Low c-Kit expression identifies primitive, therapy-resistant CML stem cells

Shah, Mansi; Kumar, Harish; Qiu, Shaowei; Li, Hui; Harris, Mason; He, Jianbo; Abraham, Ajay; Crossman, David K.; Paterson, Andrew J.; Welner, Robert S.; Bhatia, Ravi

doi:10.1172/jci.insight.157421

Cited by 8 publications

(2 citation statements)

References 56 publications

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“…The substantial treatment-induced changes observed within the stem cell population suggested that BCR::ABL1 + LSCs are themselves heterogeneous in terms of sensitivity to TKIs allowing us to define BCR::ABL1 + Lin − CD34 + CD38 −/low CD45RA − cKIT − CD26 + as the most TKI-insensitive cells. Apart from being detected at diagnosis, these cells are strikingly enriched after TKI therapy (Warfvinge et al, 2017), a finding since confirmed in a transgenic mouse model (Shah et al, 2023), and in clinical observations documenting long-term persistence of CD26 + cells in CML patients (Pacelli et al, 2023). Together, these findings argue that functional heterogeneity within LSCs cannot be predicted solely by surface markers but is intimately linked to their cell state and gene expression signature, thereby motivating a strategy to simultaneously capture their lineage potency/affiliation, BCR::ABL1 status, and molecular program in addition to the surface markers.…”

Section: Introductionmentioning

confidence: 84%

Single cell multi-omics analysis of chronic myeloid leukemia links cellular heterogeneity to therapy response

Warfvinge,

Geironson Ulfsson,

Dhapola

et al. 2023

Preprint

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The advent of tyrosine kinase inhibitors (TKIs) as treatment of chronic myeloid leukemia (CML) is a paradigm in molecularly targeted cancer therapy. Nonetheless, TKI insensitive leukemia stem cells (LSCs) persist in most patients even after years of treatment. The sustained presence, heterogeneity and evolvability of LSCs are imperative for disease progression as well as recurrence during treatment-free remission (TFR). However, dynamic changes among LSC sub-populations upon TKI therapy impede their measurement and targeting. Here, we used cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to generate high-resolution single cell multiomics maps from CML patients at diagnosis, retrospectively stratified by BCR::ABL1IS (%) following 12 months of TKI therapy as per European LeukemiaNet (ELN) recommendations. Simultaneous measurement of global gene expression profiles together with >40 surface markers from the same cells revealed that each patient harbored a unique composition of stem and progenitor cells at diagnosis demonstrating that cellular heterogeneity is a hallmark of CML. The patients with treatment failure after 12 months of therapy had markedly higher abundance of molecularly defined primitive cells at diagnosis compared to the optimal responders. Furthermore, deconvolution of an independent dataset of CML patient-derived bulk transcriptomes (n=59) into constituent cell populations showed that the proportion of primitive cells versus lineage primed sub-populations significantly connected with the TKI-treatment outcome. The multiomic feature landscape enabled visualization of the primitive fraction as a heterogenous mixture of molecularly distinct Lin-CD34+CD38-/low BCR::ABL1+ LSCs and BCR::ABL1- hematopoietic stem cells (HSCs) in variable ratio across patients and guided their prospective isolation by a combination of CD26 and CD35 cell surface markers. We for the first time show that BCR::ABL1+ LSCs and BCR::ABL1- HSCs can be distinctly separated as CD26+CD35- and CD26-CD35+ respectively. In addition, we found the relative proportion of CD26-CD35+ HSCs to be higher in optimal responders when compared to treatment failures, at diagnosis as well as following 3 months of TKI therapy, and that the LSC/HSC ratio was increased in patients with prospective treatment failure. Collectively, the patient-specific cellular heterogeneity multiomics maps build a framework towards understanding therapy response and adapting treatment by devising strategies that either extinguish TKI-insensitive LSCs or engage the immune effectors to suppress the residual leukemogenic cells.

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Section: Introductionmentioning

confidence: 84%

Single cell multi-omics analysis of chronic myeloid leukemia links cellular heterogeneity to therapy response

Warfvinge,

Geironson Ulfsson,

Dhapola

et al. 2023

Preprint

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“…In the latter, c-KIT is absent in the endothelial nucleus, while barely detectable at the endothelial cell membrane. It is noteworthy that in chronic myeloid leukemia, therapy-resistant hemopoietic stem cells responsible for the disease relapse and drug-resistance have been identified by a low c-KIT expression and pose a challenge to the efficacy of tyrosine kinase inhibitor-based therapies [69].…”

Section: The Dual Nuclear and Cell Membrane Endothelial C-kit Protein...mentioning

confidence: 99%

Pericyte-Tunnelling Nanotube-Driven Angiogenesis and C-KIT Immunolocalization in Human Developing Brain and Glioblastoma

Errede,

D’Amati,

Annese

et al. 2023

Preprint

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Pericyte and their tunnelling nanotubes (P-TNTs) have been described as involved in the early phases of angiogenesis in the human normal developing brain and glioblastoma, being a common feature of combined endothelium/pericyte vessel sprouts. Based on the few data available so far about this ‘alternative’ pericyte-TNT-driven mode of angiogenesis, whose precise function in vessel growth through vascular cells communication, has still to be determined, this study aims to cast light on the regulative molecules involved in this process, governed by intimate pericyte-endothelial interactions. After considering the existence of the sprout guiding pericyte and P-TNT, as shown by pioneering ultrastructural studies as well as by more recent observations with NG2/CD146 pericyte markers and basal lamina molecules, a step-by-step profile of the process has been suggested and an investigation undertaken on ‘unconventional’, pro-angiogenic ligand/receptor systems, that may have a role aside from the canonical pathways. In this context, a possible candidate worthy of investigation is the c-KIT receptor, a member of the tyrosine kinase family of proteins, which also includes the well-known VEGFR and PDGFR. According to the obtained results showing a primary localization of c-KIT on endothelial cells and pointing out a differential distribution of the receptor on normal vs glioblastoma vessels, it seems conceivable to propose the stem cell factor/c-KIT signaling as a key factor in pericyte-TNT-driven angiogenesis, advancing this alternative mode of angiogenesis and the c- KIT pathway as possible targets for devising effective antiangiogenic therapeutic strategies.

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p21/Zbtb18 repress the expression of cKit to regulate the self-renewal of hematopoietic stem cells

Wang,

Yang,

et al. 2024

Protein &Amp; Cell

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The maintenance of hematopoietic stem cells (HSCs) is a complex process involving numerous cell-extrinsic and -intrinsic regulators. The first member of the cyclin-dependent kinase family of inhibitors to be identified, p21, has been reported to perform a wide range of critical biological functions, including cell cycle regulation, transcription, differentiation, and so on. Given the previous inconsistent results regarding the functions of p21 in HSCs in a p21-knockout mouse model, we employed p21-tdTomato (tdT) mice to further elucidate its role in HSCs during homeostasis. The results showed that p21-tdT+ HSCs exhibited increased self-renewal capacity compared to p21-tdT− HSCs. Zbtb18, a transcriptional repressor, was upregulated in p21-tdT+ HSCs, and its knockdown significantly impaired the reconstitution capability of HSCs. Furthermore, p21 interacted with ZBTB18 to co-repress the expression of cKit in HSCs and thus regulated the self-renewal of HSCs. Our data provide novel insights into the physiological role and mechanisms of p21 in HSCs during homeostasis independent of its conventional role as a cell cycle inhibitor.

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Low c-Kit expression identifies primitive, therapy-resistant CML stem cells

Cited by 8 publications

References 56 publications

Single cell multi-omics analysis of chronic myeloid leukemia links cellular heterogeneity to therapy response

Single cell multi-omics analysis of chronic myeloid leukemia links cellular heterogeneity to therapy response

Pericyte-Tunnelling Nanotube-Driven Angiogenesis and C-KIT Immunolocalization in Human Developing Brain and Glioblastoma

p21/Zbtb18 repress the expression of cKit to regulate the self-renewal of hematopoietic stem cells

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