Targeted next‐generation sequencing reveals molecular heterogeneity in non‐chronic lymphocytic leukemia clonal B‐cell lymphocytosis

Defrancesco, Irene; Zibellini, Silvia; Boveri, Emanuela; Frigeni, Marco; Rizzo, Ettore; Bonometti, Arturo; Capuano, Francesca; Candido, Chiara; Rattotti, Sara; Tenore, Annamaria; Picone, Cristina; Flospergher, Elena; Zerbi, Caterina; Bergamini, F.; Fabbri, Nicole; Cristinelli, Caterina; Varettoni, Marzia; Paulli, Marco; Arcaini, Luca

doi:10.1002/hon.2784

Cited by 7 publications

(3 citation statements)

References 24 publications

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“…A Sleeping Beauty transposonmediated screen identified PDE4DIP as a susceptibility gene for adenomatous polyposis coli (Apc)-dependent intestinal tumorigenesis in mice [15]. PDE4DIP is a commonly mutated gene in leukemia, liver cancer, and nasopharyngeal carcinoma [16][17][18][19], and novel mutations have been reported in tumors originating in various tissues, including the lung, thyroid, ovary [20][21][22], kidney, peritoneum and bone marrow [23][24][25]. Genomic loss/gain and rearrangement of PDE4DIP have been discovered in prostate cancer, glioma, pineoblastoma, and intimal sarcoma [26][27][28][29].…”

Section: Introductionmentioning

confidence: 99%

PDE4DIP contributes to colorectal cancer growth and chemoresistance through modulation of the NF1/RAS signaling axis

et al. 2023

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Phosphodiesterase 4D interacting protein (PDE4DIP) is a centrosome/Golgi protein associated with cyclic nucleotide phosphodiesterases. PDE4DIP is commonly mutated in human cancers, and its alteration in mice leads to a predisposition to intestinal cancer. However, the biological function of PDE4DIP in human cancer remains obscure. Here, we report for the first time the oncogenic role of PDE4DIP in colorectal cancer (CRC) growth and adaptive MEK inhibitor (MEKi) resistance. We show that the expression of PDE4DIP is upregulated in CRC tissues and associated with the clinical characteristics and poor prognosis of CRC patients. Knockdown of PDE4DIP impairs the growth of KRAS-mutant CRC cells by inhibiting the core RAS signaling pathway. PDE4DIP plays an essential role in the full activation of oncogenic RAS/ERK signaling by suppressing the expression of the RAS GTPase-activating protein (RasGAP) neurofibromin (NF1). Mechanistically, PDE4DIP promotes the recruitment of PLCγ/PKCε to the Golgi apparatus, leading to constitutive activation of PKCε, which triggers the degradation of NF1. Upregulation of PDE4DIP results in adaptive MEKi resistance in KRAS-mutant CRC by reactivating the RAS/ERK pathway. Our work reveals a novel functional link between PDE4DIP and NF1/RAS signal transduction and suggests that targeting PDE4DIP is a promising therapeutic strategy for KRAS-mutant CRC.

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Section: Introductionmentioning

confidence: 99%

PDE4DIP contributes to colorectal cancer growth and chemoresistance through modulation of the NF1/RAS signaling axis

et al. 2023

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“…We conducted a mutational analysis on bone marrow samples on the 10 patients with confirmed diagnosis, by using a targeted sequencing approach with a 54 myeloid and a 138 lymphoid gene panels on a HiSeq2500 Illumina ( Supplemental Table 1 ). Detailed methods used with each gene panel have been previously published ( 7 , 8 ). Bone marrow mononuclear cells of patients at diagnosis were analyzed.…”

Section: Methodsmentioning

confidence: 99%

Enrichment of Double RUNX1 Mutations in Acute Leukemias of Ambiguous Lineage

et al. 2021

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Acute leukemia of ambiguous lineage (ALAL) is a rare type of leukemia and represents an unmet clinical need. In fact, due to heterogeneity, substantial rarity and absence of clinical trials, there are no therapeutic guidelines available. We investigated the genetic basis of 10 cases of ALAL diagnosed at our centre from 2008 and 2020, through a targeted myeloid and lymphoid sequencing approach. We show that this rare group of acute leukemias is enriched in myeloid-gene mutations. In particular we found that RUNX1 mutations, which have been found double mutated in 40% of patients and tend to involve both alleles, are associated with an undifferentiated phenotype and with lineage ambiguity. Furthermore, because this feature is typical of acute myeloid leukemia with minimal differentiation, we believe that our data strengthen the idea that acute leukemia with ambiguous lineage, especially those with an undifferentiated phenotype, might be genetically more closer to acute myeloid leukemia rather than acute lymphoblastic leukemia. These data enrich the knowledge on the genetic basis of ALAL and could have clinical implications as an acute myeloid leukemia (AML) – oriented chemotherapeutic approach might be more appropriate.

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“…Recent genetic studies have provided compelling evidence for an association between PDE4DIP variants and atrial brillation, stroke, and heart failure [21][22][23], but little is known about the biological functions of PDE4DIP in cancers. PDE4DIP alterations are common in human cancers, and mutations, genomic loss/gain, or gene rearrangements of PDE4DIP have been identi ed in multiple tumours, including leukaemia, glioma, pineoblastoma, and prostate cancer [21,[24][25][26][27]. A pancancer analysis revealed that the PDE4DIP gene has potential prognostic and immunotherapeutic value in multiple cancers [28].…”

Section: Introductionmentioning

confidence: 99%

The PDE4DIP-AKAP9 axis promotes lung cancer growth through modulation of PKA signalling

Lu,

Fu,

Huang

et al. 2024

Preprint

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Phosphodiesterase 4D interacting protein (PDE4DIP) is a Golgi/centrosome-associated protein that plays critical roles in the regulation of microtubule dynamics and maintenance of the Golgi structure. However, its biological role in human cancer remains largely unknown. In this study, we showed that PDE4DIP is overexpressed in human non-small cell lung cancer (NSCLC) tissues and that upregulated PDE4DIP expression is associated with poor prognosis in patients with lung cancer. We demonstrated that PDE4DIP knockdown inhibits NSCLC cell proliferation in vitro and tumorigenicity in vivo. We further demonstrated that PDE4DIP knockdown triggers apoptosis and cell cycle arrest in NSCLC cells by activating the PKA/CREB signalling pathway. PDE4DIP coordinates with AKAP9 to enhance the Golgi localization and stability of PKA RIIα. Depletion of PDE4DIP mislocalizes PKA RIIα from the Golgi and leads to its degradation, thereby compromising its negative regulatory effect on PKA signalling. Overall, our findings provide novel insights into the roles of the PDE4DIP-AKAP9 complex in regulating PKA signalling and NSCLC growth and highlight PDE4DIP as a promising therapeutic target for NSCLC.

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Targeted next‐generation sequencing reveals molecular heterogeneity in non‐chronic lymphocytic leukemia clonal B‐cell lymphocytosis

Cited by 7 publications

References 24 publications

PDE4DIP contributes to colorectal cancer growth and chemoresistance through modulation of the NF1/RAS signaling axis

PDE4DIP contributes to colorectal cancer growth and chemoresistance through modulation of the NF1/RAS signaling axis

Enrichment of Double RUNX1 Mutations in Acute Leukemias of Ambiguous Lineage

The PDE4DIP-AKAP9 axis promotes lung cancer growth through modulation of PKA signalling

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