Targeting CXCR4 in AML and ALL

Cancilla, Daniel; Rettig, Michael P.; DiPersio, John F.

doi:10.3389/fonc.2020.01672

Cited by 80 publications

(54 citation statements)

References 162 publications

(178 reference statements)

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“…In addition, extramedullary infiltration leads to the development of leukemic tumors in non-marrow sites and plays critical roles in leukemia progression and chemoresistance, as well as extramedullary relapse in ALL patients (63,64). (58,65). It is possible that the survival and/or proliferation of leukemia cells in the blood stream were/was inhibited by the CXCR4 antagonist, explaining no increase of leukemia cells in the blood stream.…”

Section: Discussionmentioning

confidence: 99%

Nuclear PFKP promotes CXCR4-dependent infiltration by T cell acute lymphoblastic leukemia

Gao¹,

Qin²,

Wu³

et al. 2021

Journal of Clinical Investigation

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PFKP (phosphofructokinase, platelet), the major isoform of PFK1 expressed in T cell acute lymphoblastic leukemia (T-ALL), is predominantly expressed in the cytoplasm to carry out its glycolytic function. Our study showed PFKP was a cyto-nuclear shuttling protein with functional nuclear export and nuclear localization sequences. Cyclin D3/CDK6 facilitated PFKP nuclear translocation by dimerization and by exposing the NLS of PFKP to induce the interaction between PFKP and importin 9. Nuclear PFKP stimulated the expression of C-X-C chemokine receptor type 4 (CXCR4), a chemokine receptor regulating leukemia homing/infiltration, to promote T-ALL cell invasion, which depended on the activity of c-Myc. In vivo experiments showed that nuclear PFKP promoted leukemia homing/infiltration into the bone marrow, spleen and liver, which could be blocked with CXCR4 antagonists. Immunohistochemistry staining of tissues from a clinically well-annotated cohort of T cell lymphoma/leukemia patients showed nuclear PFKP localization only in invasive cancers, but not in nonmalignant T lymph node or reactive hyperplasia. The presence of nuclear PFKP in these specimens correlated with poor survival in patients with T cell malignancy, suggesting the potential utility of nuclear PFKP as a diagnostic marker.

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Section: Discussionmentioning

confidence: 99%

Nuclear PFKP promotes CXCR4-dependent infiltration by T cell acute lymphoblastic leukemia

Gao¹,

Qin²,

Wu³

et al. 2021

Journal of Clinical Investigation

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“…MCM6 is upregulated in multiple cancers and is believed to regulate DNA replication and activate MAPK/ERK signaling 46 . CXCR4 is a chemokine receptor that facilitates HIV cell entry and regulates immune cell migration, including retention of B-cell precursors in the bone-marrow, and is being pursed as a therapeutic target in ALL and AML 47,48 .…”

Section: Discussionmentioning

confidence: 99%

Genetic Determinants of Blood Cell Traits Influence Susceptibility to Childhood Acute Lymphoblastic Leukemia

Kachuri

Jeon

DeWan

et al. 2021

Preprint

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Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Despite overlap between genetic risk loci for ALL and hematologic traits, the etiological relevance of dysregulated blood cell homeostasis remains unclear. We investigated this question in a genome-wide association study (GWAS) of ALL (2666 cases, 60,272 controls) and multi-trait GWAS of 9 blood cell indices in the UK Biobank. We identified 3000 blood cell trait-associated (P<5.0×10−8) variants, explaining 4.0% to 23.9% of trait variation, and including 115 loci associated with blood cell ratios (LMR: lymphocyte/monocyte, NLR: neutrophil/lymphocyte, PLR: platelet/lymphocyte). ALL susceptibility was genetically correlated with lymphocyte counts (rg=0.088, p=4.0×10−4) and PLR (rg= −0.072, p=0.0017). In Mendelian randomization analyses, genetically predicted increase in lymphocyte counts was associated with increased ALL risk (Odds ratio (OR)=1.16, p=0.031) and strengthened after accounting for other cell types (OR=1.48, p=8.8×10−4). We observed positive associations with increasing LMR (OR=1.22, p=0.0017) and inverse effects for NLR (OR=0.67, p=3.1×10−4) and PLR (OR=0.80, p=0.002). Our study shows that a genetically induced shift towards higher lymphocyte counts, overall and in relation to monocytes, neutrophils, and platelets, confers an increased susceptibility to childhood ALL.

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“…High expression of CXCR4 on AML blasts has been shown to predict poor prognosis [62]. The CXCL12/CXCR4 axis can also activate pathways that favor the survival, growth, and chemotherapy resistance of AML blasts [63]. CXCL12 expression seems to be reduced in MSCs in AML, fostering the migration of CXCR4-overexpressing malignant LSCs versus normal hematopoietic stem cells (HSCs) [64].…”

Section: Immunosuppressive Properties Of Mesenchymal Stromal Cells In Amlmentioning

confidence: 99%

“…The mobilization of leukemic cells from the protective BM niche is considered a promising strategy to increase their susceptibility not only to conventional chemotherapeutic agents but also to immunotherapies [121]. Small-molecule inhibitors, short peptides, and antibodies have been developed to disrupt the CXCL12/ CXCR4 axis that releases AML blasts from the BM [63], and recent findings suggest that CXCR4 antagonism can potentially synergize with immunotherapies in several clinical trials involving solid tumors.…”

Section: Car T Cells In Aml the Success Of Car T Cell Therapy In B Cellmentioning

confidence: 99%

Catch me if you can: how AML and its niche escape immunotherapy

et al. 2021

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In spite of the remarkable progress in basic and preclinical studies of acute myeloid leukemia (AML), the five-year survival rate of AML patients remains poor, highlighting the urgent need for novel and synergistic therapies. Over the past decade, increased attention has been focused on identifying suitable immunotherapeutic strategies for AML, and in particular on targeting leukemic cells and their progenitors. However, recent studies have also underlined the important contribution of the leukemic microenvironment in facilitating tumor escape mechanisms leading to disease recurrence. Here, we describe the immunological features of the AML niche, with particular attention to the crosstalk between the AML blasts and the cellular components of the altered tumor microenvironment (TME) and the mechanisms of immune escape that hamper the therapeutic effects of the most advanced treatments. Considering the AML complexity, immunotherapy approaches may benefit from a rational combination of complementary strategies aimed at preventing escape mechanisms without increasing toxicity.

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Targeting CXCR4 in AML and ALL

Cited by 80 publications

References 162 publications

Nuclear PFKP promotes CXCR4-dependent infiltration by T cell acute lymphoblastic leukemia

Nuclear PFKP promotes CXCR4-dependent infiltration by T cell acute lymphoblastic leukemia

Genetic Determinants of Blood Cell Traits Influence Susceptibility to Childhood Acute Lymphoblastic Leukemia

Catch me if you can: how AML and its niche escape immunotherapy

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