Structure and significance of cytogenetic abnormalities in adult patients with Ph-negative acute lymphoblastic leukemia

Пискунова, И. С.; Obukhova, Tatiana N.; Паровичникова, Е Н; Kulikov, Sergey; Troitskaya, Vera V.; Gavrilina, O A; Vg, Savchenko

doi:10.26442/terarkh201890730-37

Cited by 4 publications

(4 citation statements)

References 14 publications

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“…Клиническое значение активирующих мутаций в генах NRAS, KRAS, FLT3, JAK2, CRLF2 у больных, которым проводили терапию по протоколам российских многоцентровых исследований, неизвестно. Ранее в наших исследованиях при использовании принципов цитостатического воздействия, применяемых в протоколах ОЛЛ-2009, ОЛЛ-2012 и ОЛЛ-2016, нам не удалось подтвердить неблагоприятное влияние на исход заболевания ряда молекулярно-генетических маркеров, таких как делеции гена IKZF и CDKN2 (р16), которые в зарубежных исследованиях определены как факторы плохого прогноза [35][36][37]. Связано это, вероятнее всего, с тем, что разные протоколы, основанные на разных принципах цитостатического воздействия, формируют разные факторы риска.…”

Section: ââåäåíèåunclassified

Detection of activating mutations in RAS/RAF/MEK/ERK and JAK/STAT signaling pathways

Zarubina¹,

Паровичникова²,

Surin³

et al. 2020

Terapevticheskii arkhiv

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Issue.The study of activating mutations (NRAS,KRAS,FLT3,JAK2,CRLF2genes) of RAS/RAF/MEK/ERK and JAK/STAT signaling pathways in B-cell acute lymphoblastic leukemia (B-ALL) in adult patients which are included in Russian multicenter clinical trials. Materials and methods.Within the multicenter study there were 119 adult patients included withde novoB-ALL. The study was considered as prospective and retrospective. The group withBCR-ABL1-negative B-ALL consisted of up to 93 patients (45 male and 48 female, at the age of 17 to 59, the median age 31), they were treated according to the protocols ALL-2009, ALL-2016. The median follow-up lasted for 19 months (1119). The group withBCR-ABL1-positive B-ALL with up to 26 patients (10 male and 16 female, at the age of 23 to 78, the median age 34 years) was included in the study as well. The treatment was carried out according to the protocols ALL-2009 and ALL-2012 in combination with tyrosine kinase inhibitors. The median follow-up lasted for 23 months (4120). The molecular analysis of activating mutations inNRAS,KRASgenes (RAS/RAF/MEK/ERK signaling pathway) andJAK2,CRLF2genes (JAK/STAT signaling cascade) was performed via Sanger sequencing. The internal tandem duplications (ITDs) inFLT3gene were studied by fragment analysis. The evaluation of CRLF2 expression was fulfilled via flow cytometry. Results.Activating mutations inNRAS,KRAS,FLT3genes were found in 22 (23.6%) patients withBCR-ABL1-negative B-ALL. In total, 23 mutations were revealed in theNRAS(n=9),KRAS(n=12), andFLT3(n=2) genes, according to statistics that was significantly more frequent than withBCR-ABL1-positive B-ALL, these genes mutations were not identified in patients (p=0.007). The frequency of mutations detection inKRASandNRASgenes in patients withBCR-ABL1-negative B-ALL was comparable as 12.9% (12 of 93) to 9.7% (9 of 93), respectively (p=0.488). One patient was simultaneously revealed 2 mutations in theKRASgene (in codons 13 and 61).FLT3-ITD mutations were detected in 3.5% (2 of 57) cases ofBCR-ABL1-negative B-ALL. In patients withBCR-ABL1-positive B-ALLFLT3-ITD mutations were not assessed. Violations in the JAK/STAT signaling cascade were detected in 4 (4.3%) patients withBCR-ABL1-negative B-ALL. They were represented by the missense mutations ofJAK2gene (n=3) and the overexpression of CRLF2 (n=2); in one patient were detected the overexpression of CRLF2 and a mutation inJAK2gene simultaneously. No mutations were found inCRLF2gene. In patients withBCR-ABL1-positive B-ALL noJAK2mutations were detected. As long as analyzing demographic and clinical laboratory parameters between groups of patients with and without mutations, there were no statistically significant differences obtained. In the analyzed groups of patients, long-term therapy results did not differentiate according to the mutations presence inNRAS,KRAS,FLT3,JAK2genes. Also, substantive differences were not shown in the rate of the negative status achievement of the minimum residual disease between patients with and without activating mutations in the control points of the protocol (on the 70th, 133rd and 190th days). Conclusion.NRAS,KRAS,FLT3,JAK2activating mutations do not affect the long-term results of the therapy and the rate of the negative status achievement of the minimum residual disease in patients withBCR-ABL1-negative B-ALL treated by the Russian multicenter clinical trials.

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Section: ââåäåíèåunclassified

Detection of activating mutations in RAS/RAF/MEK/ERK and JAK/STAT signaling pathways

Zarubina¹,

Паровичникова²,

Surin³

et al. 2020

Terapevticheskii arkhiv

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“…However, due to inadequate specimens or lack of mitotic cells, these methods are often ineffective. Among ALL patients with a cytogenetic result, 15% to 50% have a normal karyotype [ 2 , 3 ]. Moreover, the above methods are unable to detect copy number neutral loss of heterozygosity (LOH), which can result in deregulation of cell division and apoptosis through the deletion of tumor suppressor genes [ 4 ].…”

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confidence: 99%

Loss of Heterozygosity in the Tumor DNA of De Novo Diagnosed Patients Is Associated with Poor Outcome for B-ALL but Not for T-ALL

Risinskaya

Kozhevnikova

Gavrilina

et al. 2022

Genes

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Despite the introduction of new technologies in molecular diagnostics, one should not underestimate the traditional routine methods for studying tumor DNA. Here we present the evidence that short tandem repeat (STR) profiling of tumor DNA relative to DNA from healthy cells might identify chromosomal aberrations affecting therapy outcome. Tumor STR profiles of 87 adult patients with de novo Ph-negative ALL (40 B-ALL, 43 T-ALL, 4 mixed phenotype acute leukemia (MPAL)) treated according to the “RALL-2016” regimen were analyzed. DNA of tumor cells was isolated from patient bone marrow samples taken at diagnosis. Control DNA samples were taken from the buccal swab or the blood of patients in complete remission. Overall survival (OS) analysis was used to assess the independent impact of the LOH as a risk factor. Of the 87 patients, 21 were found with LOH in various STR loci (24%). For B-ALL patients, LOH (except 12p LOH) was an independent risk factor (OS hazard ratio 3.89, log-rank p-value 0.0395). In contrast, for T-ALL patients, the OS hazard ratio was 0.59 (log-rank p-value 0.62). LOH in particular STR loci measured at the onset of the disease could be used as a prognostic factor for poor outcome in B-ALL, but not in T-ALL.

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“…1) [4]. При ОЛЛ к неблагоприятным цитогенетическим аномалиям относят t (9;22), t (4;11), t (1;19) [5]. При обнаружении этих аберраций следует рассматривать вопрос о трансплантации аллогенных гемопоэтических стволовых клеток (алло-ТГСК) [1].…”

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“…При сравнении иммунологических вариантов В-ОЛЛ характеризуется худшим течением болезни, чем Т-ОЛЛ [6]. Существуют мнения о неблагоприятном прогностическом значении мутаций генов IKZF1 (Ikaros family zinc fi nger 1) [7] и CDKN2A (cyclindependent kinase inhibitor 2A) [5].…”

unclassified

The role of interleukin-3 and its receptor in acute leukemia pathogenesis

Бальжанова¹,

Савченко²

2020

Gematologiâ i transfuziologiâ

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Introduction. Interleukin-3 (IL-3) is the key cytokine involved in the regulation of normal haematopoiesis. Some leukemic cells demonstrate high expression of the α-subunit of the receptor for interleukin-3 (CD123).Aim: to summarize the current understanding of IL-3 and its receptor CD123 in the pathogenesis of acute leukemia. General fi ndings: IL-3 regulates the proliferation and differentiation of normal hematopoietic progenitor cells in the early stages of hematopoiesis. The IL-3 receptor (CD123) is expressed on normal hematopoietic cells. High expression of CD123 was confi rmed on blast cells of AML, B-ALL and on the leukemia-initiating CD34+ CD38– cells. IL-3 inhibits apoptosis and promotes the autonomous growth of blast cells. Currently, different approaches of blocking the IL-3 mediated signal are being investigated.

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Structure and significance of cytogenetic abnormalities in adult patients with Ph-negative acute lymphoblastic leukemia

Cited by 4 publications

References 14 publications

Detection of activating mutations in RAS/RAF/MEK/ERK and JAK/STAT signaling pathways

Detection of activating mutations in RAS/RAF/MEK/ERK and JAK/STAT signaling pathways

Loss of Heterozygosity in the Tumor DNA of De Novo Diagnosed Patients Is Associated with Poor Outcome for B-ALL but Not for T-ALL

The role of interleukin-3 and its receptor in acute leukemia pathogenesis

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