Nikolay Mamaev - Academia.edu (original) (raw)

Papers by Nikolay Mamaev

$Research paper thumbnail of First experience with BAALC-expressing leukemia stem cell fraction in juvenile myelomonocytic leukemia patients treated by hematopoietic stem cell transplantation$

Cellular Therapy Transplantation, Jun 15, 2024

We report our initial study of BAALC-expressing stem cell subpopulation (BAALC-e SCs) in patient... more We report our initial study of BAALC-expressing stem
cell subpopulation (BAALC-e SCs) in patients with juvenile myelomonocytic leukemia (JMML) treated by
hematopoietic stem cell transplantation (HSCT). Our
study group included 13 patients (10 boys, 3 girls at the
age of 0.3-6 years; mean age, 2.8 years). Most of them
(n=8) harbored PTPN11 gene mutations and, less frequently, NF1 and CBL (each on one case) which related
to RAS signaling pathway), along with NRAS gene mutations (n=4). Importantly, four patients under 1 year did
achieve complete post-transplant remission, being alive
to date. At the same time, four out of five patients who
exhibited EVI1 – positive variant of JMML died in sooner
time. A patient, treated with haplo-HSCT still developed
complete clinical and molecular remission and survived
so far without any relapses. According to our findings,
the size of BAALC-e SCs subpopulation in patients with
JMML detected with real-time quantitative polymerase
chain reaction (RT-qPCR) ranged from 73 and 9%, and
exceeded the pre-established cut-off level (31%) in 9 of
13 cases (70%). No associations were revealed between
this index and gene mutations affecting RAS signaling
pathway, or WBC counts. We believe that this parameter, being monitored in cohort studies, might be implemented in clinical setting for risk stratification of JMML
patients as well as for evaluation of therapeutic efficacy,
e.g., in HSCT patients. .
Keywords
Juvenile myelomonocytic leukemia, leukemia stem cells,
BAALC-expressing, WT1, EVI1, overexpression, hematopoietic stem cell transplantation.

Journal of hematology research, Oct 16, 2023

Cellular therapy and transplantation, Oct 31, 2023

Chromosome copy number changes, also known as aneuploidy, is a ubiquitous feature of cancer cell ... more Chromosome copy number changes, also known as aneuploidy, is a ubiquitous feature of cancer cell genome. DNA sequencing studies of the tumor cells have shown that the aneuploidy patterns are nonrandom, and specific chromosome gains occur quite frequently, thus, probably, playing an oncogene-like role in tumor development. It is well known that certain copy number changes, such as 1q gain, are of predictive value in many tumor types. It has been recently shown that the 1q gain is associated with increased expression of the MDM4 oncogene located at 1q32 which is responsible for the downregulation of TP53 gene in Fanconi anemia and clonal hematopoiesis development. Case presentation Here we present a rare case of Fanconi anemia in a 31-year-old Syrian male patient at the early stage of MDS/AML transformation. His bone marrow cells showed 1q and 3q gains combined with severely suppressed TP53 gene expression, along with low WT1 and BAALC gene expression. Conclusion Since acquisition of additional 1q/MDM4 copies is common to many solid tumors and oncohematological diseases is considered a reliable marker predictive of cancer progression, this molecular feature needs further indepth study.

Experimental hematology & oncology, 2014

The gene RUNX1 at chromosome 21q22 encodes the alpha subunit of Core binding factor (CBF), a hete... more The gene RUNX1 at chromosome 21q22 encodes the alpha subunit of Core binding factor (CBF), a heterodimeric transcription factor involved in the development of normal hematopoiesis. Translocations of RUNX1 are seen in several types of leukemia with at least 21 identified partner genes. The cryptic t(7;21)(p22;q22) rearrangement involving the USP42 gene appears to be a specific and recurrent cytogenetic abnormality. Eight of the 9 cases identified in the literature with this translocation were associated with acute myeloid leukemia (AML), with the remaining case showing refractory anemia with excess blasts, type 2. Herein, we present a patient with two preceding years of leukopenia and one year of anemia prior to the diagnosis of AML, NOS with monocytic differentiation (myelomonocytic leukemia) whose conventional cytogenetics showed an abnormal clone with 5q deletion. Interphase FISH using LSI RUNX1/RUNXT1 showed three signals for RUNX1. FISH studies on previously G-banded metaphases ...

Cellular Therapy Transplantation, 2023

A rare case of Fanconi anemia in a 31-year-old Syrian male patient at the early stage of MDS?AML ... more A rare case of Fanconi anemia in a 31-year-old Syrian male patient at the early stage of MDS?AML transformation is presented/ Yis bone marrow cells showed 1q and 3q gains combined with severely suppressed TP53 gene expression, along with low WT1 and BAALC gene expressions.

Clinical oncohematology, 2017

Aim. To evaluate the effectiveness of preventive and prophylactic post-transplantation therapy us... more Aim. To evaluate the effectiveness of preventive and prophylactic post-transplantation therapy using azacitidine (5-AZA) in patients at high risk of post-transplantation relapse. Methods. 136 patients were included in the study performed by the pairwise comparison: 68 of them received 5-AZA after allo-HSCT and 68 patients were included in the historical control group. 5-AZA was prescribed for prophylactic or preventive purposes. The results were assessed according to the OS, RR, EFS, DUM, and relapse-free and GVHR-free survival. Results. 1-year OS was 76 % in the 5-AZA group (95% CI 60-84 %) and 44 % in the reference group (95% CI 33-55 %) (р = 0.001); 2-year OS was 63 % (95% CI 39-67 %) and 37 % (95% CI 26-48 %) (р = 0.007), respectively. The relapse rate (RR) in the 5-AZA group was 34 % (95% CI 22-46 %) during 1 year and 51 % (95% CI 38-64 %) in the reference group (р = 0.02). 1- and 2-year disease unrelated mortality (DUM) was similar: 5 % in the 5-AZA group (95% CI 0.1-14.0 %) a...

Cellular Therapy Transplantation, 2021

There is evidence that relapses of acute myeloid leukemia (AML) are closely related to heterogene... more There is evidence that relapses of acute myeloid leukemia (AML) are closely related to heterogeneous population of leukemic precursors. At least, two classes of
the leukemia-initiating cells (LIC) may be discerned, according to recent experimental studies with hematopoietic cell transplants to immunodeficient mice. The main
class of LICs is presented by immature precursors with
CD34+CD38–
immunophenotype which, in turn, are capable of selective expression of BAALC gene. The second
class of LICs is presented by relatively mature precursors with more differentiated immunophenotypes. According to indirect findings, they are able of WT1 gene
expression, along with blast cells. Since both BAALC
and WT1 mRNAs may be quantitatively evaluated by
means of standardized quantitative polymerase reaction
in real time (qRT-PCR), this approach may be effective
for specifying the mechanisms of relapses and resistance
to therapy in AML patients. The aim of this work was
to perform simultaneous dynamic evaluation of BAALC
and WT1 genes expressions along with determination of
blast numbers in the tested bone marrow samples in 14
AML patients treated at our Center with Gemtuzumab
ozogamicin (GO, Mylotarg), which was combined with
high-dose chemotherapy (ChT), followed by allogeneic
hematopoietic stem cell transplantation (allo-HSCT).
Our preliminary results are as follows: a) superior 3-year
overall survival (OS) in general group of patients with
normal or nearly-normal karyotypes, and FLT3-mutated AML variants as compared to those with more complex karyotypes and EVI1 gene overexpression (85.7%
vs 16.7%; p=0.032); b) highly sensitive response of immature BAALC-expressing precursors to combined ChT
and GO treatment; c) hypothetical participation of some
mature precursors, along with blast cells, in WT1 gene
expression; d) real evidence for switching hematopoietic
regulation from immature BAALC-expressing precursors to more mature WT1-expressing progeny. These
results suggest diagnostic utility of combined BAALC/
WT1/blast counts panel for quantitative studies and assessment of distinct precursors in AML progression and
emergence of relapses.

Clinical Oncohematology, 2014

The results of allogeneic hematopoietic stem cell transplantation (HSCT) in 17 patients (pts, 11 ... more The results of allogeneic hematopoietic stem cell transplantation (HSCT) in 17 patients (pts, 11 male, 6 female) with myelodysplastic syndromes (3 RA/RARS/RCMD, 5 RAEB-1, 7
RAEB-2, 2 JMML) are presented. The median age was 26
years with a range between 1 and 55 years. Serial cytogenetic investigations were carried out in all of them. Seven pts
demonstrated monosomy 7, which was associated with other
chromosome abnormalities in 4 cases. In addition, deletion at
11q23 (n = 3), trisomy 8 (n = 2) and 21 (n = 2), involvement
into rearrangement at 3q (n = 2), t(6;9) translocation, and others more rare abnormalities were found. Prior to aHSCT, 11
of 7 received hypomethylating agents (HA) which proved to
be effective in a half of them. In order to prepare for aHSCT,
ablative (busulfan, cyclophosphamide) or non-ablative (fludarabine, cyclophosphamide) conditioning regimes were applied
(4 and 13 respectively). Repeated aHSCT was carried out in
6 pts because of transplant rejection or post-transplant relapses. Molecular monitoring of minimal residual disease as well
as early diagnosis of these relapses was performed by means
of serial tests of the WT1 gene level expression and donor chimerism. Maximum WT1 values varied between 15 and 43133
copies/104
copies of ABL gene; and molecular relapses were
registered in a half of them, including 5 patients with transformation into acute leukemia (AL). HA were used for prevention
and treatment of relapses in 4 (24 %) patients; and HA were
combined with donor lymphocyte infusions. Standard chemotherapy was applied for these purposes relatively rarely. This
study demonstrated WT1 gene overexpression to be not only
an important marker for diagnosis of post-transplant MDS/AL
relapses, but it also can be used for evaluation of the treatment efficacy

We present the clinical and laboratory data on a 13-year old patient with the recently described... more We present the clinical and laboratory data on a 13-year old
patient with the recently described variant of CD56-positive
acute myeloid leukemia with criptic t(7;21)(p22;q22) translocation involving rearrangements of RUNX1 and USP42
genes, 5q deletion, and hemophagocytosis. According to
the literature, this rare recently described AML subvariant
mostly occurs in males, is resistant to chemotherapy, and
can be successfully treated using allogeneic hematopoietic
stem cell transplantation.

The book deals with the depth nature of leukemic stem cells (LSC) which is attributed to leukemia... more The book deals with the depth nature of leukemic stem cells (LSC) which is attributed to leukemia cell type. Among the other expressing molecular markers, the BAALC gene expression holds a specifuc place. The BAALC genewho tied their work with in depth studies in onco seems to be selectively linked with active fraction of Leukemia Stem Cells (aLSC) which, in turn, will allow cliniciens to use it actively for aLSC"s burdrns estimating at the clinical setting by means standard Real-time qPCR. Meanwhile, the book contains the data of recently carried out author"s studies on the topic which is capable to convince future readers and researches in term-line of these investigations in oncohematology. The book is accounted not only hematologists but biologists too who tied their work with in depth studies in oncohematology. In whole, original concept of BAALC-expressing LSC opens a wide avenue for in depth investigations in the field: a) Leukemia and MDS pathogenesis; and b) efficacy assay of new agents and more ineresting novel therapeutic approaches on the level of earlier LSCs.

Journal Hematology Research, 2023

: A discovery of nonrandom recurrent interstitial aberration at the long arm of chromosome 5 was ... more : A discovery of nonrandom recurrent interstitial aberration at the long arm of chromosome 5 was made by Van
den Berghe et al. in 1974. For a long time, this entity was classified as myelodysplastic syndrome (MDS). Meanwhile, its
definition as well as classification criteria were repeatedly changed due to both clinical studies and advances in new
techniques. In particular an insufficiency of ribosome-forming protein (RPS14) gene was found soon after similar gene
RPS19 discovery in patients with severe inherited Diamond-Blackfan anemia (DBA). It cannot be excluded that basic
pathogenetic mechanisms, including participation of activated gene TP53, seem to be similar in both entities.
This article for the first time presents the quantitative data on the BAALC expression in the majority (25/31) of patients
tested with 5q- deletions to be under the cut-off values. It concerns a group of 14/16 patients with isolated 5q- anomaly,
and 11 other cases in whom 5q- deletion was combined with additional non-identical chromosomal aberrations. On the
contrary, this molecular parameter exceeded the cut-off levels in all (n=10) MDS patients without 5q- abnormality.
Hence, these data might effectively support an assumption of a ribosomopathy in cases of isolated 5q- deletion. Since
about 8-10 % of these patients are transformed into MDS and/or secondary AML, a possible exclusion of isolated 5qdeletion syndrome from MDS category should be discussed carefully and this assumption is needed an additional
support in larger studies.
Keywords: 5q- deletion, BAAL

Cellular Therapy Transplantation, 2019

The aim of this study was to clarify close associations between population of bone marrow blast ... more The aim of this study was to clarify close associations
between population of bone marrow blast elements defining cytological relapse, and that of leukemic precursor cells by means of serial quantitative measurement of
WT1 and BAALC molecular markers expressed by appropriate cell types. In clinical terms, we sought to evaluate a potential for evolving leukemia relapses following
hematopoietic stem cell transplantation (HSCT). The
post-transplant relapses (PTR), in view of their biological mechanisms, may be detected by overexpression of
distinct differentiation-related genes.
Patients and methods
We have done parallel serial measurements of BAALC
and WT1 gene expression in bone marrow cells of the
patients with acute myeloid leukemia, using quantitative
real-time PCR (qPCR) with gene-specific primers.
Results
An initial pilot study was carried out in twelve patients
with elevated WT1 expression levels and normal blast
counts (<5%) in bone marrow at the time of allogeneic
HSCT. It has shown that the relapse occurrence and
shorter relapse-free survival (RFS) post-transplant were
more common in the subgroup with higher BAALC gene
expression level as compared to those without BAALC expression elevation (p=0.002, and p=0.019, respectively).
Moreover, when analyzing the validating patient cohort, we have found that the simultaneous elevation of
both BAALC and WT1 expression, known as unfavorable prognostic factor, was more frequently observed in
the patients with AML М1, М2, and М0 FAB-variants.
Preliminary results show an inferior overall survival
(a mean of 228 days) in AML patients with combined
overexpression of the both genes immediately before
HSCT, like as in post-transplant period. In conclusion, it
should be noted that our findings of simultaneous overexpressions of BAALC and WT1 genes in great cohort of
adults and children patients with different FAB- variants
of AML treated by means of allo-HSCT were revealed
for the first time. Being associated with poor prognosis,
this double test should be used actively for post-transplant monitoring of all patients with AML.

Clinical Onkohematology , 2017

Aim. To evaluate the effectiveness of preventive and prophy-lactic post-transplantation therapy u... more Aim. To evaluate the effectiveness of preventive and prophy-lactic post-transplantation therapy using azacytidine (5-AZA) inpatients at high risk of post-transplantation relapse.
Methods. 136 patients were included in the study performed by the pairwise comparison: 68 of them received 5-AZA after allo-HSCT and 68 patients were included in the historical control group. 5-AZA was prescribed for prophylactic or preventive purposes. The results were assessed according to the OS, RR,EFS, DUM, and relapse-free and GVHR-free survival.
Results. 1-year OS was 76 % in the 5-AZA group (95% CI60–84 %) and 44 % in the reference group (95% CI 33–55 %)(p = 0.001); 2-year OS was 63 % (95% CI 39–67 %) and 37 %(95% CI 26–48 %) (p = 0.007), respectively. The relapse rate (RR)in the 5-AZA group was 34 % (95% CI 22–46 %) during 1 year and 51 % (95% CI 38–64 %) in the reference group (p = 0.02). 1-and 2-year disease unrelated mortality (DUM) was similar: 5 % in the 5-AZA group (95% CI 0.1–14.0 %) and 25 % (95% CI 13–37 %)in the reference group ( p = 0.005). 1-year EFS was 76 % in the5-AZA group (95% CI 61–85 %) and 44 % in the reference group(95% CI 33–55 %) (p = 0.001); 2-year EFS was 63 % (95% CI39–67 %) and 37 % (95% CI 26–48 %) (p = 0.01), respectively.1-year relapse-free and GVHR-free survival was 55 % in the5-AZA group (95% CI 41–69 %) and 28 % in the reference group(95% CI 17–39 %) (p = 0.001); 2-year relapse-free and GVHR-free survival was 47 % (95% CI 32–62 %) and 27 % (95% CI 17–37 %)(p = 0.002), respectively.
Conclusion. The use of 5-AZA for prophylactic and preventive purposes after allo-HSCT does not increase the risk of GVHR and DUM, does not suppress the GVL effect and can be used in combination with the donor lymphocyte infusion (DLI). The therapy with 5-AZA is safe during the early period after allo-HSCT. The drug does not suppress the GVL effect and can be used in high risk patients to prevent early post-transplantation relapse. The use of 5-AZA in combination with DLI does not increase the incidence of severe GVHR

(PDF) Acute Myeloblastic Leukemia and Myelodysplastic Syndrome: Azacitidine for Prophylactic and Preventive Purposes after Allogeneic Hematopoietic Stem Cell Transplantation. Available from: https://www.researchgate.net/publication/313465198_Acute_Myeloblastic_Leukemia_and_Myelodysplastic_Syndrome_Azacitidine_for_Prophylactic_and_Preventive_Purposes_after_Allogeneic_Hematopoietic_Stem_Cell_Transplantation [accessed Nov 20 2023].

(PDF) Acute Myeloblastic Leukemia and Myelodysplastic Syndrome: Azacytidine for Prophylactic and Preventive Purposes after Allogeneic Hematopoietic Stem Cell Transplantation. Available from: https://www.researchgate.net/publication/313465198_Acute_Myeloblastic_Leukemia_and_Myelodysplastic_Syndrome_Azacitidine_for_Prophylactic_and_Preventive_Purposes_after_Allogeneic_Hematopoietic_Stem_Cell_Transplantation [accessed Nov 20 2023].

We present the case of successful treatment of posttransplantation relapse of prognostically unfa... more We present the case of successful treatment of posttransplantation relapse of prognostically unfavorable AML with inv(3)(q21q26), -7 and EVI1 oncogene overexpression, when stable donor hematopoiesis reconstitution was achieved due to one high-dose cytarabine course, DLI, and hypomethylating agents (decitabine, 5-azacitidine). Possible molecular mechanisms of this effect are discussed with respect to the new approaches to management of such patients.

Clinical Oncohematology, 2021

EVI1 gene overexpression was evidenced and analyzed in 27 patients (17 males, 10 females, mean ag... more EVI1 gene overexpression was evidenced and analyzed in 27 patients (17 males, 10 females, mean age 34,3 ± 18,4 years) with acute myeloid leukemia (AML, n = 9), myelodysplastic syndromes (MDS, n = 3), chronic myeloid leukemia, resistant to tyrosine-kinase inhibitors (CML, n = 14), and Ph+ acute lymphoblastic leukemia (Ph+ ALL, n = 1). The higher levels of EVI1 gene expression (69,03 and 55,48 per 100 expressions of ABL gene) were diagnosed in patients with AML and Ph+ ALL, respectively. According to our data, the levels of EVI1 gene expressions ranged from 4,01 to 52,1 and from 10,36 to 69,03 per 100 expressions of ABL gene in patients with CML and AML-MDS, respectively. These pts. are characterized by different cytogenetic and molecular profiles, but EVI1 gene overexpression is not associated with such poor prognostic mutation of BCR/ABL gene as T3151. Despite allogeneic haematopoietic stem cell transplantation (HSCT) is considered to be a single curative approach in these patients,...