FLT3 overexpression in acute leukaemias: New insights into the search for molecular mechanisms

Poubel, Caroline P.; Mansur, Marcela Braga; Boroni, Mariana; Emerenciano, Mariana

doi:10.1016/j.bbcan.2019.06.001

Cited by 8 publications

(13 citation statements)

References 63 publications

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“…Of note, ETP-ALL has been defined based on its unique GEP, 1 in which the oncogenes LMO2, LYL1, FLT3, ZEB2, and MEF2C are upregulated and act as important players in this leukemia development. 2,[11][12][13][14] Aware of the high frequency of CRLF2 overexpression in ETP-ALL patients, we assessed the transcript levels of the genes included in the classical ETP-ALL GEP. First, we observed that some non-ETP CRLF2-high samples showed a very similar upregulation profile to ETP-ALL (Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

CRLF2 overexpression defines an immature‐like subgroup which is rescued through restoration of the PRC2 function in T‐cell precursor acute lymphoblastic leukemia

Maciel

Wolch

Emerenciano

et al. 2022

Genes Chromosomes & Cancer

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CRLF2 overexpression has been described as a biomarker of poor prognosis in T‐cell acute lymphoblastic leukemia (T‐ALL). In the present study, we aimed to unravel the genomic profile underlying CRLF2 overexpression (CRLF2‐high) by analyzing RNA‐seq, WES, and SNP‐array data from 264 T‐ALL patients and five cell lines deposited on the TARGET initiative, Cancer Cell Line Encyclopedia and Gene Expression Omnibus. These data allowed us to delineate the genomic landscape of CRLF2‐high in T‐ALL, which was associated with PTEN, JAK3, PHF6, EZH2, and RUNX1 mutations. We also observed an enrichment of CRLF2‐high in early T‐precursor (ETP)‐ALL (23.08% vs. 4.02%, P = 7.579e−06) and a very similar gene upregulation profile between these two entities. The inhibition of BET (iBET) proteins is a strategy previously demonstrated to reverse the gene upregulation pattern of ETP cells through restoration of polycomb repressive complex 2 (PRC2) activity. While CRLF2 expression was rescued by using this strategy in LOUCY (untreated vs. iBET P = 0.0095, DMSO vs. iBET P = 0.0286), a classical ETP‐ALL cell line, PRC2 loss was not sufficient to promote CRLF2 upregulation in JURKAT, a more mature T‐ALL cell line. Considering the role of IKZF1 in CRLF2 regulation and in recruitment of PCR2, we evaluated IKZF1 status according to CRLF2‐expression subgroups. We identified that IKZF1 transcripts with intron retention were upregulated in the CRLF2‐high subgroup. Here, we delineated the gene expression profile of CRLF2‐high T‐ALL samples and unraveled the crucial role of PRC2 in CRLF2 regulation in ETP‐ALL.

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Section: Resultsmentioning

confidence: 99%

CRLF2 overexpression defines an immature‐like subgroup which is rescued through restoration of the PRC2 function in T‐cell precursor acute lymphoblastic leukemia

Maciel

Wolch

Emerenciano

et al. 2022

Genes Chromosomes & Cancer

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“…Aberrant expression of FLT3 is closely related to the occurrence of AML and other malignant tumors. FLT3 is overexpressed in more than 70% of AML cases, so FTL3 is an effective target for AML treatment [90]. 7370 is an anti-FLT3/CD3 IgG-based BsAb with advantages of a long half-life and high affinity.…”

Section: Flt3/cd3mentioning

confidence: 99%

Bispecific T cell engagers: an emerging therapy for management of hematologic malignancies

et al. 2021

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Harnessing the power of immune cells, especially T cells, to enhance anti-tumor activities has become a promising strategy in clinical management of hematologic malignancies. The emerging bispecific antibodies (BsAbs), which recruit T cells to tumor cells, exemplified by bispecific T cell engagers (BiTEs), have facilitated the development of tumor immunotherapy. Here we discussed the advances and challenges in BiTE therapy developed for the treatment of hematologic malignancies. Blinatumomab, the first BiTE approved for the treatment of acute lymphocytic leukemia (ALL), is appreciated for its high efficacy and safety. Recent studies have focused on improving the efficacy of BiTEs by optimizing treatment regimens and refining the molecular structures of BiTEs. A considerable number of bispecific T cell-recruiting antibodies which are potentially effective in hematologic malignancies have been derived from BiTEs. The elucidation of mechanisms of BiTE action and neonatal techniques used for the construction of BsAbs can improve the treatment of hematological malignancies. This review summarized the features of bispecific T cell-recruiting antibodies for the treatment of hematologic malignancies with special focus on preclinical experiments and clinical studies.

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“…FLT3 promotes the proliferation and differentiation of hematopoietic cells by binding to its ligand [ 189 , 190 ]. FLT3 is overexpressed in AML, and its mutations have been detected in approximately 30% of patients with AML [ 191 , 192 ]. The mutation of FLT3 causes ligand-independent FLT3 signaling and leads to a poor prognosis of patients with AML [ 193 , 194 ].…”

Section: Role Of Known and Emerging Targets Of Icesmentioning

confidence: 99%

Bispecific Antibody-Based Immune-Cell Engagers and Their Emerging Therapeutic Targets in Cancer Immunotherapy

Shin

Yang

Yoon

et al. 2022

IJMS

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Cancer is the second leading cause of death worldwide after cardiovascular diseases. Harnessing the power of immune cells is a promising strategy to improve the antitumor effect of cancer immunotherapy. Recent progress in recombinant DNA technology and antibody engineering has ushered in a new era of bispecific antibody (bsAb)-based immune-cell engagers (ICEs), including T- and natural-killer-cell engagers. Since the first approval of blinatumomab by the United States Food and Drug Administration (US FDA), various bsAb-based ICEs have been developed for the effective treatment of patients with cancer. Simultaneously, several potential therapeutic targets of bsAb-based ICEs have been identified in various cancers. Therefore, this review focused on not only highlighting the action mechanism, design and structure, and status of bsAb-based ICEs in clinical development and their approval by the US FDA for human malignancy treatment, but also on summarizing the currently known and emerging therapeutic targets in cancer. This review provides insights into practical considerations for developing next-generation ICEs.

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FLT3 overexpression in acute leukaemias: New insights into the search for molecular mechanisms

Cited by 8 publications

References 63 publications

CRLF2 overexpression defines an immature‐like subgroup which is rescued through restoration of the PRC2 function in T‐cell precursor acute lymphoblastic leukemia

CRLF2 overexpression defines an immature‐like subgroup which is rescued through restoration of the PRC2 function in T‐cell precursor acute lymphoblastic leukemia

Bispecific T cell engagers: an emerging therapy for management of hematologic malignancies

Bispecific Antibody-Based Immune-Cell Engagers and Their Emerging Therapeutic Targets in Cancer Immunotherapy

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