Stephen S. Chung

The University of Texas Southwestern Medical Center

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Yazan F. Madanat

The University of Texas Southwestern Medical Center

Robert H. Collins

Southwestern Medical Center

Christopher Y. Park

Rockefeller University

Farrukh T. Awan

The Ohio State University

Gurbakhash Kaur

Icahn School of Medicine at Mount Sinai

Larry D. Anderson

The University of Texas Southwestern Medical Center

Aimaz Afrough

The University of Texas Southwestern Medical Center

Madhuri Vusirikala

Actinium Pharmaceuticals (United States)

Praveen Ramakrishnan Geethakumari

The University of Texas Southwestern Medical Center

Wenhuo Hu

Memorial Sloan Kettering Cancer Center

Cooperative Institutions

The University of Texas Southwestern Medical Center

251

Southwestern Medical Center

185

Memorial Sloan Kettering Cancer Center

156

Cornell University

111

Kettering University

University of Hong Kong

Harvard University

Harold C. Simmons Comprehensive Cancer Center

Weill Cornell Medicine

The University of Texas MD Anderson Cancer Center

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Risk Prediction for Clonal Cytopenia: Multicenter Real-World Evidence

Blood (2024)

Zhuoer Xie Rami S. Komrokji Najla Al-Ali Alexandra Regelson Susan Geyer

Cytopenia

Cumulative incidence

10.1182/blood.2024024756

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Citations (8)

Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia

New England Journal of Medicine (2015)

Enrico Tiacci Jae H. Park Luca De Carolis Stephen S. Chung Alessandro Broccoli

BRAF V600E is the genetic lesion underlying hairy-cell leukemia. We assessed the safety and activity of the oral BRAF inhibitor vemurafenib in patients with hairy-cell leukemia that had relapsed after treatment with a purine analogue or who had disease that was refractory to purine analogues.

Purine analogue

Refractory (planetary science)

10.1056/nejmoa1506583

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Citations (309)

RAS-mutant leukaemia stem cells drive clinical resistance to venetoclax

Nature (2024)

Junya Sango Saul Carcamo Maria Sirenko Abhishek Maiti Hager Mansour

Cancer driver mutations often show distinct temporal acquisition patterns, but the biological basis for this, if any, remains unknown. RAS mutations occur invariably late in the course of acute myeloid leukaemia, upon progression or relapsed/refractory disease1–6. Here, by using human leukaemogenesis models, we first show that RAS mutations are obligatory late events that need to succeed earlier cooperating mutations. We provide the mechanistic explanation for this in a requirement for mutant RAS to specifically transform committed progenitors of the myelomonocytic lineage (granulocyte–monocyte progenitors) harbouring previously acquired driver mutations, showing that advanced leukaemic clones can originate from a different cell type in the haematopoietic hierarchy than ancestral clones. Furthermore, we demonstrate that RAS-mutant leukaemia stem cells (LSCs) give rise to monocytic disease, as observed frequently in patients with poor responses to treatment with the BCL2 inhibitor venetoclax. We show that this is because RAS-mutant LSCs, in contrast to RAS-wild-type LSCs, have altered BCL2 family gene expression and are resistant to venetoclax, driving clinical resistance and relapse with monocytic features. Our findings demonstrate that a specific genetic driver shapes the non-genetic cellular hierarchy of acute myeloid leukaemia by imposing a specific LSC target cell restriction and critically affects therapeutic outcomes in patients. We find that RAS-mutant leukaemia stem cells are resistant to venetoclax, driving clinical resistance and relapse with monocytic features.

Venetoclax

10.1038/s41586-024-08137-x

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Citations (4)

Oncogenic TRK fusions are amenable to inhibition in hematologic malignancies

Journal of Clinical Investigation (2018)

Justin Taylor Dean C. Pavlick Akihide Yoshimi Christina Marcelus Stephen S. Chung

Rearrangements involving the neurotrophic receptor kinase genes (NTRK1, NTRK2, and NTRK3; hereafter referred to as TRK) produce oncogenic fusions in a wide variety of cancers in adults and children. Although TRK fusions occur in fewer than 1% of all solid tumors, inhibition of TRK results in profound therapeutic responses, resulting in Breakthrough Therapy FDA approval of the TRK inhibitor larotrectinib for adult and pediatric patients with solid tumors, regardless of histology. In contrast to solid tumors, the frequency of TRK fusions and the clinical effects of targeting TRK in hematologic malignancies are unknown. Here, through an evaluation for TRK fusions across more than 7,000 patients with hematologic malignancies, we identified TRK fusions in acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), histiocytosis, multiple myeloma, and dendritic cell neoplasms. Although TRK fusions occurred in only 0.1% of patients (8 of 7,311 patients), they conferred responsiveness to TRK inhibition in vitro and in vivo in a patient-derived xenograft and a corresponding AML patient with ETV6-NTRK2 fusion. These data identify that despite their individual rarity, collectively, TRK fusions are present in a wide variety of hematologic malignancies and predict clinically significant therapeutic responses to TRK inhibition.

Trk receptor

10.1172/jci120787

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Citations (50)

Supplementary Data from Hypoxic Activation of the PERK/eIF2α Arm of the Unfolded Protein Response Promotes Metastasis through Induction of LAMP3

Hilda Mujčić Anika Nagelkerke Kasper M.A. Rouschop Stephen S. Chung Naz Chaudary

<p>Supplementary Data - PDF file 113K, This file contains supplementary materials and methods, and the legends of the 14 supplementary figures. Suppl. Table 1 shows the patients characteristic from the clinical study described in main Fig 1. Suppl. Table 2 shows the relationship between LAMP3 protein expression and continuous clinical parameters, incl. HP5. Suppl. Table 3 shows the relationship between LAMP3 protein expression and categorical clinical parameters, incl. FIGO stage. Suppl. Fig 1 shows the association between LAMP3 gene copy number and LAMP3 gene expression in human cervix tumors described in main Fig 1, as well as the LAMP3 gene copy numbers in normal human cervix tissues. Suppl. Fig 2 provides in vitro evidence for the inducibility of the ME180 cancer cell line. Suppl. Fig 3 provides in vivo evidence for the metastatic capacity of the isogenic ME180 cell line, as well as its inducibility. Suppl. Fig 4 shows in vitro validation of the ME180-GADD34-C cells. Suppl. Fig 5 contains the raw data that belongs to main Fig 3C, which shows that Inhibition of UPR signaling suppresses hypoxia-induced lymph node metastasis. Suppl. Fig 6 shows the in vitro validation of ME180 LAMP3-knockdown cells. Suppl. Fig 7 shows representative images of LAMP3 expression in LAMP3 knockdown and empty vector control tumors described in main Fig 4B. Suppl. Fig 8 contains the raw data that belongs to main Fig 4C, which shows that knockdown of LAMP3 inhibits hypoxia-induced lymph node metastasis. Suppl. Fig 9 shows the human VEGF mRNA expression in ME180-GADD34-C orthotopic xenografts described in main Fig 3B. Suppl. Fig 10 shows the quantification of the microvessel density and hVEGF expression in shLAMP3 orthotopic xenografts described in main Fig 4B. Suppl. Fig 11 shows the hypoxic fraction shLAMP3 orthotopic xenografts described in main Fig 4B. Suppl. Fig 12 contains data from the soft agar colony formation assay that shows that knockdown of LAMP3 in HeLa cells inhibits colony formation. Suppl. Fig 13 is supplementary to main Fig 6B and shows that knockdown of LAMP3 in HeLa cells, just like in ME180 cells, inhibits transwell migration. Suppl. Fig 14 is supplementary to main Fig 6D and shows that knockdown of LAMP3 in Caski cells, just like in ME180 cells, inhibits wound closure in the scratch wound healing assay. This figure also shows that overexpression of LAMP3 accelerates wound closure</p>

10.1158/1078-0432.22450563

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Abstract 2310 Unexpected mechanisms of ETV6 dysfunction in hematologic disease

Journal of Biological Chemistry (2024)

Glen Liszczak Michael McConville Toby Thomas Ryan Beckner Catherine Valadez

Germline and somatic missense mutations in the transcriptional repressor ETV6 are strongly associated with blood diseases, including thrombocytopenia and leukemia. These dominant negative mutations, which are scattered throughout the ETV6 DNA binding domain and a functionally unannotated linker region, cause the protein to mislocalize to the cytoplasm. We set out to answer the following question: why do seemingly unrelated ETV6 missense mutations cause similar protein mislocalization phenotypes? A combination of chemical, biochemical, and cellular approaches revealed multiple unique mechanisms through which ETV6 disease mutations disrupt proper protein localization. Our discoveries have: (i) inspired small molecule- and genetics-based strategies to rescue mutant ETV6 localization and function, (ii) enabled development of new animal models for ETV6 dysfunction in disease, and (iii) uncovered new regulatory mechanisms of ETV6 localization and function. We thank the Cancer Prevention and Research Institute of Texas, the Welch Foundation, and the National Institute of General Medical Sciences for funding this work.

Hematologic disease

10.1016/j.jbc.2024.107072

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Clinical Relevant Alterations Identified By Comprehensive Genomic Profiling Can Potentially Improve Therapeutic Option and Change Prognosis in Hematologic Malignancies

Blood (2016)

Jie He Minal Patel Irene Phillip Mark Bailey Ellin Berman

10.1182/blood.v128.22.5109.5109

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Citations (2)

3089 – ELUCIDATING NEW MECHANISMS OF ACQUIRED RESISTANCE TO IDH INHIBITION BY SATURATION VARIANT SCREENING OF BASE-EDITED LEUKEMIA CELLS

Experimental Hematology (2021)

Junhua Lyu Yuxuan Liu Lihu Gong Mingyi Chen Yazan F. Madanat

10.1016/j.exphem.2021.12.307

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Disabling Uncompetitive Inhibition of Oncogenic IDH Mutations Drives Acquired Resistance

Cancer Discovery (2022)

Junhua Lyu Yuxuan Liu Lihu Gong Mingyi Chen Yazan F. Madanat

Abstract Mutations in IDH genes occur frequently in acute myeloid leukemia (AML) and other human cancers to generate the oncometabolite R-2HG. Allosteric inhibition of mutant IDH suppresses R-2HG production in a subset of patients with AML; however, acquired resistance emerges as a new challenge, and the underlying mechanisms remain incompletely understood. Here we establish isogenic leukemia cells containing common IDH oncogenic mutations by CRISPR base editing. By mutational scanning of IDH single amino acid variants in base-edited cells, we describe a repertoire of IDH second-site mutations responsible for therapy resistance through disabling uncompetitive enzyme inhibition. Recurrent mutations at NADPH binding sites within IDH heterodimers act in cis or trans to prevent the formation of stable enzyme–inhibitor complexes, restore R-2HG production in the presence of inhibitors, and drive therapy resistance in IDH-mutant AML cells and patients. We therefore uncover a new class of pathogenic mutations and mechanisms for acquired resistance to targeted cancer therapies. Significance: Comprehensive scanning of IDH single amino acid variants in base-edited leukemia cells uncovers recurrent mutations conferring resistance to IDH inhibition through disabling NADPH-dependent uncompetitive inhibition. Together with targeted sequencing, structural, and functional studies, we identify a new class of pathogenic mutations and mechanisms for acquired resistance to IDH-targeting cancer therapies. This article is highlighted in the In This Issue feature, p. 1

10.1158/2159-8290.cd-21-1661

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Citations (10)

Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations

Blood (2017)

Benjamin H. Durham Bartlomiej Getta Sascha Dietrich Justin Taylor Helen Won

10.1182/blood-2017-01-765107

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Citations (106)