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Article ; Online: BCMA-targeted bortezomib nanotherapy improves therapeutic efficacy, overcomes resistance, and modulates the immune microenvironment in multiple myeloma.

Dutta, Debasmita / Liu, Jiye / Wen, Kenneth / Kurata, Keiji / Fulciniti, Mariateresa / Gulla, Annamaria / Hideshima, Teru / Anderson, Kenneth C

Blood cancer journal

2023 Volume 13, Issue 1, Page(s) 184

Abstract: Bortezomib (BTZ) is a standard-of-care treatment in multiple myeloma (MM); however, adverse side effects and development of resistance limit its long term benefit. To improve target specificity, therapeutic efficacy, and overcome resistance, we designed ... ...

Abstract	Bortezomib (BTZ) is a standard-of-care treatment in multiple myeloma (MM); however, adverse side effects and development of resistance limit its long term benefit. To improve target specificity, therapeutic efficacy, and overcome resistance, we designed nanoparticles that encapsulate BTZ and are surface-functionalized with BCMA antibodies (BCMA-BTZ-NPs). We confirmed efficient cellular internalization of the BCMA-BTZ-NPs only in BCMA-expressing MM cells, but not in BCMA-knockout (KO) cells. In addition, BCMA-BTZ-NPs showed target-specific cytotoxicity against MM cell lines and primary tumor cells from MM patients. The BCMA-BTZ-NPs entered the cell through receptor-mediated uptake, which escapes a mechanism of BTZ resistance based on upregulating P-glycoprotein. Furthermore, BCMA-BTZ-NPs induced cell death more efficiently than non-targeted nanoparticles or free BTZ, triggering potent mitochondrial depolarization followed by apoptosis. In BTZ-resistant cells, BCMA-BTZ-NPs inhibited proteasome activity more effectively than free BTZ or non-targeted nanoparticles. Additionally, BCMA-BTZ-NPs enhanced immunogenic cell death and activated the autophagic pathway more than free BTZ. Finally, we found that BCMA-BTZ-NPs selectively accumulated at the tumor site in a murine xenograft model, enhanced tumor reduction, and prolonged host survival. These results suggest BCMA-BTZ-NPs provide a promising therapeutic strategy for enhancing the efficacy of BTZ and establish a framework for their evaluation in a clinical setting.
MeSH term(s)	Humans ; Animals ; Mice ; Bortezomib/pharmacology ; Bortezomib/therapeutic use ; Multiple Myeloma/pathology ; B-Cell Maturation Antigen ; Drug Resistance, Neoplasm ; Cell Line, Tumor ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Tumor Microenvironment
Chemical Substances	Bortezomib (69G8BD63PP) ; B-Cell Maturation Antigen ; Antineoplastic Agents
Language	English
Publishing date	2023-12-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2600560-8
ISSN	2044-5385 ; 2044-5385
ISSN (online)	2044-5385
ISSN	2044-5385
DOI	10.1038/s41408-023-00955-y
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Article ; Online: CRISPR Interference (CRISPRi) and CRISPR Activation (CRISPRa) to Explore the Oncogenic lncRNA Network.

Morelli, Eugenio / Gulla', Annamaria / Amodio, Nicola / Taiana, Elisa / Neri, Antonino / Fulciniti, Mariateresa / Munshi, Nikhil C

Methods in molecular biology (Clifton, N.J.)

2021 Volume 2348, Page(s) 189–204

Abstract: The human genome contains thousands of long noncoding RNAs (lncRNAs), even outnumbering protein-coding genes. These molecules can play a pivotal role in the development and progression of human disease, including cancer, and are susceptible to ... ...

Abstract	The human genome contains thousands of long noncoding RNAs (lncRNAs), even outnumbering protein-coding genes. These molecules can play a pivotal role in the development and progression of human disease, including cancer, and are susceptible to therapeutic intervention. Evidence of biologic function, however, is still missing for the vast majority of them. Both loss-of-function (LOF) and gain-of-function (GOF) studies are therefore necessary to advance our understanding of lncRNA networks and programs driving tumorigenesis. Here, we describe a protocol to perform lncRNA's LOF or GOF studies in multiple myeloma (MM) cells, using CRISPR interference (CRISPRi) or CRISPR activation (CRISPRa) technologies, respectively. These approaches have many advantages, including applicability to large-scale genetic screens in mammalian cells and possible reversibility of modulating effects; moreover, CRISPRa offers the unique opportunity to enhance lncRNA expression at the site of transcription, with relevant biologic implications.
MeSH term(s)	CRISPR-Cas Systems ; Cell Line, Tumor ; Clustered Regularly Interspaced Short Palindromic Repeats ; Gene Editing ; Gene Expression Regulation, Neoplastic ; Gene Regulatory Networks ; Genetic Vectors/genetics ; Humans ; Multiple Myeloma/genetics ; Mutation ; Oncogenes/genetics ; RNA, Guide, CRISPR-Cas Systems ; RNA, Long Noncoding/genetics ; Transduction, Genetic
Chemical Substances	RNA, Guide, CRISPR-Cas Systems ; RNA, Long Noncoding
Language	English
Publishing date	2021-06-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-1581-2_13
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Article ; Online: Author Correction: The Cyclophilin A-CD147 complex promotes the proliferation and homing of multiple myeloma cells.

Nature medicine

2024 Volume 30, Issue 4, Page(s) 1210

Language	English
Publishing date	2024-01-25
Publishing country	United States
Document type	Published Erratum
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/s41591-024-02820-2
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Article ; Online: Ubiquitin receptor PSMD4/Rpn10 is a novel therapeutic target in multiple myeloma.

Du, Ting / Song, Yan / Ray, Arghya / Wan, Xueping / Yao, Yao / Samur, Mehmet K / Shen, Chen / Penailillo, Johany / Sewastianik, Tomasz / Tai, Yu-Tzu / Fulciniti, Mariateresa / Munshi, Nikhil C / Wu, Hao / Carrasco, Ruben D / Chauhan, Dharminder / Anderson, Kenneth C

Blood

2023 Volume 141, Issue 21, Page(s) 2599–2614

Abstract: PSMD4/Rpn10 is a subunit of the 19S proteasome unit that is involved with feeding target proteins into the catalytic machinery of the 26S proteasome. Because proteasome inhibition is a common therapeutic strategy in multiple myeloma (MM), we investigated ...

Abstract	PSMD4/Rpn10 is a subunit of the 19S proteasome unit that is involved with feeding target proteins into the catalytic machinery of the 26S proteasome. Because proteasome inhibition is a common therapeutic strategy in multiple myeloma (MM), we investigated Rpn10 and found that it is highly expressed in MM cells compared with normal plasma cells. Rpn10 levels inversely correlated with overall survival in patients with MM. Inducible knockout or knockdown of Rpn10 decreased MM cell viability both in vitro and in vivo by triggering the accumulation of polyubiquitinated proteins, cell cycle arrest, and apoptosis associated with the activation of caspases and unfolded protein response-related pathways. Proteomic analysis revealed that inhibiting Rpn10 increased autophagy, antigen presentation, and the activation of CD4+ T and natural killer cells. We developed an in vitro AlphaScreen binding assay for high-throughput screening and identified a novel Rpn10 inhibitor, SB699551 (SB). Treating MM cell lines, leukemic cell lines, and primary cells from patients with MM with SB decreased cell viability without affecting the viability of normal peripheral blood mononuclear cells. SB inhibited the proliferation of MM cells even in the presence of the tumor-promoting bone marrow milieu and overcame proteasome inhibitor (PI) resistance without blocking the 20S proteasome catalytic function or the 19S deubiquitinating activity. Rpn10 blockade by SB triggered MM cell death via similar pathways as the genetic strategy. In MM xenograft models, SB was well tolerated, inhibited tumor growth, and prolonged survival. Our data suggest that inhibiting Rpn10 will enhance cytotoxicity and overcome PI resistance in MM, providing the basis for further optimization studies of Rpn10 inhibitors for clinical application.
MeSH term(s)	Humans ; Proteasome Endopeptidase Complex/metabolism ; Ubiquitin/metabolism ; Multiple Myeloma/drug therapy ; Multiple Myeloma/genetics ; Proteomics ; Leukocytes, Mononuclear/metabolism ; Carrier Proteins/genetics ; Proteins/metabolism ; RNA-Binding Proteins
Chemical Substances	Proteasome Endopeptidase Complex (EC 3.4.25.1) ; Ubiquitin ; Carrier Proteins ; Proteins ; PSMD4 protein, human ; RNA-Binding Proteins
Language	English
Publishing date	2023-01-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2022017897
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Article ; Online: In-depth analysis of alternative splicing landscape in multiple myeloma and potential role of dysregulated splicing factors.

Aktas Samur, Anil / Fulciniti, Mariateresa / Avet-Loiseau, Herve / Lopez, Michael A / Derebail, Sanika / Corre, Jill / Minvielle, Stephane / Magrangeas, Florence / Moreau, Philippe / Anderson, Kenneth C / Parmigiani, Giovanni / Samur, Mehmet K / Munshi, Nikhil C

Blood cancer journal

2022 Volume 12, Issue 12, Page(s) 171

Abstract: Splicing changes are common in cancer and are associated with dysregulated splicing factors. Here, we analyzed RNA-seq data from 323 newly diagnosed multiple myeloma (MM) patients and described the alternative splicing (AS) landscape. We observed a large ...

Abstract	Splicing changes are common in cancer and are associated with dysregulated splicing factors. Here, we analyzed RNA-seq data from 323 newly diagnosed multiple myeloma (MM) patients and described the alternative splicing (AS) landscape. We observed a large number of splicing pattern changes in MM cells compared to normal plasma cells (NPC). The most common events were alterations of mutually exclusive exons and exon skipping. Most of these events were observed in the absence of overall changes in gene expression and often impacted the coding potential of the alternatively spliced genes. To understand the molecular mechanisms driving frequent aberrant AS, we investigated 115 splicing factors (SFs) and associated them with the AS events in MM. We observed that ~40% of SFs were dysregulated in MM cells compared to NPC and found a significant enrichment of SRSF1, SRSF9, and PCB1 binding motifs around AS events. Importantly, SRSF1 overexpression was linked with shorter survival in two independent MM datasets and was correlated with the number of AS events, impacting tumor cell proliferation. Together with the observation that MM cells are vulnerable to splicing inhibition, our results may lay the foundation for developing new therapeutic strategies for MM. We have developed a web portal that allows custom alternative splicing event queries by using gene symbols and visualizes AS events in MM and subgroups. Our portals can be accessed at http://rconnect.dfci.harvard.edu/mmsplicing/ and https://rconnect.dfci.harvard.edu/mmleafcutter/ .
MeSH term(s)	Humans ; Alternative Splicing ; RNA Splicing Factors/genetics ; Multiple Myeloma/genetics ; Exons ; Serine-Arginine Splicing Factors/genetics
Chemical Substances	RNA Splicing Factors ; SRSF1 protein, human ; Serine-Arginine Splicing Factors (170974-22-8)
Language	English
Publishing date	2022-12-20
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2600560-8
ISSN	2044-5385 ; 2044-5385
ISSN (online)	2044-5385
ISSN	2044-5385
DOI	10.1038/s41408-022-00759-6
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Article ; Online: Deep Response in Multiple Myeloma: A Critical Review.

Fulciniti, Mariateresa / Munshi, Nikhil C / Martinez-Lopez, Joaquin

BioMed research international

2015 Volume 2015, Page(s) 832049

Abstract: Novel and more effective treatment strategies against multiple myeloma (MM) have significantly prolonged patients' survival and raised interest in the depth of response and its association with clinical outcome. Minimal residual disease (MRD) has emerged ...

Abstract	Novel and more effective treatment strategies against multiple myeloma (MM) have significantly prolonged patients' survival and raised interest in the depth of response and its association with clinical outcome. Minimal residual disease (MRD) has emerged as one of the most relevant prognostic factors in MM and should be included in a new definition of complete response (CR). Although further standardization is still required, MRD monitoring should be applied in prospective clinical trials as a sensitive tool to compare and evaluate the efficacy of different treatment strategies, particularly in the consolidation and maintenance settings, and implement individualized therapy-monitoring approaches. Here, we review current definition of deep response in MM, advantages and limitations of current MRD assessment assays, clinical evidences for MRD monitoring as a prognostic tool for therapeutic decisions in MM, and challenges to develop uniform criteria for MRD monitoring.
MeSH term(s)	Humans ; Multiple Myeloma/drug therapy ; Multiple Myeloma/pathology ; Neoplasm, Residual/diagnosis ; Neoplasm, Residual/pathology ; Prognosis ; Remission Induction ; Treatment Outcome
Language	English
Publishing date	2015
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2698540-8
ISSN	2314-6141 ; 2314-6133
ISSN (online)	2314-6141
ISSN	2314-6133
DOI	10.1155/2015/832049
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Article ; Online: Improving NK cell function in multiple myeloma with NKTR-255, a novel polymer-conjugated human IL-15.

Fernandez, Rafael Alonso / Mayoral, Jessica Encinas / Pierre-Louis, Laetitia / Yao, Yao / Xu, Yan / Mu, Shidai / Martinez-Lopez, Joaquin / Primo, Daniel / Miyazaki, Takahiro / Prabhala, Rao / Anderson, Kenneth C / Overwijk, Willem W / Munshi, Nikhil C / Fulciniti, Mariateresa

Blood advances

2022 Volume 7, Issue 1, Page(s) 9–19

Abstract: Multiple myeloma (MM) is characterized by an immunosuppressive microenvironment that enables tumor development. One of the mechanisms of immune evasion used by MM cells is the inhibition of natural killer (NK) cell effector functions; thus, the ... ...

Abstract	Multiple myeloma (MM) is characterized by an immunosuppressive microenvironment that enables tumor development. One of the mechanisms of immune evasion used by MM cells is the inhibition of natural killer (NK) cell effector functions; thus, the restoration of NK cell antitumor activity represents a key goal to increase tumor cell recognition, avoid tumor escape and potentially enhancing the effect of other drugs. In this study, we evaluated the ability of the investigational medicine NKTR-255, an IL-15 receptor agonist, to engage the IL-15 pathway and stimulate NK cells against MM cells. We observed that incubation with NKTR-255 was able to tilt the balance toward an activated phenotype in NK cells isolated from peripheral blood mononuclear cells of patients with MM, with increased expression of activating receptors on the surface of treated NK cells. This resulted in an enhanced degranulation, cytokine release, and anti-tumor cytotoxicity when the NK cells were exposed to both MM cell lines and primary MM cells. We further evaluated the in vivo effect of NKTR-255 in fully humanized immunocompetent mice subcutaneously engrafted with H929 MM cells. Compared with placebo, weekly injection of the mice with NKTR-255 increased the number of circulating NK cells in peripheral blood and delayed tumor growth. Finally, we observed that combination of NKTR-255 with the anti-CD38 antibody, daratumumab, was effective against MM cells in vitro and in vivo. Taken together, our data suggest a significant impact of NKTR-255 in inducing NK cell function against MM cells with important translational implications.
MeSH term(s)	Humans ; Animals ; Mice ; Interleukin-15/metabolism ; Multiple Myeloma/therapy ; Polymers/metabolism ; Polymers/pharmacology ; Polymers/therapeutic use ; Leukocytes, Mononuclear ; Cell Line, Tumor ; Immunologic Factors/therapeutic use ; Antineoplastic Agents/therapeutic use ; Killer Cells, Natural ; Tumor Microenvironment
Chemical Substances	NKTR-255 ; Interleukin-15 ; Polymers ; Immunologic Factors ; Antineoplastic Agents
Language	English
Publishing date	2022-07-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2022007985
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Article: Immunomodulation of NK, NKT and B/T cell subtypes in relapsed/refractory multiple myeloma patients treated with pomalidomide along with velcade and dexamethasone and its association with improved progression-free survival.

Frontiers in oncology

2023 Volume 13, Page(s) 1271807

Abstract: Background: Multiple Myeloma (MM) patients exhibit dysregulated immune system, which is further weakened by chemotherapeutic agents. While cereblon-modulating agents, such as pomalidomide and lenalidomide, have been found to improve the immune profile, ... ...

Abstract	Background: Multiple Myeloma (MM) patients exhibit dysregulated immune system, which is further weakened by chemotherapeutic agents. While cereblon-modulating agents, such as pomalidomide and lenalidomide, have been found to improve the immune profile, the efficacy of their impact in combination with other treatments is yet unknown. Methods: We conducted an immune-profiling of a longitudinal cohort of 366 peripheral blood samples from the CC4047-MM-007 (OPTIMISMM, NCT01734928) study. This study followed relapsed/refractory Multiple Myeloma (RRMM) patients who were treated with Velcade + dexamethasone (Vd), or Vd with pomalidomide (PVd). 366 blood samples from 186 patients were evaluated using multi-color flow cytometry at 3 timepoints: screening, day 8 of cycle 1, and cycle 3. Results: Among NK and NKT cell populations, adding pomalidomide showed no inhibition in the frequency of NK cells. When expression of double positivity for activation markers like, p46/NKG2D, on NK cells was higher than the median, PVd treated patients showed significantly better (p=0.05) progression-free survival (PFS) (additional 15 months) than patients with lower than the median expression of p46/NKG2D on NK cells. PVd treated patients who expressed CD158a/b below the median at cycle 1 demonstrated a significantly better PFS (more than 18months). Among B cell subtypes, PVd treatment significantly increased the abundance of B1b cells (p<0.05) and decreased Bregs (p<0.05) at day 8 of both cycle 1 and cycle 3 when compared to screening samples. Of all the B cell-markers evaluated among paired samples, a higher expression of MZB cells at day 8 of cycle 1 has resulted in enhanced PFS in PVd treated patients. Within T cells, pomalidomide treatment did not decrease the frequency of CD8 T cells when compared with screening samples. The higher the surface expression of OX-40 on CD8 T cells and the lower the expression of PD-1 and CD25 on CD4 T cells by PVd treatment resulted in improved PFS. Conclusion: The prognostic significance for the number of immune markers is only seen in the PVd arm and none of these immune markers exhibit prognostic values in the Vd arm. This study demonstrates the importance of the immunomodulatory effects and the therapeutic benefit of adding pomalidomide to Vd treatment.
Language	English
Publishing date	2023-12-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2023.1271807
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Article ; Online: IgM-MM is predominantly a pre-germinal center disorder and has a distinct genomic and transcriptomic signature from WM.

Bazarbachi, Abdul Hamid / Avet-Loiseau, Hervé / Szalat, Raphael / Samur, Anil Aktas / Hunter, Zachary / Shammas, Masood / Corre, Jill / Fulciniti, Mariateresa / Anderson, Kenneth C / Parmigiani, Giovanni / Treon, Steven P / Mohty, Mohamad / Munshi, Nikhil C / Samur, Mehmet Kemal

Blood

2021 Volume 138, Issue 20, Page(s) 1980–1985

Abstract: Immunoglobulin M (IgM) multiple myeloma (MM) is a rare disease subgroup. Its differentiation from other IgM-producing gammopathies such as Waldenström macroglobulinemia (WM) has not been well characterized but is essential for proper risk assessment and ... ...

Abstract	Immunoglobulin M (IgM) multiple myeloma (MM) is a rare disease subgroup. Its differentiation from other IgM-producing gammopathies such as Waldenström macroglobulinemia (WM) has not been well characterized but is essential for proper risk assessment and treatment. In this study, we investigated genomic and transcriptomic characteristics of IgM-MM samples using whole-genome and transcriptome sequencing to identify differentiating characteristics from non-IgM-MM and WM. Our results suggest that IgM-MM shares most of its defining structural variants and gene-expression profiling with MM, but has some key characteristics, including t(11;14) translocation, chromosome 6 and 13 deletion as well as distinct molecular and transcription-factor signatures. Furthermore, IgM-MM translocations were predominantly characterized by VHDHJH recombination-induced breakpoints, as opposed to the usual class-switching region breakpoints; coupled with its lack of class switching, these data favor a pre-germinal center origin. Finally, we found elevated expression of clinically relevant targets, including CD20 and Bruton tyrosine kinase, as well as high BCL2/BCL2L1 ratio in IgM-MM, providing potential for targeted therapeutics.
MeSH term(s)	DNA Copy Number Variations ; Germinal Center/metabolism ; Humans ; Immunoglobulin M/genetics ; Multiple Myeloma/diagnosis ; Multiple Myeloma/genetics ; Mutation ; Transcriptome ; Translocation, Genetic ; Waldenstrom Macroglobulinemia/diagnosis ; Waldenstrom Macroglobulinemia/genetics
Chemical Substances	Immunoglobulin M
Language	English
Publishing date	2021-12-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2021011452
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Article ; Online: CDK7 controls E2F- and MYC-driven proliferative and metabolic vulnerabilities in multiple myeloma.

Blood

2023 Volume 141, Issue 23, Page(s) 2841–2852

Abstract: Therapeutic targeting of CDK7 has proven beneficial in preclinical studies, yet the off-target effects of currently available CDK7 inhibitors make it difficult to pinpoint the exact mechanisms behind MM cell death mediated by CDK7 inhibition. Here, we ... ...

Abstract	Therapeutic targeting of CDK7 has proven beneficial in preclinical studies, yet the off-target effects of currently available CDK7 inhibitors make it difficult to pinpoint the exact mechanisms behind MM cell death mediated by CDK7 inhibition. Here, we show that CDK7 expression positively correlates with E2F and MYC transcriptional programs in cells from patients with multiple myeloma (MM); its selective targeting counteracts E2F activity via perturbation of the cyclin-dependent kinases/Rb axis and impairs MYC-regulated metabolic gene signatures translating into defects in glycolysis and reduced levels of lactate production in MM cells. CDK7 inhibition using the covalent small-molecule inhibitor YKL-5-124 elicits a strong therapeutic response with minimal effects on normal cells, and causes in vivo tumor regression, increasing survival in several mouse models of MM including a genetically engineered mouse model of MYC-dependent MM. Through its role as a critical cofactor and regulator of MYC and E2F activity, CDK7 is therefore a master regulator of oncogenic cellular programs supporting MM growth and survival, and a valuable therapeutic target providing rationale for development of YKL-5-124 for clinical use.
MeSH term(s)	Animals ; Mice ; Cyclin-Dependent Kinase-Activating Kinase ; Cyclin-Dependent Kinases/genetics ; Cyclin-Dependent Kinases/metabolism ; Multiple Myeloma/genetics
Chemical Substances	Cyclin-Dependent Kinase-Activating Kinase (EC 2.7.11.22) ; Cyclin-Dependent Kinases (EC 2.7.11.22) ; Cdk7 protein, mouse
Language	English
Publishing date	2023-03-04
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2022018885
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