Hematopoietic stem cells express multiple myeloid markers: implications for the origin and targeted therapy of acute myeloid leukemia

Taussig, David; Pearce, Daniel J.; Simpson, Cathy A.; Rohatiner, A. Z. S.; Lister, T. Andrew; Kelly, Gavin; Luongo, Jennifer L.; Danet-Desnoyers, Gwenn-ael; Bonnet, Dominique

doi:10.1182/blood-2005-03-1072

Cited by 329 publications

(283 citation statements)

References 29 publications

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“…3D). This explanation can be supported by a recent report suggesting a highly positive correlation between myeloid marker expression and the engraftment potential of human CD34 + HSPCs [30]. These results warrant more studies to investigate molecular and cellular mechanisms.…”

Section: Discussionsupporting

confidence: 62%

Functional nanofiber scaffolds with different spacers modulate adhesion and expansion of cryopreserved umbilical cord blood hematopoietic stem/progenitor cells

Chua

Chai

Lee

et al. 2007

Experimental Hematology

114

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Objective-Nanofiber scaffolds with amino groups conjugated to fiber surface through different spacers (ethylene, butylenes, and hexylene groups, respectively) were prepared and the effect of spacer length on adhesion and expansion of umbilical cord blood hematopoietic stem/progenitor cells (HSPCs) was investigated.Materials and Methods-Electrospun polymer nanofiber scaffolds were functionalized with poly (acrylic acid) grafting, followed by conjugation of amino groups with different spacers. HSPCs were expanded on aminated scaffolds for 10 days. Cell proliferation, surface marker expression, clonogenic potential, and nonobese diabetic (NOD)/severe combined immunodeficient (SCID) repopulation potential of the expanded cells were evaluated following expansion culture.Results-Aminated nanofiber scaffolds with ethylene and butylene spacers showed high-expansion efficiencies (773-and 805-fold expansion of total cells, 200-and 235-fold expansion of CD34 + CD45 + cells, respectively). HSPC proliferation on aminated scaffold with hexylene spacer was significantly lower (210-fold expansion of total cells and 86-fold expansion of CD34 + CD45 + cells), but maintained the highest CD34 + CD45 + cell fraction (41.1%). Colony-forming unit granulocyte-erythrocyte-monocyte-megakaryocyte and long-term culture-initiating cell maintenance was similar for HSPCs expanded on all three aminated nanofiber scaffolds; nevertheless, the NOD/SCID mice engraftment potential of HSPCs expanded on aminoethyl and aminobutyl conjugated nanofibers was significantly higher than that on aminohexyl conjugated nanofibers.Conclusion-This study demonstrated that aminated nanofibers are superior substrates for ex vivo HSPC expansion, which was correlated with the enhanced HSPC adhesion to these aminated nanofibers. The spacer, through which amino groups were conjugated to nanofiber surface, affected the expansion outcome. Our results highlighted the importance of scaffold topography and cellsubstrate interaction to regulating HSPC proliferation and self-renewal in cytokine-supplemented expansion.Offprint requests to: Hai-Quan Mao, Ph.D., Department of Materials Science and Engineering, Johns Hopkins University, 102 Maryland Hall, 3400 N. Charles Street, Baltimore, MD 21218; E-mail: hmao@jhu.edu. In conventional ex vivo expansion culture, HSPCs are generally regarded as suspension cells and numerous protocols implement HSPC suspension cultures in flasks or bags in the presence of various combinations of early acting cytokines [3][4][5][6][7]. The importance of topographical and substrate-immobilized biochemical cues has not been taken into consideration in these culture systems. Suspension culture conditions differ drastically from conditions provided by the natural bone marrow microenvironment, where a complex network of stromal cells and extracellular matrix (ECM) serves as a stem cell niche that regulates HSPC functions such as homing, self-renewal, proliferation, and fate choice [2,8]. A growing body of evidence has suggested the importance of...

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Section: Discussionsupporting

confidence: 62%

Functional nanofiber scaffolds with different spacers modulate adhesion and expansion of cryopreserved umbilical cord blood hematopoietic stem/progenitor cells

Chua

Chai

Lee

et al. 2007

Experimental Hematology

114

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“…7,10–12,40,46 We are not aware of any published reports indicating that they should differ from AML blasts in their intrinsic susceptibility to RDL by antibodies or antibody-derived agents in combination with NK cells. For most patients with CD34-positive AML, the relapse-relevant AML-LSCs are contained predominantly in the compartments of CD34-positive and (CD34-positive CD38-negative) cells.…”

Section: Resultsmentioning

confidence: 99%

“…For most patients with CD34-positive AML, the relapse-relevant AML-LSCs are contained predominantly in the compartments of CD34-positive and (CD34-positive CD38-negative) cells. 12,40,43–46,73 Therefore, we have first enriched CD34-bearing cells from 2 patients with CD34-positive AML, for whom sufficient cell numbers were available (patients 9 & 11; Table 3), by immuno-magnetic sorting with a commercial kit. Both samples carried intermediate combined densities of CD33 plus CD123 on their blasts (MNCs; approx.…”

Section: Resultsmentioning

confidence: 99%

“…40 Another prominent study also reported CD123 expressed on the surface of CD34pos CD38neg AML cells, but in this study the antigen was also present on the corresponding cellular subsets from healthy bone marrow (BM) and cord blood (CB), although expression levels on the enriched normal BM cells were at least 10-fold lower than on on the corresponding AML cells. 12 CD123 is also expressed on normal HSCs from AML patients in follow-up after induction therapy. 46 On aggregate, the published reports agree that CD123 is expressed with far greater frequency and surface densities on AML-LSCs and progenitor cells than on normal HSCs.…”

Section: Introductionmentioning

confidence: 99%

“…We anticipate that SPM-2 will be able to discriminate at least to a degree between AML-LSCs and remaining normal HSCs of a patient, due to its dual-targeting capacity and the greater combined surface density of CD33 and CD123 on AML-LSCs than on normal HSCs. 11,12,24,27,40,46 A preferential elimination of AML-LSCs over normal HSCs would be a distinct advantage, if it could be reached, because the surviving HSCs may be able to reconstitute the patient’s hematopoietic system after the end of therapy at least in part, possibly even without the need for a stem cell transplant. Here we have studied, whether SPM-2 in conjunction with activated human NK cells was capable of eliminating blasts from patients with a very broad range of AML subtypes, as predicted, 8 and found the prediction to be fulfilled.…”

Section: Introductionmentioning

confidence: 99%

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Dual-targeting triplebody 33-16-123 (SPM-2) mediates effective redirected lysis of primary blasts from patients with a broad range of AML subtypes in combination with natural killer cells

et al. 2018

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A number of agents designed for immunotherapy of Acute Myeloid Leukemia (AML) are in preclinical and early clinical development. Most of them target a single antigen on the surface of AML cells. Here we describe the development and key biological properties of a tri-specific agent, the dual-targeting triplebody SPM-2, with binding sites for target antigens CD33 and CD123, and for CD16 to engage NK cells as cytolytic effectors. Primary blasts of nearly all AML patients carry at least one of these target antigens and the pair is particularly promising for the elimination of blasts and leukemia stem cells (LSCs) from a majority of AML patients by dual-targeting agents. The cytolytic activity of NK cells mediated by SPM-2 was analyzed in vitro for primary leukemic cells from 29 patients with a broad range of AML-subtypes. Blasts from all 29 patients, including patients with genomic alterations associated with an unfavorable genetic subtype, were lysed at nanomolar concentrations of SPM-2. Maximum susceptibility was observed for cells with a combined density of CD33 and CD123 above 10,000 copies/cell. Cell populations enriched for AML-LSCs (CD34pos and CD34pos CD38neg cells) from 2 AML patients carried an increased combined antigen density and were lysed at correspondingly lower concentrations of SPM-2 than unsorted blasts. These initial findings raise the expectation that SPM-2 may also be capable of eliminating AML-LSCs and thus of prolonging survival. In the future, patients with a broad range of AML subtypes may benefit from treatment with SPM-2.

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CD300f epitopes are specific targets for acute myeloid leukemia with monocytic differentiation

et al. 2019

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Antibody‐based therapy in acute myeloid leukemia (AML) has been marred by significant hematologic toxicity due to targeting of both hematopoietic stem and progenitor cells (HSPCs). Achieving greater success with therapeutic antibodies requires careful characterization of the potential target molecules on AML. One potential target is CD300f, which is an immunoregulatory molecule expressed predominantly on myeloid lineage cells. To confirm the value of CD300f as a leukemic target, we showed that CD300f antibodies bind to AML from 85% of patient samples. While one CD300f monoclonal antibody (mAb) reportedly did not bind healthy hematopoietic stem cells, transcriptomic analysis found that CD300f transcripts are expressed by healthy HSPC. Several CD300f protein isoforms exist as a result of alternative splicing. Importantly for antibody targeting, the extracellular region of CD300f can be present with or without the exon 4‐encoded sequence. This results in CD300f isoforms that are differentially bound by CD300f‐specific antibodies. Furthermore, binding of one mAb, DCR‐2, to CD300f exposes a structural epitope recognized by a second CD300f mAb, UP‐D2. Detailed analysis of publicly available transcriptomic data indicated that CD34+ HSPC expressed fewer CD300f transcripts that lacked exon 4 compared to AML with monocytic differentiation. Analysis of a small cohort of AML cells revealed that the UP‐D2 conformational binding site could be induced in cells from AML patients with monocytic differentiation but not those from other AML or HSPC. This provides the opportunity to develop an antibody‐based strategy to target AMLs with monocytic differentiation but not healthy CD34+ HSPCs. This would be a major step forward in developing effective anti‐AML therapeutic antibodies with reduced hematologic toxicity.

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Hematopoietic stem cells express multiple myeloid markers: implications for the origin and targeted therapy of acute myeloid leukemia

Cited by 329 publications

References 29 publications

Functional nanofiber scaffolds with different spacers modulate adhesion and expansion of cryopreserved umbilical cord blood hematopoietic stem/progenitor cells

Functional nanofiber scaffolds with different spacers modulate adhesion and expansion of cryopreserved umbilical cord blood hematopoietic stem/progenitor cells

Dual-targeting triplebody 33-16-123 (SPM-2) mediates effective redirected lysis of primary blasts from patients with a broad range of AML subtypes in combination with natural killer cells

CD300f epitopes are specific targets for acute myeloid leukemia with monocytic differentiation

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