CD99 as a novel therapeutic target on leukemic progenitor cells in FLT3-ITDmut AML

Travaglini, Serena; Ottone, Tiziana; Angelini, Daniela F.; Fiori, Valentina; Dominici, Sabrina; Noguera, Nélida I.; Śniegocka, Martyna; Antonelli, Silvia; Consalvo, María Antonietta Irno; Bardi, Marco De; Banella, Cristina; Divona, Mariadomenica; Marchesi, Francesco; Masciarelli, Silvia; Fazi, Francesco; Pieraccioli, Marco; Palmieri, Raffaele; Angelis, Gottardo De; Buccisano, Francesco; Venditti, Adriano; Battistini, Luca; Magnani, Mauro; Voso, Maria Teresa

doi:10.1038/s41375-022-01566-5

Cited by 6 publications

(3 citation statements)

References 10 publications

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“…In acute myeloid leukemia (AML), they induce cell death and inhibit xenografts without the involvement of immune effector cells, via SRC family kinase activation [39]. Notably, AML with FLT3 internal tandem duplication mutations displays strong apoptotic activity from anti-CD99 antibodies, involving the intrinsic and extrinsic apoptotic pathways [29]. Additionally, these antibodies prove effective in mantle B-cell lymphoma [40].…”

Section: Discussionmentioning

confidence: 99%

“…The relative qRT-PCR for CD99wt and CD99sh quantitation was performed on Applied Biosystems 7500 apparatus (Thermo Fisher Scientific, Waltham, MA, USA) using primers and probe elsewhere described [29]: 2 isoform-specific CD99 reverse primer for the CD99 wild-type (CD99_ wild-type: 5 ′ -ATGTCCACCTCCCCTTGTT-3 ′ ) and short (CD99_Sh: 5 ′ -TGCTCACCCCTAGGTCTT-3 ′ ) isoforms, and a common forward primer (CD99 Fw: 5 ′ -CTGGAGCCATCTCTAGCTT-3 ′ ) and probe (5 ′ -(FAM)TTCTTTTTCTGGTAAGCA-3 ′ ). GAPDH was used as reference gene for normalization and was amplified in a multiplex reaction with CD99 using primers and probe described in [30]: GAPDH Up: 5 ′ -ATGGGTGTGAACCATGAGAA-3 ′ , GAPDH Low: 5 ′ -GTGCTAAGCAGTTGGTGGTG-3 ′ , and the probe 5 ′ -(VIC) CCTCAAGATCATCAGCAATGCCTCC-3 ′ .…”

Section: Quantitative Real-time Pcrmentioning

confidence: 99%

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CD99 Expression and Prognostic Impact in Glioblastoma: A Single-Center Cohort Study

Rocca,

Giudici,

Donofrio

et al. 2024

Cells

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Glioblastoma is the most frequent and aggressive brain tumor in adults. This study aims to evaluate the expression and prognostic impact of CD99, a membrane glycoprotein involved in cellular migration and invasion. In a cohort of patients with glioblastoma treated with surgery, radiotherapy and temozolomide, we retrospectively analyzed tumor expression of CD99 by immunohistochemistry (IHC) and by quantitative real-time polymerase chain reaction (qRT-PCR) for both the wild type (CD99wt) and the truncated (CD99sh) isoforms. The impact on overall survival (OS) was assessed with the Kaplan–Meier method and log-rank test and by multivariable Cox regression. Forty-six patients with glioblastoma entered this study. Immunohistochemical expression of CD99 was present in 83%. Only the CD99wt isoform was detected by qRT-PCR and was significantly correlated with CD99 expression evaluated by IHC (rho = 0.309, p = 0.037). CD99 expression was not associated with OS, regardless of the assessment methodology used (p = 0.61 for qRT-PCR and p = 0.73 for IHC). In an exploratory analysis of The Cancer Genome Atlas, casuistry of glioblastomas CD99 expression was not associated with OS nor with progression-free survival. This study confirms a high expression of CD99 in glioblastoma but does not show any significant impact on survival. Further preclinical studies are needed to define its role as a therapeutic target in glioblastoma.

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Section: Discussionmentioning

confidence: 99%

Section: Quantitative Real-time Pcrmentioning

confidence: 99%

CD99 Expression and Prognostic Impact in Glioblastoma: A Single-Center Cohort Study

Rocca,

Giudici,

Donofrio

et al. 2024

Cells

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“…CD99 targeting also reduced glycolysis and mitochondrial respiration. 220 Targeting CD33 with gemtuzumab ozogamicin (GO), a calicheamicin-conjugated mAb, in combination with induction chemotherapy in pediatric patients with high FLT3-ITD AR reduced relapse. 221 An active clinical trial (NCT04385290) is investigating the safety and efficacy of midostaurin plus GO as frontline therapy in newly diagnosed FLT3 mutated patients.…”

Section: Targeted Flt3 Aml Therapeutics Beyond Flt3 Inhibitorsmentioning

confidence: 99%

Therapeutic Targeting of FLT3 in Acute Myeloid Leukemia: Current Status and Novel Approaches

Tecik¹,

Adan²

2022

OTT

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FMS-like tyrosine kinase 3 (FLT3) is mutated in approximately 30% of acute myeloid leukemia (AML) patients. The presence of FLT3-ITD (internal tandem duplication, 20–25%) mutation and, to a lesser extent, FLT3-TKD (tyrosine kinase domain, 5–10%) mutation is associated with poorer diagnosis and therapy response since the leukemic cells become hyperproliferative and resistant to apoptosis after continuous activation of FLT3 signaling. Targeting FLT3 has been the focus of many pre-clinical and clinical studies. Hence, many small-molecule FLT3 inhibitors (FLT3is) have been developed, some of which are approved such as midostaurin and gilteritinib to be used in different clinical settings, either in combination with chemotherapy or alone. However, many questions regarding the best treatment strategy remain to be answered. On the other hand, various FLT3-dependent and -independent resistance mechanisms could be evolved during FLT3i therapy which limit their clinical impact. Therefore, identifying molecular mechanisms of resistance and developing novel strategies to overcome this obstacle is a current interest in the field. In this review, recent studies of approved FLT3i and knowledge about major resistance mechanisms of clinically approved FLT3i’s will be discussed together with novel treatment approaches such as designing novel FLT3i and dual FLT3i and combination strategies including approved FLT3i plus small-molecule agents targeting altered molecules in the resistant cells to abrogate resistance. Moreover, how to choose an appropriate FLT3i for the patients will be summarized based on what is currently known from available clinical data. In addition, strategies beyond FLT3i’s including immunotherapeutics, small-molecule FLT3 degraders, and flavonoids will be summarized to highlight potential alternatives in FLT3-mutated AML therapy.

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Advances in the pathogenesis of FLT3-mutated acute myeloid leukemia and targeted treatments

Travaglini,

Gurnari,

Ottone

et al. 2024

Current Opinion in Oncology

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Purpose of review FLT3 mutations are among the most common myeloid drivers identified in adult acute myeloid leukemia (AML). Their identification is crucial for the precise risk assessment because of the strong prognostic significance of the most recurrent type of FLT3 alterations, namely internal tandem duplications (ITDs). Recent advances in the pathogenesis and biology of FLT3-mutated AML have opened an opportunity for development and application of selective inhibition of FLT3 pathway. Recent findings In the last decade, at least three targeted treatments have been approved by regulatory agencies and several others are currently under investigations. Here, we review the latest advance in the role of FLT3 mutations in AML, providing an outline of the available therapeutic strategies, their mechanisms of actions and of resistance, as well as routes for potential improvement. Summary The availability of FLT3 inhibitors has improved outcomes in AML harboring such mutations, currently also reflected in disease stratification and recommendations. Newer inhibitors are under investigations, and combinations with chemotherapy or other targeted treatments are being explored to further improve disease outcomes.

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CD99 as a novel therapeutic target on leukemic progenitor cells in FLT3-ITDmut AML

Cited by 6 publications

References 10 publications

CD99 Expression and Prognostic Impact in Glioblastoma: A Single-Center Cohort Study

CD99 Expression and Prognostic Impact in Glioblastoma: A Single-Center Cohort Study

Therapeutic Targeting of FLT3 in Acute Myeloid Leukemia: Current Status and Novel Approaches

Advances in the pathogenesis of FLT3-mutated acute myeloid leukemia and targeted treatments

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