Stem cell mutations can be detected in myeloma patients years before onset of secondary leukemias

Sridharan, Ashwin; Schinke, Carolina; Georgiev, George I; Ferreira, Mariana da Silva; Thiruthuvanathan, Victor; MacArthur, Ian; Bhagat, Tushar D.; Choudhary, Gaurav S.; Aluri, Srinivas; Pradhan, Kith; Xia, Yu; Panjikaran, Maya; Sims, Gregory E.; Bhagat, Chirag; Bender, Ryan; Keeler, Lauryn; Graber, Armin; Heuck, Christoph; Fletcher, Frederick A.; Alapat, Daisy; Weinhold, Niels; Johnson, Sarah K.; Wickrema, Amittha; Barlogie, Bart; Morgan, Gareth J.; Shastri, Aditi; Steidl, Ulrich; Will, Britta; Verma, Amit

doi:10.1182/bloodadvances.2019000731

Cited by 14 publications

(7 citation statements)

References 21 publications

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“…The same mechanism was recently demonstrated in a cohort of MM patients, years before the evolution to t-MN [115]. In these cases, the presence of pre-existing mutant HSC clones was revealed, mainly harboring TP53 mutations, that became the dominant population at the time of t-MN evolution [115]. This mechanism could explain the high frequency of TP53 mutations in these patients.…”

Section: Therapy-related Mdssupporting

confidence: 70%

“…However, it was shown that the same TP53 mutant clones found at diagnosis had been detected at low frequencies (<1%), 3-6 years before the development of t-MN and even prior to any chemotherapy treatment, supporting the conclusion that t-MN is related to the cytotoxic selection of pre-existing chemo-resistant clones preferentially expanded after treatment [114]. The same mechanism was recently demonstrated in a cohort of MM patients, years before the evolution to t-MN [115]. In these cases, the presence of pre-existing mutant HSC clones was revealed, mainly harboring TP53 mutations, that became the dominant population at the time of t-MN evolution [115].…”

Section: Therapy-related Mdssupporting

confidence: 69%

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TP53 in Myelodysplastic Syndromes: Recent Biological and Clinical Findings

Cumbo

Tota

Anelli

et al. 2020

IJMS

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TP53 dysregulation plays a pivotal role in the molecular pathogenesis of myelodysplastic syndromes (MDS), identifying a subgroup of patients with peculiar features. In this review we report the recent biological and clinical findings of TP53-mutated MDS, focusing on the molecular pathways activation and on its impact on the cellular physiology. In MDS, TP53 mutational status is deeply associated with del(5q) syndrome and its dysregulation impacts on cell cycle, DNA repair and apoptosis inducing chromosomal instability and the clonal evolution of disease. TP53 defects influence adversely the MDS clinical outcome and the treatment response rate, thus new therapeutic approaches are being developed for these patients. TP53 allelic state characterization and the mutational burden evaluation can therefore predict prognosis and identify the subgroup of patients eligible for targeted therapy. For these reasons, in the era of precision medicine, the MDS diagnostic workup cannot do without the complete assessment of TP53 mutational profile.

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Section: Therapy-related Mdssupporting

confidence: 70%

Section: Therapy-related Mdssupporting

confidence: 69%

TP53 in Myelodysplastic Syndromes: Recent Biological and Clinical Findings

Cumbo

Tota

Anelli

et al. 2020

IJMS

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“…A comprehensive characterization of the genomic changes, and its correlation with the resultant morphological changes, may help identify patients at the risk of imminent leukemic transformation and devise effective preventive strategies. Hence, the identification of individuals at high-risk of developing t-MN and employment of preventative approaches may improvement outcomes for this difficult-to-treat group of patients [ 16 , 38 – 40 ].…”

Section: Discussionmentioning

confidence: 99%

TP53 mutation variant allele frequency of ≥10% is associated with poor prognosis in therapy-related myeloid neoplasms

et al. 2023

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Revised diagnostic criteria for myeloid neoplasms (MN) issued by the International Consensus Classification (ICC) and the World Health Organization (WHO) recommended major change pertaining to TP53-mutated (TP53mut) MN. However, these assertions have not been specifically examined in therapy-related myeloid neoplasm (t-MN), a subset enriched with TP53mut. We analyzed 488 t-MN patients for TP53mut. At least one TP53mut with variant allele frequency (VAF) ≥ 2% with or without loss of TP53 locus was noted in 182 (37.3%) patients and 88.2% of TP53mut t-MN had a VAF ≥10%. TP53mut t-MN with VAF ≥ 10% had a distinct clinical and biological profile compared to both TP53mut VAF < 10% and wild-type TP53 (TP53wt) cases. Notably, TP53mut VAF ≥ 10% had a significantly shorter survival compared to TP53wt (8.3 vs. 21.6 months; P < 0.001), while the survival of TP53mut VAF < 10% was comparable to TP53wt. Within TP53mut VAF ≥ 10% cohort, the inferior outcomes persisted irrespective of the single- or multi-hit status, co-mutation pattern, or treatments received. Finally, survival of TP53mut patients was poor across all the blast categories and MDS patients with >10% blasts had inferior survival compared to <5%. In summary, TP53mut VAF ≥10% signified a clinically and molecularly homogenous cohort regardless of the allelic status.

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“…Various agents have been developed as drugs able to target CD123 on malignant leukemic cells ( 52 ). In patients with MM who developed AML/Myelodysplastic Syndromes, stem, and progenitor cells (collected years before the onset of secondary disease) expressed high CD123 levels ( 53 ). Here we reported that the expression of CD123 was higher on MM-EV-treated HSCs compared to untreated ones.…”

Section: Discussionmentioning

confidence: 99%

Multiple Myeloma-Derived Extracellular Vesicles Impair Normal Hematopoiesis by Acting on Hematopoietic Stem and Progenitor Cells

et al. 2021

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Multiple myeloma (MM) is characterized by the abnormal proliferation of clonal plasma cells (PCs) in bone marrow (BM). MM-PCs progressively occupy and likely alter BM niches where reside hematopoietic stem and progenitor cells (HSPCs) whose viability, self-renewal, proliferation, commitment, and differentiation are essential for normal hematopoiesis. Extracellular vesicles (EVs) are particles released by normal and neoplastic cells, such as MM cells. They are important cell-to-cell communicators able to modify the phenotype, genotype, and the fate of the recipient cells. Investigation of mechanisms and mediators underlying HSPC-MM-PC crosstalk is warranted to better understand the MM hematopoietic impairment and for the identification of novel therapeutic strategies against this incurable malignancy. This study is aimed to evaluate whether EVs released by MM-PCs interact with HSPCs, what effects they exert, and the underlying mechanisms involved. Therefore, we investigated the viability, cell cycle, phenotype, clonogenicity, and microRNA profile of HSPCs exposed to MM cell line-released EVs (MM-EVs). Our data showed that: (i) MM cells released a heterogeneous population of EVs; (ii) MM-EVs caused a dose-dependent reduction of HSPCs viability; (iii) MM-EVs caused a redistribution of the HSPC pool characterized by a significant increase in the frequency of stem and early precursors accompanied by a reduction of late precursor cells, such as common myeloid progenitors (CMPs), megakaryocyte erythroid progenitors (MEPs), B and NK progenitors, and a slight increase of granulocyte macrophage progenitors (GMPs); (iv) MM-EVs caused an increase of stem and early precursors in S phase with a decreased number of cells in G0/G1 phase in a dose-dependent manner; (v) MM-EVs reduced the HSPC colony formation; and (vi) MM-EVs caused an increased expression level of C-X-C motif chemokine receptor type 4 (CXCR4) and activation of miRNAs. In conclusion, MM cells through the release of EVs, by acting directly on normal HSPCs, negatively dysregulate normal hematopoiesis, and this could have important therapeutic implications.

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Stem cell mutations can be detected in myeloma patients years before onset of secondary leukemias

Abstract: Key Points Leukemia-associated mutations can be detected many years before the onset of secondary leukemias in myeloma patients. Stem and progenitor cells can act as reservoirs of mutations before the onset of secondary MDS and AML after treatment of myeloma.

Cited by 14 publications

References 21 publications

TP53 in Myelodysplastic Syndromes: Recent Biological and Clinical Findings

TP53 in Myelodysplastic Syndromes: Recent Biological and Clinical Findings

TP53 mutation variant allele frequency of ≥10% is associated with poor prognosis in therapy-related myeloid neoplasms

Multiple Myeloma-Derived Extracellular Vesicles Impair Normal Hematopoiesis by Acting on Hematopoietic Stem and Progenitor Cells

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