protective feedback signalling of leukaemia cells in response to treatment with TKI. We identify BCL6 as a central component of this drug-resistance pathway and demonstrate that targeted inhibition of BCL6 leads to eradication of drug-resistant and leukaemia-initiating subclones.


Journal of Experimental Medicine | 2010

BCL6 is critical for the development of a diverse primary B cell repertoire

Cihangir Duy; J. Jessica Yu; Rahul Nahar; Srividya Swaminathan; Soo Mi Kweon; Jose M. Polo; Ester Valls; Lars Klemm; Seyedmehdi Shojaee; Leandro Cerchietti; Wolfgang Schuh; Hans-Martin Jäck; Christian Hurtz; Parham Ramezani-Rad; Sebastian Herzog; Hassan Jumaa; H. Phillip Koeffler; Ignacio Moreno de Alborán; Ari Melnick; B. Hilda Ye; Markus Müschen

BCL6 protects germinal center (GC) B cells against DNA damage–induced apoptosis during somatic hypermutation and class-switch recombination. Although expression of BCL6 was not found in early IL-7–dependent B cell precursors, we report that IL-7Rα–Stat5 signaling negatively regulates BCL6. Upon productive VH-DJH gene rearrangement and expression of a μ heavy chain, however, activation of pre–B cell receptor signaling strongly induces BCL6 expression, whereas IL-7Rα–Stat5 signaling is attenuated. At the transition from IL-7–dependent to –independent stages of B cell development, BCL6 is activated, reaches expression levels resembling those in GC B cells, and protects pre–B cells from DNA damage–induced apoptosis during immunoglobulin (Ig) light chain gene recombination. In the absence of BCL6, DNA breaks during Ig light chain gene rearrangement lead to excessive up-regulation of Arf and p53. As a consequence, the pool of new bone marrow immature B cells is markedly reduced in size and clonal diversity. We conclude that negative regulation of Arf by BCL6 is required for pre–B cell self-renewal and the formation of a diverse polyclonal B cell repertoire.


Nature | 2015

Signalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia.

Zhengshan Chen; Seyedmehdi Shojaee; Maike Buchner; Huimin Geng; Jae-Woong Lee; Lars Klemm; Björn Titz; Thomas G. Graeber; Eugene Park; Ying Xim Tan; Anne B. Satterthwaite; Elisabeth Paietta; Stephen P. Hunger; Cheryl L. Willman; Ari Melnick; Mignon L. Loh; Jae U. Jung; John E. Coligan; Silvia Bolland; Tak W. Mak; Andre Limnander; Hassan Jumaa; Michael Reth; Arthur Weiss; Clifford A. Lowell; Markus Müschen

B cells are selected for an intermediate level of B-cell antigen receptor (BCR) signalling strength: attenuation below minimum (for example, non-functional BCR) or hyperactivation above maximum (for example, self-reactive BCR) thresholds of signalling strength causes negative selection. In ∼25% of cases, acute lymphoblastic leukaemia (ALL) cells carry the oncogenic BCR-ABL1 tyrosine kinase (Philadelphia chromosome positive), which mimics constitutively active pre-BCR signalling. Current therapeutic approaches are largely focused on the development of more potent tyrosine kinase inhibitors to suppress oncogenic signalling below a minimum threshold for survival. We tested the hypothesis that targeted hyperactivation—above a maximum threshold—will engage a deletional checkpoint for removal of self-reactive B cells and selectively kill ALL cells. Here we find, by testing various components of proximal pre-BCR signalling in mouse BCR–ABL1 cells, that an incremental increase of Syk tyrosine kinase activity was required and sufficient to induce cell death. Hyperactive Syk was functionally equivalent to acute activation of a self-reactive BCR on ALL cells. Despite oncogenic transformation, this basic mechanism of negative selection was still functional in ALL cells. Unlike normal pre-B cells, patient-derived ALL cells express the inhibitory receptors PECAM1, CD300A and LAIR1 at high levels. Genetic studies revealed that Pecam1, Cd300a and Lair1 are critical to calibrate oncogenic signalling strength through recruitment of the inhibitory phosphatases Ptpn6 (ref. 7) and Inpp5d (ref. 8). Using a novel small-molecule inhibitor of INPP5D (also known as SHIP1), we demonstrated that pharmacological hyperactivation of SYK and engagement of negative B-cell selection represents a promising new strategy to overcome drug resistance in human ALL.


Blood | 2013

Integrin alpha4 blockade sensitizes drug resistant pre-B acute lymphoblastic leukemia to chemotherapy

Yao-Te Hsieh; EunJi Gang; Huimin Geng; Eugene Park; Sandra Huantes; Doreen Chudziak; Katrin Dauber; Schaefer P; Carlton Scharman; Hiroyuki Shimada; Seyedmehdi Shojaee; Lars Klemm; Reshmi Parameswaran; Mignon L. Loh; Eun Suk Kang; Hong Hoe Koo; Wolf-Karsten Hofmann; Andrade J; Crooks Gm; Cheryl L. Willman; Markus Müschen; T Papayannopoulou; Nora Heisterkamp; Halvard Bonig; Yong Mi Kim

Bone marrow (BM) provides chemoprotection for acute lymphoblastic leukemia (ALL) cells, contributing to lack of efficacy of current therapies. Integrin alpha4 (alpha4) mediates stromal adhesion of normal and malignant B-cell precursors, and according to gene expression analyses from 207 children with minimal residual disease, is highly associated with poorest outcome. We tested whether interference with alpha4-mediated stromal adhesion might be a new ALL treatment. Two models of leukemia were used, one genetic (conditional alpha4 ablation of BCR-ABL1 [p210(+)] leukemia) and one pharmacological (anti-functional alpha4 antibody treatment of primary ALL). Conditional deletion of alpha4 sensitized leukemia cell to nilotinib. Adhesion of primary pre-B ALL cells was alpha4-dependent; alpha4 blockade sensitized primary ALL cells toward chemotherapy. Chemotherapy combined with Natalizumab prolonged survival of NOD/SCID recipients of primary ALL, suggesting adjuvant alpha4 inhibition as a novel strategy for pre-B ALL.


Cancer Cell | 2015

Self-Enforcing Feedback Activation between BCL6 and Pre-B Cell Receptor Signaling Defines a Distinct Subtype of Acute Lymphoblastic Leukemia

Huimin Geng; Christian Hurtz; Kyle Lenz; Zhengshan Chen; Dirk Baumjohann; Sarah K. Thompson; Natalya A. Goloviznina; Wei Yi Chen; Jianya Huan; Dorian LaTocha; Erica Ballabio; Gang Xiao; Jae-Woong Lee; Anne Deucher; Zhongxia Qi; Eugene Park; Chuanxin Huang; Rahul Nahar; Soo Mi Kweon; Seyedmehdi Shojaee; Lai N. Chan; Jingwei Yu; Steven M. Kornblau; Janetta Jacoba Bijl; B. Hilda Ye; K. Mark Ansel; Elisabeth Paietta; Ari Melnick; Stephen P. Hunger; Peter Kurre

Studying 830 pre-B ALL cases from four clinical trials, we found that human ALL can be divided into two fundamentally distinct subtypes based on pre-BCR function. While absent in the majority of ALL cases, tonic pre-BCR signaling was found in 112 cases (13.5%). In these cases, tonic pre-BCR signaling induced activation of BCL6, which in turn increased pre-BCR signaling output at the transcriptional level. Interestingly, inhibition of pre-BCR-related tyrosine kinases reduced constitutive BCL6 expression and selectively killed patient-derived pre-BCR(+) ALL cells. These findings identify a genetically and phenotypically distinct subset of human ALL that critically depends on tonic pre-BCR signaling. In vivo treatment studies suggested that pre-BCR tyrosine kinase inhibitors are useful for the treatment of patients with pre-BCR(+) ALL.


Cancer Discovery | 2012

Integrative Epigenomic Analysis Identifies Biomarkers and Therapeutic Targets in Adult B-Acute Lymphoblastic Leukemia

Huimin Geng; Sarah Brennan; Thomas A. Milne; Wei Yi Chen; Yushan Li; Christian Hurtz; Soo Mi Kweon; Lynette Zickl; Seyedmehdi Shojaee; Donna Neuberg; Chuanxin Huang; Debabrata Biswas; Yuan Xin; Janis Racevskis; Rhett P. Ketterling; Selina M. Luger; Hillard M. Lazarus; Martin S. Tallman; Jacob M. Rowe; Mark R. Litzow; Monica L. Guzman; C. David Allis; Robert G. Roeder; Markus Müschen; Elisabeth Paietta; Olivier Elemento; Ari Melnick

UNLABELLED Genetic lesions such as BCR-ABL1, E2A-PBX1, and MLL rearrangements (MLLr) are associated with unfavorable outcomes in adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Leukemia oncoproteins may directly or indirectly disrupt cytosine methylation patterning to mediate the malignant phenotype. We postulated that DNA methylation signatures in these aggressive B-ALLs would point toward disease mechanisms and useful biomarkers and therapeutic targets. We therefore conducted DNA methylation and gene expression profiling on a cohort of 215 adult patients with B-ALL enrolled in a single phase III clinical trial (ECOG E2993) and normal control B cells. In BCR-ABL1-positive B-ALLs, aberrant cytosine methylation patterning centered around a cytokine network defined by hypomethylation and overexpression of IL2RA(CD25). The E2993 trial clinical data showed that CD25 expression was strongly associated with a poor outcome in patients with ALL regardless of BCR-ABL1 status, suggesting CD25 as a novel prognostic biomarker for risk stratification in B-ALLs. In E2A-PBX1-positive B-ALLs, aberrant DNA methylation patterning was strongly associated with direct fusion protein binding as shown by the E2A-PBX1 chromatin immunoprecipitation (ChIP) sequencing (ChIP-seq), suggesting that E2A-PBX1 fusion protein directly remodels the epigenome to impose an aggressive B-ALL phenotype. MLLr B-ALL featured prominent cytosine hypomethylation, which was linked with MLL fusion protein binding, H3K79 dimethylation, and transcriptional upregulation, affecting a set of known and newly identified MLL fusion direct targets with oncogenic activity such as FLT3 and BCL6. Notably, BCL6 blockade or loss of function suppressed proliferation and survival of MLLr leukemia cells, suggesting BCL6-targeted therapy as a new therapeutic strategy for MLLr B-ALLs. SIGNIFICANCE We conducted the first integrative epigenomic study in adult B-ALLs, as a correlative study to the ECOG E2993 phase III clinical trial. This study links for the first time the direct actions of oncogenic fusion proteins with disruption of epigenetic regulation mediated by cytosine methylation. We identify a novel clinically actionable biomarker in B-ALLs: IL2RA (CD25), which is linked with BCR-ABL1 and an inflammatory signaling network associated with chemotherapy resistance. We show that BCL6 is a novel MLL fusion protein target that is required to maintain the proliferation and survival of primary human adult MLLr cells and provide the basis for a clinical trial with BCL6 inhibitors for patients with MLLr.


Nature | 2017

Metabolic gatekeeper function of B-lymphoid transcription factors

Lai N. Chan; Zhengshan Chen; Daniel Braas; Jae-Woong Lee; Gang Xiao; Huimin Geng; Kadriye Nehir Cosgun; Christian Hurtz; Seyedmehdi Shojaee; Valeria Cazzaniga; Hilde Schjerven; Thomas Ernst; Andreas Hochhaus; Steven M. Kornblau; Marina Konopleva; Miles A. Pufall; Giovanni Cazzaniga; Grace J. Liu; Thomas A. Milne; H. Phillip Koeffler; Theodora S. Ross; Isidro Sánchez-García; Arndt Borkhardt; Keith R. Yamamoto; Ross A. Dickins; Thomas G. Graeber; Markus Müschen

B-lymphoid transcription factors, such as PAX5 and IKZF1, are critical for early B-cell development, yet lesions of the genes encoding these transcription factors occur in over 80% of cases of pre-B-cell acute lymphoblastic leukaemia (ALL). The importance of these lesions in ALL has, until now, remained unclear. Here, by combining studies using chromatin immunoprecipitation with sequencing and RNA sequencing, we identify a novel B-lymphoid program for transcriptional repression of glucose and energy supply. Our metabolic analyses revealed that PAX5 and IKZF1 enforce a state of chronic energy deprivation, resulting in constitutive activation of the energy-stress sensor AMPK. Dominant-negative mutants of PAX5 and IKZF1, however, relieved this glucose and energy restriction. In a transgenic pre-B ALL mouse model, the heterozygous deletion of Pax5 increased glucose uptake and ATP levels by more than 25-fold. Reconstitution of PAX5 and IKZF1 in samples from patients with pre-B ALL restored a non-permissive state and induced energy crisis and cell death. A CRISPR/Cas9-based screen of PAX5 and IKZF1 transcriptional targets identified the products of NR3C1 (encoding the glucocorticoid receptor), TXNIP (encoding a glucose-feedback sensor) and CNR2 (encoding a cannabinoid receptor) as central effectors of B-lymphoid restriction of glucose and energy supply. Notably, transport-independent lipophilic methyl-conjugates of pyruvate and tricarboxylic acid cycle metabolites bypassed the gatekeeper function of PAX5 and IKZF1 and readily enabled leukaemic transformation. Conversely, pharmacological TXNIP and CNR2 agonists and a small-molecule AMPK inhibitor strongly synergized with glucocorticoids, identifying TXNIP, CNR2 and AMPK as potential therapeutic targets. Furthermore, our results provide a mechanistic explanation for the empirical finding that glucocorticoids are effective in the treatment of B-lymphoid but not myeloid malignancies. Thus, B-lymphoid transcription factors function as metabolic gatekeepers by limiting the amount of cellular ATP to levels that are insufficient for malignant transformation.


Nature Medicine | 2016

PTEN opposes negative selection and enables oncogenic transformation of pre-B cells

Seyedmehdi Shojaee; Lai N. Chan; Maike Buchner; Valeria Cazzaniga; Kadriye Nehir Cosgun; Huimin Geng; Yi Hua Qiu; Marcus Dühren-von Minden; Thomas Ernst; Andreas Hochhaus; Giovanni Cazzaniga; Ari Melnick; Steven M. Kornblau; Thomas G. Graeber; Hong Wu; Hassan Jumaa; Markus Müschen

Phosphatase and tensin homolog (PTEN) is a negative regulator of the phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) signaling pathway and a potent tumor suppressor in many types of cancer. To test a tumor suppressive role for PTEN in pre-B acute lymphoblastic leukemia (ALL), we induced Cre-mediated deletion of Pten in mouse models of pre-B ALL. In contrast to its role as a tumor suppressor in other cancers, loss of one or both alleles of Pten caused rapid cell death of pre-B ALL cells and was sufficient to clear transplant recipient mice of leukemia. Small-molecule inhibition of PTEN in human pre-B ALL cells resulted in hyperactivation of AKT, activation of the p53 tumor suppressor cell cycle checkpoint and cell death. Loss of PTEN function in pre-B ALL cells was functionally equivalent to acute activation of autoreactive pre–B cell receptor signaling, which engaged a deletional checkpoint for the removal of autoreactive B cells. We propose that targeted inhibition of PTEN and hyperactivation of AKT triggers a checkpoint for the elimination of autoreactive B cells and represents a new strategy to overcome drug resistance in human ALL.


Leukemia | 2016

BCOR regulates myeloid cell proliferation and differentiation.

Qi Cao; Micah D. Gearhart; Sigal Gery; Seyedmehdi Shojaee; Henry Yang; Haibo Sun; De-Chen Lin; J. W. Bai; M. Mead; Z. Zhao; Q. Chen; Wenwen Chien; Serhan Alkan; T. Alpermann; Torsten Haferlach; Markus Müschen; Vivian J. Bardwell; Hp Koeffler

BCOR is a component of a variant Polycomb group repressive complex 1 (PRC1). Recently, we and others reported recurrent somatic BCOR loss-of-function mutations in myelodysplastic syndrome and acute myelogenous leukemia (AML). However, the role of BCOR in normal hematopoiesis is largely unknown. Here, we explored the function of BCOR in myeloid cells using myeloid murine models with Bcor conditional loss-of-function or overexpression alleles. Bcor mutant bone marrow cells showed significantly higher proliferation and differentiation rates with upregulated expression of Hox genes. Mutation of Bcor reduced protein levels of RING1B, an H2A ubiquitin ligase subunit of PRC1 family complexes and reduced H2AK119ub upstream of upregulated HoxA genes. Global RNA expression profiling in murine cells and AML patient samples with BCOR loss-of-function mutation suggested that loss of BCOR expression is associated with enhanced cell proliferation and myeloid differentiation. Our results strongly suggest that BCOR plays an indispensable role in hematopoiesis by inhibiting myeloid cell proliferation and differentiation and offer a mechanistic explanation for how BCOR regulates gene expression such as Hox genes.


Nature | 2018

Author Correction: Metabolic gatekeeper function of B-lymphoid transcription factors

Lai N. Chan; Zhengshan Chen; Daniel Braas; Jae-Woong Lee; Gang Xiao; Huimin Geng; Kadriye Nehir Cosgun; Christian Hurtz; Seyedmehdi Shojaee; Valeria Cazzaniga; Hilde Schjerven; Thomas Ernst; Andreas Hochhaus; Steven M. Kornblau; Marina Konopleva; Miles A. Pufall; Giovanni Cazzaniga; Grace J. Liu; Thomas A. Milne; H. Phillip Koeffler; Theodora S. Ross; Isidro Sánchez-García; Arndt Borkhardt; Keith R. Yamamoto; Ross A. Dickins; Thomas G. Graeber; Markus Müschen

Author(s): Chan, LN; Chen, Z; Braas, D; Lee, J-W; Xiao, G; Geng, H; Cosgun, KN; Hurtz, C; Shojaee, S; Cazzaniga, V; Schjerven, H; Ernst, T; Hochhaus, A; Kornblau, SM; Konopleva, M; Pufall, MA; Cazzaniga, G; Liu, GJ; Milne, TA; Koeffler, HP; Ross, TS; Sanchez-Garcia, I; Borkhardt, A; Yamamoto, KR; Dickins, RA; Graeber, TG; Muschen, M | Abstract: In Fig. 3c of this Letter, the the effects of CRISPR-Cas9-mediated deletion of NR3C1, TXNIP and CNR2 in patient-derived B-lineage leukaemia cells were shown. For curves depicting NR3C1 (left graph), data s for TXNIP (middle graph) were inadvertently plotted. This figure has been corrected online, and the original Fig. 3c is shown as Supplementary Information to this Amendment for transparency. The error does not affect the conclusions of the Letter. In addition, Source Data files have been added for the Figs. 1-4 and Extended Data Figs. 1-10 of the original Letter.

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Huimin Geng

University of California

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Maike Buchner

University of California

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Lai N. Chan

University of California

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Lars Klemm

University of California

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Zhengshan Chen

University of California

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Jae-Woong Lee

University of California

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