Functional Analysis Of SEPT9-ABL1 Chimeric Fusion Gene Derived From T-Prolymphocytic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3806-3806
Author(s):  
Kawai Hidetsugu ◽  
Matsushita Hiromichi ◽  
Suzuki Rikio ◽  
Sheng Yin ◽  
Lu Jun ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Cellular Proliferation ◽  
Fusion Gene ◽  
Myeloproliferative Neoplasms ◽  
Lymphoblastic Leukemia ◽  
Exon 2 ◽  
Prolymphocytic Leukemia ◽  
Infected Cells

Abstract ABL1 gene encoding a non-receptor tyrosine kinase has been involved as ABL1 chimeric genes in hematological malignancies. Their partner genes include BCR in chronic myeloid leukemia (CML), B-acute lymphoblastic leukemia (B-ALL), T-acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML), ETV6 in B-ALL, T-ALL, AML and myeloproliferative neoplasms (MPNs), RCSD1, SFPQ, ZMIZ1, FOXP1, SNX2, GAG in B-ALL, NUP214 and EML1 in T-ALL. The resultant chimeric gene products have been shown to associate with a cellular proliferation through constitutive activation of ABL1 signaling. In addition, they are the therapeutic targets for tyrosine kinase inhibitors (TKIs). We identified a novel chimeric fusion gene SEPT9 (Septin9)-ABL1 in a case of T-prolymphocytic leukemia (T-PLL) using 5’- RACE PCR. It is generated by an in-frame fusion between SEPT9 exon 4 and ABL1 exon 2. The case was treated with imatinib and dasatinib, but the tumor burden did not reduce at all. The purpose of this study was to analyze the biological functions of the SEPT9-ABL1 gene product including TKIs sensitivity. The expression analysis in the case using RT-PCR and Western blot revealed that there were at least 4 isoforms applying SEPT9a, SEPT9d, SEPT9e and SEPT9f as the fusion partners. SEPT9a-ABL1 was expressed most strongly among the SEPT9-ABL1 isoforms. The SEPT9-ABL1 isoforms were retrovirally transduced into 32D cells, a murine interleukin3 (IL-3) dependent hematopoietic cell line. All of these isoforms caused 32D cells an IL-3 independent proliferation. Their proliferation rates were less than 32D cells with BCR-ABL1, and that of 32D cells with SEPT9d-ABL1 was subtle (day0, 1×105 cells/ ml; day2, the densities of 32D cells with BCR-ABL1, SEPT9a-ABL1, SEPT9d-ABL1 SEPT9e-ABL1 and SEPT9f-ABL1 were 17.8×105, 6.7×105, 2.7×105, 6.0×105 and 6.1×105 cells /ml, respectively). In consistent with the results of cellular proliferation, the immunocytological analysis revealed SEPT9a-ABL1, SEPT9e-ABL1 and SEPT9f-ABL1 proteins localized mainly in the cytoplasm. When these cells were transplanted into C3H/HeJ mice (5×106/ mouse). Mice with SEPT9e-ABL1- and SEPT9f-ABL1-infected cells died with the infiltration of transplanted cells into bone marrow, spleen and liver within 50 days. It was later than mice with BCR-ABL1 infected cells. Half maximal inhibitory concentrations (IC50) of imatinb in 32D cells infected with BCR-ABL1, SEPT9a-ABL1, SEPT9e-ABL1 and SEPT9f-ABL1 were 2.52μM, 0.96μM, and 2.08μM, respectively. They were higher than IC50 with BCR-ABL1 (0.28μM)( SEPT9a-ABL1, 9.0 times, p<0.001; SEPT9e-ABL1, 3.4 times, p=0.011; SEPT9f-ABL1, 9.0 times, p=0.009). In addition, IC50 of dasatinib in the above cells were 12.6nM, 15.8nM and 16.0nM, respectively. They were also higher than IC50 with BCR-ABL1 (0.66nM) (SEPT9a-ABL1, 19.1 times, p=0.019; SEPT9e-ABL1, 23.9 times, p=0.016; SEPT9f-ABL1, 24.2 times, p<0.001) These data demonstrated that SEPT9-ABL1 fusion gene provide autonomous cellular proliferation in vitro and in vivo, according to the isoforms which showed different cellular distribution. In addition, the sensitivity of 3 evaluated SEPT9-ABL1 isoforms to TKIs was significantly higher than BCR-ABL1, confirming the TKI- resistant character as seen in the case. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Droplet Digital PCR Phasing (DROP-PHASE): A Novel Method for Straightforward Detection of BCR-ABL1 Compound Mutations in Tyrosine Kinase Inhibitors Resistant Chronic Myeloid Leukemia (CML) and Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4660-4660 ◽  
Author(s):  
Pascal Vannuffel ◽  
Luana Bavaro ◽  
Friedel Nollet ◽  
Asena Aynaci ◽  
Margherita Martelli ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Lymphoblastic Leukemia ◽  
Digital Pcr ◽  
Kinase Domain ◽  
Droplet Digital Pcr ◽  
Drop Phase

Chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) are, respectively, a myeloproliferative and a lymphoproliferative neoplasm that can be characterized by the chimeric fusion oncogene BCR-ABL1. Tyrosine Kinase Inhibitors (TKI) are the standard therapy for patients with CML/ALL. However, mutations of the BCR-ABL1 kinase domain constitute a major cause of treatment failure in CML and ALL receiving TKI therapy. While 2nd and 3rd generation TKI have proven their efficacy against mutated BCR-ABL1-mediated clonal expansion, the presence of compound mutations can produce high level of resistance to these TKIs. Even the last addition to the TKI armamentarium, ponatinib, remains ineffective against some BCR-ABL1 compound mutations (Zabriskie, M.S., et al., BCR-ABL1 Compound Mutations Combining Key Kinase Domain Positions Confer Clinical Resistance to Ponatinib in Ph Chromosome-Positive Leukemia. Cancer Cell, 2014. 26(3):p.428-442). Therefore, the distinction between compound (different mutations present on 1 unique malignant clone) and polyclonal mutations (different mutations present on 2 or more different clones) is of great clinical importance in order to select the most suitable treatment and to estimate outcomes. The objective of this study is to determine in a straightforward way whether BCR-ABL1 mutations discovered by Next Generation Sequencing are compound mutations or polyclonal mutations. A simple proof-of-concept experiment was first performed by using 3 synthetic oligonucleotides (gBlocks, IDT) mimicking the presence of compound mutations versus polyclonal mutations in resistant leukemia cells. The first oligo harbored the M237I mutation, the second oligo mutations E255K, E279K, V299L, T315I, F359V, A380S, H396R, S417Y, F459K and F486S and the third one contained all the mutations. Dual-color probes assays have been set up to target specifically 2 different mutations. Mixtures of 2 oligonucleotides harboring 1 mutation each versus 1 oligonucleotide harboring 2 mutations have been compared by performing duplex droplet digital PCR (ddPCR) reactions on the Bio-Rad ddPCR QX200 System. Linkage detection is based on the observation that the presence of 2 targets on the same DNA molecule increases the number of double-positive droplets relative to the number expected due to chance. Automatic linkage evaluation was made by the QuantaSoft Software and mathematical calculations refer to (Regan, J.F., et al., A rapid molecular approach for chromosomal phasing. PLoS One, 2015. 10(3): p. e0118270). The first experiment successfully validated the detection of mutations residing on two different oligonucleotides (polyclonal mutations) versus mutations on the same molecule (compound mutations). When performing serial dilutions of 2 oligonucleotides containing different mutations, a sensitivity of 10%:90% was achieved with a good linearity (r2=0.97). Mixing experiment also showed that ddPCR phasing could distinguish between a mixture of compound and polyclonal mutations versus and the sole presence of polyclonal mutations at the same sensitivity and linearity levels. Moreover, no influence of the genomic distance between mutations (from position 255 to position 562) was observed. The strategy was further applied to 20 clinical samples from CML/ALL patients characterized by multiple resistance mutations. Drop-phase is a rapid (< 4 hours), scalable (100 samples), technically easy to perform and cost-effective method. This strategy will help to identify compound mutations in patients with TKI-resistant CML/ALL and allow to modulate the patient's drug strategy and to prevent progression and therapeutic failure. Disclosures Vannuffel: Incyte: Consultancy. Soverini:Incyte: Consultancy.

scholarly journals Expression of the ABL-BCR fusion gene in Philadelphia-positive acute lymphoblastic leukemia

Blood ◽  
1993 ◽  
Vol 81 (10) ◽  
pp. 2488-2491 ◽  
Author(s):  
JV Melo ◽  
DE Gordon ◽  
A Tuszynski ◽  
S Dhut ◽  
BD Young ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Fusion Gene ◽  
Polymerase Chain Reaction Amplification ◽  
Lymphoblastic Leukemia ◽  
Derivative Chromosome ◽  
Exon 2 ◽  
Chromosome 9Q ◽  
Ph Chromosome ◽  
Junction Type ◽  
Reaction Amplification

We have previously shown that the chimeric gene ABL-BCR, formed on the derivative chromosome 9q+ as a result of the t(9;22) translocation, is transcriptionally active in 65% of chronic myeloid leukemia patients. We have now used the same technique, reverse transcription/polymerase chain reaction amplification of ABL-BCR transcripts, to study nine patients with Philadelphia (Ph) chromosome-positive acute lymphoblastic leukemia (ALL); seven expressed the P190 and two the P210 type of BCR- ABL fusion protein. All seven patients with P190 had ABL-BCR transcripts containing a junction between ABL exon Ib and BCR exon 2 (Ib-e2); in two cases, ABL-BCR transcripts with the Ia-e2 junction type were also present. Of the two P210 ALL patients, one had a Ib-b4 ABL- BCR transcript and the other showed no detectable ABL-BCR expression. Although the BCR-ABL gene is probably fundamental in the pathogenesis of the Ph+ leukemias, differential expression of the ABL-BCR gene could contribute to the biologic heterogeneity of the disease.

scholarly journals Expression of the ABL-BCR fusion gene in Philadelphia-positive acute lymphoblastic leukemia

Blood ◽  
1993 ◽  
Vol 81 (10) ◽  
pp. 2488-2491 ◽  
Author(s):  
JV Melo ◽  
DE Gordon ◽  
A Tuszynski ◽  
S Dhut ◽  
BD Young ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Fusion Gene ◽  
Polymerase Chain Reaction Amplification ◽  
Lymphoblastic Leukemia ◽  
Derivative Chromosome ◽  
Exon 2 ◽  
Chromosome 9Q ◽  
Ph Chromosome ◽  
Junction Type ◽  
Reaction Amplification

Abstract We have previously shown that the chimeric gene ABL-BCR, formed on the derivative chromosome 9q+ as a result of the t(9;22) translocation, is transcriptionally active in 65% of chronic myeloid leukemia patients. We have now used the same technique, reverse transcription/polymerase chain reaction amplification of ABL-BCR transcripts, to study nine patients with Philadelphia (Ph) chromosome-positive acute lymphoblastic leukemia (ALL); seven expressed the P190 and two the P210 type of BCR- ABL fusion protein. All seven patients with P190 had ABL-BCR transcripts containing a junction between ABL exon Ib and BCR exon 2 (Ib-e2); in two cases, ABL-BCR transcripts with the Ia-e2 junction type were also present. Of the two P210 ALL patients, one had a Ib-b4 ABL- BCR transcript and the other showed no detectable ABL-BCR expression. Although the BCR-ABL gene is probably fundamental in the pathogenesis of the Ph+ leukemias, differential expression of the ABL-BCR gene could contribute to the biologic heterogeneity of the disease.

scholarly journals Fusion of EML1 to ABL1 in T-cell acute lymphoblastic leukemia with cryptic t(9;14)(q34;q32)

Blood ◽  
2005 ◽  
Vol 105 (12) ◽  
pp. 4849-4852 ◽  
Author(s):  
Kim De Keersmaecker ◽  
Carlos Graux ◽  
Maria D. Odero ◽  
Nicole Mentens ◽  
Riet Somers ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Coiled Coil ◽  
Signal Transducers ◽  
Extracellular Signal ◽  
Cell Acute Lymphoblastic Leukemia

Abstract The BCR-ABL1 fusion kinase is frequently associated with chronic myeloid leukemia and B-cell acute lymphoblastic leukemia but is rare in T-cell acute lymphoblastic leukemia (T-ALL). We recently identified NUP214-ABL1 as a variant ABL1 fusion gene in 6% of T-ALL patients. Here we describe the identification of another ABL1 fusion, EML1-ABL1, in a T-ALL patient with a cryptic t(9;14)(q34;q32) associated with deletion of CDKN2A (p16) and expression of TLX1 (HOX11). Echinoderm microtubule-associated protein-like 1-Abelson 1 (EML1-ABL1) is a constitutively phosphorylated tyrosine kinase that transforms Ba/F3 cells to growth factor-independent growth through activation of survival and proliferation pathways, including extracellular signal-related kinase 1/2 (Erk1/2), signal transducers and activators of transcription 5 (Stat5), and Lyn kinase. Deletion of the coiled-coil domain of EML1 abrogated the transforming properties of the fusion kinase. EML1-ABL1 and breakpoint cluster region (BCR)-ABL1 were equally sensitive to the tyrosine kinase inhibitor imatinib. These data further demonstrate the involvement of ABL1 fusions in the pathogenesis of T-ALL and identify EML1-ABL1 as a novel therapeutic target of imatinib. (Blood. 2005;105:4849-4852)

scholarly journals Dasatinib—A Generation Ahead

2021 ◽  
Author(s):  
Subramaniam Murali Carthikeyan ◽  
Perumal Kalaiyarasi Jayachandran
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Pleural Effusion ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Molecular Responses ◽  
Ph Chromosome

AbstractDasatinib is a highly potent second-generation (2G) tyrosine kinase inhibitor (TKI) used in the management of Philadelphia (Ph) chromosome-positive leukemias, chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL). In CML, dasatinib produces higher rates of early and deeper molecular responses compared with imatinib. The drug has its share of toxicities, namely, cytopenias, cardiovascular, and pleural effusion. This review describes the pharmacological aspects of dasatinib, clinically relevant toxicities, and their management.

scholarly journals Case Report: The First Report of NUP214-ABL1 Fusion Gene in Acute Myeloid Leukemia Patient Detected by Next-Generation Sequencing

2021 ◽  
Vol 11 ◽  
Author(s):  
Huan-Ping Wang ◽  
Jun-Jun He ◽  
Qiao-Yun Zhu ◽  
Lin Wang ◽  
Jian-Hu Li ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
First Case ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Generation Sequencing ◽  
Acute Myeloid

The NUP214-ABL1 fusion gene is a constitutively active tyrosine kinase that can be detected in 6% of T-cell acute lymphoblastic leukemia (T-ALL) patients, and it can also be found in B-cell acute lymphoblastic leukaemia (B-ALL). However the NUP214-ABL1 fusion in acute myeloid leukemia (AML) has not yet been reported. Up to now, the sensitivity of NUP214-ABL1-positive patients to tyrosine kinase inhibitor (TKI) is still controversial. Here we report the first case of an AML patient carrying NUP214-ABL1 fusion gene. The conventional AML chemotherapy regimen for the patient was successful. Identification of additional AML patients with NUP214-ABL1 fusion gene will provide treatment experience and prognostic evaluation.

scholarly journals Identification of the Novel Fusion Gene, SPAG9-JAK2, in Adolescent Acute Lymphoblastic Leukemia (ALL) with t(9;17)(p24;q21), and Its Association with Gene Alterations Involved in Ph1/BCR-ABL1-like ALL

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5356-5356
Author(s):  
Machiko Kawamura ◽  
Tomohiko Taki ◽  
Kentarou Ohki ◽  
Yasuhide Hayashi
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Tyrosine Kinase ◽  
Bone Marrow Cells ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Snp Array ◽  
Fusion Transcript ◽  
Marrow Cells

Abstract Introduction: JAK2, which is located on chromosome 9p24, encodes a cytoplasmic tyrosine kinase involved in cytokine-mediated signal transduction, and is fused to 10 partner genes in hematological malignancies, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia, atypical chronic myelogenous leukemia, myelodysplastic syndrome/ myeloproliferative neoplasms (MPN), and Hodgkin lymphoma with 9p24 translocations. Furthermore, a somatic acquired activating mutation of JAK2 (V617F) was noted in a majority of patients with MPN, and mutations at R683 of JAK2 was detected not only in ALL with Down syndrome, but also in high-risk pediatric B-cell progenitor (BCP)-ALL. Case presentation: A 14-year-old boy presenting with a persistent fever was admitted to our hospital because of hyperleukocytosis and thrombocytopenia. Cytogenetic analysis demonstrated the 46,XY,t(9;17)(p24;q21) in 17 of 20 bone marrow cells. He was classified as extremely high risk BCP-ALL with myeloid marker and treated on TCCSG L95-14 HEX/SCT protocol. He obtained a complete remission after the induction therapy, relapsed after 7 months. Although he underwent an auto bone marrow transplant because he had no matched donor, 19 months after the initial diagnosis, he died due to progressive disease. Materials&Methods: To characterize the breakpoints, FISH analysis was performed on metaphase chromosome using BAC clones closely flanking JAK2. Genomic DNA and total RNA were isolated from bone marrow cells at diagnosis and relapse. For the mRNA-Seq sample preparation, sequencing libraries were generated according to the standard Illumina protocol for high-throughput sequencing. Using a HiSeq 2000 sequencer, 100 bp-paired end reads were obtained. Mapping reads to genes were performed by using a Bowtie software and fusion transcript discovery was done by a deFuse data analysis software. We evaluated DNA copy number changes by multiplex ligation-dependent probe amplification (MLPA) analysis and Single nucleotide polymorphism (SNP) array analysis. Results: FISH showed a fusion signal on normal chromosome 9, and split signals on der(9) and der(17). We identified a novel JAK2 fusion gene by paired-end mRNA-seq. This fusion transcript was identified. RT-PCR followed by direct sequencing confirmed the in-frame fusion of SPAG9 exon 26 and JAK2 exon 19. Moreover, the homozygous deletion of CDKN2A, TRG, TRA/D, and IGH and hemizygous deletion of CDKN2B, PAX5, BTG1, CDK6, TRB, ADARB2, IGL and IKZF1were identified by MLPA and SNP array. Discussion: This ALL having both rearrangement activating tyrosine kinase and genomic lesions affecting lymphoid transcription factors is similar to the Philadelphia chromosome (Ph1)/BCR-ABL1 like ALL subgroup. In conclusion, we have identified SPAG9 as a novel fusion partner of JAK2 gene in adolescent BCP-ALL as a consequence of a t(9;17)(p24;q21). The further examination of this fusion gene may be worthwhile to consider that JAK2 would be a good target for treatment in refractory ALL patients with rearrangements in JAK2. Disclosures No relevant conflicts of interest to declare.

scholarly journals Targeting Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia with a Novel Transcriptional Inhibitor

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2737-2737
Author(s):  
Shintaro Maeda ◽  
Ken Morita ◽  
Kensho Suzuki ◽  
Hiroshi Sugiyama ◽  
Souichi Adachi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Transcription Factor ◽  
Body Weight ◽  
Acute Lymphoblastic Leukemia ◽  
Tyrosine Kinase ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Survival Period ◽  
T315i Mutation

Abstract Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) is caused by reciprocal translocation between chromosome 9 (region q34) and chromosome 22 (region q11). This translocation results in oncogenic BCR-ABL fusion gene that encodes a chimeric BCR-ABL protein, continuously activated tyrosine kinase which causes unregulated cell division and leukemia. Although tyrosine kinase inhibitors (TKIs) are the most useful treatment against Ph+ALL patients, a part of them steadily become refractory to current therapy mainly through acquired mutations in ATP binding sites of BCR-ABL, necessitating a novel strategy to treat TKI resistant Ph+ALL. Here we show that our novel small molecule which targets specific transcriptional factor induces Ph+ALL cell death through directly controlling the expression of BCR-ABL gene. We have previously reported the fundamental requirement of transcription factor A (TFA) in the development of acute myeloid leukemia (AML), another form of acute leukemia originating from myeloid progenitor cells. Since previous reports suggest the involvement of TFA family genes in the development of lymphoid cells also, we first addressed the role of TFA in Ph+ALL cells using tetracycline-responsive short hairpin RNA (shRNA)-mediated gene knockdown system. Upon doxycycline treatment, shRNAs targeting TFA (sh_TFA)-transduced SU-Ph2 (Ph+ALL) and SU/SR (SU-Ph2 with BCR-ABL T315I mutation, therefore resistant to Imatinib) cells showed decreased proliferation rate with cell cycle arrest at G0/G1 phase and profound apoptosis. Intriguingly, TFA knockdown suppressed the expression of BCR-ABL fusion gene both at mRNA and protein levels. Concomitant down-regulation of BCR-ABL cytoplasmic gene targets such as mTOR-AKT, STAT and MEK-ERK pathways were also observed in sh_TFA-transduced ALL cells. These results indicate the possible interaction between BCR-ABL and TFA. Since expression of BCR-ABL fusion gene is tightly regulated by gene promoter of BCR andthere exists a TFA-consensus binding site in the proximal promoter region of BCR, we next addressed the TFA-mediated transcriptional regulation of BCR-ABL. In silico data analysis of gene expression array sets extracted from ALL patients revealed the positive correlation of BCR and TFA expressions. Analysis of chromatin immunoprecipitation and sequencing (ChIP-Seq) in mouse ES cells disclosed the potential TFA binding in the proximal regulatory region of BCR, which we have confirmed by ChIP assay in SU/SR cells. These findings suggest that TFA positively and directly controls BCR-ABLexpression through BCR promoter binding in ALL cells. We next sought to explore the effect of TFA inhibition in ALL cells in vivo. Immunodeficient NOG mice transplanted with SU/SR cells that are transduced with sh_TFA or control vector were followed for overall survival and chimerism of ALL cells in the peripheral blood. As expected, TFA inhibition decelerated the dissemination of leukemia and prolonged overall survival period in these mice. We next challenged this ALL-xenografted mice with newly synthesized small compound which irreversibly attenuates the function of TFA as a transcription factor. Existence of T315I mutation in BCR-ABL gene in SU/SR cells naturally provides TKI-therapy resistance to these mice, and oral Imatinib treatment at 100 mg/kg body weight did not prolonged their survivals actually. In contrast, our novel compound was highly effective in these mice at 375 microgram/kg body weight and significantly prolonged the overall survival period without serious side effects, overcoming TKIs resistance. These findings collectively underscore the importance of TFA in the maintenance of ALL cells with resistance to TKIs and is a druggable target in the leukemia therapy. Disclosures No relevant conflicts of interest to declare.

scholarly journals Allogeneic Hematopoietic Stem Cell Transplantation for aBCR-FGFR1Myeloproliferative Neoplasm Presenting as Acute Lymphoblastic Leukemia

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Karl Haslam ◽  
Stephen E. Langabeer ◽  
Johanna Kelly ◽  
Natasha Coen ◽  
Niamh M. O’Connell ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Tyrosine Kinase ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasms ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Stem

Hematopoietic myeloproliferative neoplasms (MPNS) with rearrangements of the receptor tyrosine kinaseFGFR1gene, located on chromosome 8p11, are uncommon and associated with diverse presentations such as atypical chronic myeloid leukemia, acute myeloid leukemia, or an acute T- or B-lymphoblastic leukemia, reflecting the hematopoietic stem cell origin of the disease. A review of MPN patients with the t(8;22) translocation that results in a chimericBCR-FGFR1fusion gene reveals that this disease either presents or rapidly transforms into an acute leukemia that is generally unresponsive to currently available chemotherapeutic regimens including tyrosine kinase inhibitors (TKIS). The first case of a rareBCR-FGFR1MPN presenting in a B-acute lymphoblastic phase who underwent allogeneic hematopoietic stem cell transplantation (HSCT) with a subsequent sustained complete molecular remission is described. Allogeneic HSCT is currently the only available therapy capable of achieving long-term remission inBCR-FGFR1MPN patients.

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