The cell of origin and the leukemia stem cell in acute myeloid leukemia

Chopra, Martin; Bohlander, Stefan K.

doi:10.1002/gcc.22805

Cited by 51 publications

(37 citation statements)

References 74 publications

(114 reference statements)

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“…Acute leukemia is maintained by a pool of self-renewing cells denominated leukemic stem cells (LSCs), that express CD34+CD38− and increased aldehyde dehydrogenase activity (39) with properties similar to other cancer stem cells (CSC) (40)(41)(42)(43)(44). The LSCs can originate from hematopoietic stem cells (HSCs) or from committed cells that have an inner higher self-renewal potential (45). In ALL, there is a strong possibility that these stem cells originate from fully differentiated cells that during malignant transformation re-gain stem-like properties.…”

Section: The Role Of Leukemia Stem Cells (Lscs) In the Development Of Cns Leukemiamentioning

confidence: 99%

A narrative review of central nervous system involvement in acute leukemias

Deak¹,

Gorcea-Andronic²,

Sas³

et al. 2021

Ann Transl Med

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Acute leukemias (both myeloid and lymphoblastic) are a group of diseases for which each year more successful therapies are implemented. However, in a subset of cases the overall survival (OS) is still exceptionally low due to the infiltration of leukemic cells in the central nervous system (CNS) and the subsequent formation of brain tumors. The CNS involvement is more common in acute lymphocytic leukemia (ALL), than in adult acute myeloid leukemia (AML), although the rates for the second case might be underestimated. The main reasons for CNS invasion are related to the expression of specific adhesion molecules (VLA-4, ICAM-1, VCAM, L-selectin, PECAM-1, CD18, LFA-1, CD58, CD44, CXCL12) by a subpopulation of leukemic cells, called "sticky cells" which have the ability to interact and adhere to endothelial cells. Moreover, the microenvironment becomes hypoxic and together with secretion of VEGF-A by ALL or AML cells the permeability of vasculature in the bone marrow increases, coupled with the disruption of blood brain barrier. There is a single subpopulation of leukemia cells, called leukemia stem cells (LSCs) that is able to resist in the new microenvironment due to its high adaptability. The LCSs enter into the arachnoid, migrate, and intensively proliferate in cerebrospinal fluid (CSF) and consequently infiltrate perivascular spaces and brain parenchyma. Moreover, the CNS is an immune privileged site that also protects leukemic cells from chemotherapy. CD56/NCAM is the most important surface molecule often overexpressed by leukemic stem cells that offers them the ability to infiltrate in the CNS. Although

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Section: The Role Of Leukemia Stem Cells (Lscs) In the Development Of Cns Leukemiamentioning

confidence: 99%

A narrative review of central nervous system involvement in acute leukemias

Deak¹,

Gorcea-Andronic²,

Sas³

et al. 2021

Ann Transl Med

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“…While the BM microenvironment supports proper development of hematopoietic stem and progenitor cells (HSPCs), it can also serve as a shelter for malignant cells by shielding them from cytotoxic chemotherapy ( Figure 1C ). It has been proposed that there is a sub-population of leukemic cells in AML and ALL know as leukemia initiating stem cells (LSC) that reside within the protective niche of the bone marrow ( 47 – 50 ). These cells are thought to be powerful contributors to drug resistance and relapse in these diseases.…”

Section: Cxcr4 Inhibition For Chemotherapy Sensitizationmentioning

confidence: 99%

Targeting CXCR4 in AML and ALL

2020

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The interaction of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) blasts with the bone marrow microenvironment regulates self-renewal, growth signaling, as well as chemotherapy resistance. The chemokine receptor, CXC receptor 4 (CXCR4), with its ligand chemokine ligand 12 (CXCL12), plays a key role in the survival and migration of normal and malignant stem cells to the bone marrow. High expression of CXCR4 on AML and ALL blasts has been shown to be a predictor of poor prognosis for these diseases. Several small molecule inhibitors, short peptides, antibodies, and antibody drug conjugates have been developed for the purposes of more effective targeting and killing of malignant cells expressing CXCR4. In this review we will discuss recent results and strategies in targeting CXCR4 with these agents in patients with AML or ALL.

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“…Consistent with these biological effects, selinexor reduces the growth and viability of many solid tumors, non-Hodgkin lymphoma, myeloma and leukemia cells in vitro and in vivo [ 16 , 30 , 46 , 47 ]. Notably, studies in AML and ALL have suggest selinexor also targets the leukemic stem cells, a small subpopulation of leukemia cells, which are thought drive the relapse in AML [ 48 , 49 ]. Selinexor treatment reduces engraftment in a mouse leukemia xenograft model and reduces frequencies of LSC in selinexor-treated xenografts [ 50 ].…”

Section: Selective Inhibitors Of Nuclear Export (Sine)mentioning

confidence: 99%

Targeting nuclear import and export in hematological malignancies

Nachmias

Schimmer

2020

Leukemia

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The transport of proteins across the nuclear membrane is a highly regulated process, essential for the cell function. This transport is actively mediated by members of the karyopherin family, termed importins, or exportins, depending on the direction of transport. These proteins play an active part in tumorigenesis, through aberrant localization of their cargoes, which include oncogenes, tumor-suppressor genes and mediators of key signal transduction pathways. Overexpression of importins and exportins is reported in many malignancies, with implications in cell growth and viability, differentiation, drug resistance, and tumor microenvironment. Given their broad significance across tumors and pathways, much effort is being put to develop specific inhibitors as a novel anticancer therapeutics. Already, selinexor, a specific inhibitor of exportin-1 (XPO1), is approved for clinical use. This review will focus on the role of importins and exportins in hematological malignancies. We will discuss current preclinical and clinical data on importins and exportins, and demonstrate how our growing understanding of their functions has identified new therapeutic targets.

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The cell of origin and the leukemia stem cell in acute myeloid leukemia

Cited by 51 publications

References 74 publications

A narrative review of central nervous system involvement in acute leukemias

A narrative review of central nervous system involvement in acute leukemias

Targeting CXCR4 in AML and ALL

Targeting nuclear import and export in hematological malignancies

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