High Musashi-2 Expression Is an Unfavorable Prognostic Factor in Adult B-Cell Acute Lymphoblastic Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2508-2508
Author(s):  
Qitian Mu ◽  
Yungui Wang ◽  
Bing Chen ◽  
Wenbin Qian ◽  
Haitao Meng ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Myelogenous Leukemia ◽  
High Expression ◽  
Expression Level ◽  
Hematopoietic Stem ◽  
Expression Levels ◽  
Hes1 Expression

Abstract Abstract 2508 Background: Musashi-2 (MSI2) can inhibit translation of the mRNA encoding NUMB, the NOTCH signaling inhibitor, and play a vital role in the maintenance of hematopoietic stem cells. Musashi-1 (MSI1), another isoform of Musashi family, positively regulates NOTCH1 expression. Recent studies have demonstrated that MSI2 expression was up-regulated during chronic myelogenous leukemia (CML) progression and its high expression was associated with poor outcome of CML and acute myeloid leukemia (AML). However, the prognostic significance of MSI2 expression and the relation between MSI2 and NOTCH1 expressions in acute lymphoblastic leukemia (ALL) remain unknown. Methods: In this study, real-time PCR was used to measured expression levels of MSI2 and NOTCH1 signaling related genes in 116 B-ALL and 24 T-ALL patients, in whom more than 70% leukemic cells were morphologically detected in bone morrow (BM) at diagnosis. Clinical and Molecular data in relation with MSI2 expression level were analyzed. Results: In our B-ALL cohort, although MSI2 expression was not associated with gender, age, white blood cell (WBC), t(9;22)/BCR-ABL and IK6 variant of IKZF1, patients with high MSI2 expression had inferior overall survival (OS) (P=0.007) and event free survival (EFS) (P=0.002) than patients with low MSI2 expression. Multivariate analysis showed that high MSI2 expression was an independently prognosic factor in OS (P=0.001, HR=2.641, 95%CI, 1.494–4.668), EFS (P<0.001, HR=2.562, 95%CI, 1.513–4.218) and RFS (P=0.043, HR=2.057, 95%CI, 1.023–4.137). Moreover, MSI2 expression level had a positive correlation with that of NOTCH1 (P<0.001), but not c-MYC (P=0.432) or HES1 (P=0.509). Similarly, NOTCH1 expression level in patients with high MSI2 expression (0.98, range 0.02 to 13.58) was significantly higher than that in patients with low MSI2 expression (0.42, range 0.01 to 3.55, P=0.001), but c-MYC and HES1 expression levels between patients with high MSI2 expression and low MSI2 expression showed no significant differences (both P>0.05). Conclusion: Our data suggests MSI2 high expression can indicate poor prognosis in adult B-ALL accompanying with elevated NOTCH1 expression but not activating NOTCH1 downstream pathway. Disclosures: No relevant conflicts of interest to declare.

Characteristics and Prognostic Significance of CRLF2 High Expression and the Co-Existence with JAK1 Mutations and Ikaros Deletion in Adult Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3800-3800 ◽  
Author(s):  
Zheng Ge ◽  
Juan Liu ◽  
Run Zhang ◽  
Xing Guo ◽  
Jing-Yan Xu ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Conflicts Of Interest ◽  
Direct Sequencing ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Philadelphia Chromosome ◽  
Point Mutations ◽  
High Expression ◽  
Newly Diagnosed

Abstract Objective Cytokine receptor-like factor 2 (CRLF2) play an important role in differentiation and proliferation of lymphoid precursor cells through activation of JAK signaling pathway. Increased CRLF2 expression associates with mutations in JAK2, a combination that transforms hematopoietic cells, suggesting that mutants in JAK family members and CRLF2 may cooperate to contribute to acute lymphoblastic leukemia (ALL) pathogenesis. Moreover, the Ikaros deletion is also associated with the development of T-/B-cell ALL with poor outcome and relapse of high-risk leukemia. The aim of this study was to determine the clinical characterization and prognostic values of CRLF2 high expression and its concomitant expression with JAK1 mutations and Ikaros deletion in adult ALL patients. Methods Quantitative PCR (qPCR) was performed to detect the expression of CRLF2 in 133 newly diagnosed adult patients with ALL. Genomic DNA was amplified to detect the mutations of the exon 13, 14, 16, 18 and 19 of JAK1, and IKZF1 exons 4 through 7 deletions (△4–7) by direct sequencing or sequencing after cloning. The CD34, CD13, CD33 and other markers were detected on the leukemia cells from bone marrow of the patients by flow cytometry, and the correlations of the CRLF2 high expression with the clinical features, survival, and with co-expression of JAK1 mutations and Ikaros deletion were statistically analyzed with Pearson's chi-square test or Fisher's exact test and Kaplan–Meier curves analysis. Results CRLF2 high expression was detected in 22.8% of newly diagnosed adult ALL. The patients with CRLF2 high expression has significantly higher percentage of CD34, CD13 or CD33 positive than those with low expression（91.3% vs 62%, P=0.008; 76.2% vs 46.3%, P=0.016; 80.0% vs 37.9%, P=0.001), higher frequency of splenomegaly（60.0% vs 32.0%, P=0.040) in the adult ALL and shorter overall survival and event-free survival（9.5 months vs 16 months, P=0.029; 3 months vs 9 months, P=0.030）in the Philadelphia chromosome negative ALL. Moreover, the 4 JAK1 point mutations with amino acid changes were detected in the patients, which had significant CRLF2 high expression compared to that without mutation（75% vs 21.3%, P=0.037). The co-existence of CRLF2 high expression and IKZF1 exons 4-7 deletion (isoform Ik6) was found in 4 of 10 patients. Conclusion CRLF2 high expression predicts poor survival, and significantly co-exists with JAK1 mutation and Ikaros deletion in adult ALL patients. Our result also suggested that CRLF2, JAK1 and IKZF1 could be integrated in future prognostic model of adult ALL as possible markers for high-risk leukemia. Disclosures No relevant conflicts of interest to declare.

Expression of Mir-196b Is Not Exclusively MLL-Driven but Especially Linked to Activation of HOXA Genes in Children with Acute Lymphoblastic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 580-580
Author(s):  
Diana Schotte ◽  
Ellen Lange-Turenhout ◽  
Dominique JPM Stumpel ◽  
Ronald W. Stam ◽  
Jessica Buijs-Gladdines ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Chromosome 7 ◽  
High Expression ◽  
Expression Level ◽  
Aberrant Expression ◽  
Expression Levels ◽  
Pediatric All ◽  
Hoxa Genes ◽  
High Expression Level

Abstract Abstract 580 MicroRNAs (miRNAs) play important roles in diverse biological processes including hematopoiesis. As a consequence, aberrant expression of miRNAs may contribute to hematopoietic malignancies. It has been reported that miR-196b is transcriptionally activated by MLL and MLL-fusion genes and is therefore highly expressed in MLL-rearranged leukemia. In order to investigate whether high expression levels of miR-196b are restricted to MLL-rearranged leukemia cases, we measured the expression in samples of 72 selected pediatric acute lymphoblastic leukemia (ALL) cases i.e. MLL-rearranged and non-MLL-rearranged precursor B-ALL and T-ALL patients. MiR-196b was highly expressed in 9/12 MLL-rearranged precursor B-ALL patients, but also in 14/22 T-ALL patients. In particular, 100% of T-ALL cases carrying CALM-AF10 (n=5), MLL-AF6 (n=2), SET-NUP214 (n=3) and an inversion of chromosome 7 (n=1) showed high expression levels of miR-196b comparable to the high levels found in MLL-rearranged ALL. Like MLL-rearrangements, these genetic abnormalities have been functionally linked with upregulation of HOXA cluster genes. MiR-196b expression levels in these patients were strongly correlated with the expression of HOXA family but not with HOXB and HOXC cluster genes (Rs ≥ 0.7, P≤0.003). Since miR-196b is located between HOXA9 and HOXA10 on chromosome 7, our data suggest co-activation of miR-196b and HOXA family genes in pediatric ALL. In parallel to the high expression level of miR-196b we found decreased methylation at CpG islands located 5' of miR-196b in MLL-rearranged cases compared to normal bone marrow cells, which suggests an epigenetic origin for the high expression level of miR-196b in these patients. Despite the fact that MLL-rearranged ALL patients often respond poorly to prednisolone and L-asparaginase, upregulation of miR-196b was not indicative for the resistance to these drugs in pediatric ALL. In conclusion, high-level expression of miR-196b is not only MLL-driven, but can also be found in other types of leukemia that display aberrant activation of HOXA genes. Disclosures: No relevant conflicts of interest to declare.

Simulataneous Vaccination and Delayed Lymphocyte Infusion for Enhancement of Immune Reactivity Against Acute Lymphoblastic Leukemia or Lymphoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5248-5248
Author(s):  
Craig A. Mullen ◽  
Olga Sevastianova
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
T Cell Responses ◽  
Myelogenous Leukemia ◽  
Lymphoid Tissues ◽  
Spleen Cells ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Cell Responses

Abstract BACKGROUND: Delayed lymphocyte infusion (DLI) can be employed as an antileukemia immune therapy when patients with leukemia relapse after allogeneic hematopoietic stem cell transplantation (HSCT). While effective in patients with chronic myelogenous leukemia, it is generally ineffective with relapse of acute lymphoblastic leukemia (ALL). This ineffectiveness may be multifactorial and possible reasons include rapid leukemia cell growth in ALL, reduced propensity to apoptosis signals, and poor presentation of antigens present on lymphoblasts resulting in failure to generate a significant immune response. If the failure of malignant lymphoblasts in marrow and lymphoid tissues to elicit meaningful T cell responses plays a role in the ineffectiveness of DLI, it is possible that therapeutic vaccines may be able to ameliorate this barrier. We have recently demonstrated that vaccination immediately prior to HSCT enhances antigen specific T cell responses in the post-transplant immune repertoire (Bone Marrow Transplantation, 35:793–801, 2005.) HYPOTHESIS: Vaccination with leukemia related antigens at the time of DLI will increase donor T cell responses to leukemia related antigens without exacerbation of GVHD responses to ubiquitous host minor histocompatibility antigens (mHA). METHODS: We employ a murine MHC matched allogeneic HSCT model in which 6 antigens are molecularly characterized. C3.SW mice are donors and C57BL/6 mice are recipients. In this model the H7 mHA is the immunodominant antigen, while alloresponses to H3 and H13 are also present. By using spontaneously arising lymphoblastic leukemia/lymphoma cells from Ig-cmyc transgenic male C57BL/6 as the model malignancy in a female to female transplant the male HY associated antigens Uty, Dby and Smcy can be used as antigens restricted to the lymphoid malignancy. Four weeks after allogeneic HSCT mice were vaccinated with 107 cells expressing the HY antigens and the C57BL/6 H7, H3 and H13 minor antigens. The cells used for pre-DLI vaccination were either irradiated male C57BL/6 spleen cells or irradiated male malignant lymphoblasts. One day later mice received iv infusion of 107 spleen cells from C3.SW female donor mice previously primed against HY antigens by immunization with male C3.SW cells. Ten days interferon gamma Elispot assays were performed on HSCT recipient spleen cells using the peptide-defined antigens. RESULTS: Vaccination of HSCT recipients with male spleen cells 1 day prior to DLI from HY immune donors significantly increased T cell responses to HY peptide epitopes. Recipients of DLI alone harbored 40 interferon secreting cells per 106, while combination of vaccination and DLI yielded 94 per 106(p &lt; 0.05). In contrast, there was no change in the number of T cells responding to the H7, H3 and H13 mHA. DLI only exhibited 26 per 106 while DLI plus vaccine exhibited 27 per 106 (p &lt; 0.05). Whole cell irradiated lymphoblasts were not as effective as irradiated splenocytes in augmenting the HY responses, although they were equally effective in producing T cell responses in normal, nontransplanted mice. CONCLUSIONS: Simultaneous vaccination and DLI can lead to significant expansion of donor cells potentially reactive with antigens present on malignant lymphoblasts without exacerbation of T cell responses to ubiquitous mHA associated with GVHD. Current work is exploring methods by which indirect presentation of antigens from lymphoblasts can be enhanced, since it is unlikely that vaccines relying on direct antigen presentation by lymphoblasts will be effective.

Outcome After First Relapse In Adult Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3084-3084
Author(s):  
Shinichi Kako ◽  
Heiwa Kanamori ◽  
Naoki Kobayashi ◽  
Akio Shigematsu ◽  
Yasuhito Nannya ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Median Duration ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Salvage Chemotherapy ◽  
Adult Patients ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
First Relapse

Abstract Abstract 3084 With modern intensive chemotherapy, 78% to 93% of adult patients with acute lymphoblastic leukemia (ALL) achieve complete remission (CR). However, the disease-free survival rate is only 30% to 40% due to the high rate of relapse. A part of relapsed patients can achieve second remission (CR2) with salvage therapy, and allogeneic hematopoietic stem cell transplantation (HSCT) in CR2 will be the only curative strategy. Prognosis after relapse in adult patients with ALL is considered to be extremely poor, but reports as to the outcome after relapse have been limited. To elucidate the outcome of relapsed patients and prognostic factors after relapse, we retrospectively collected and analyzed clinical data from 69 institutions in Japan on patients with Philadelphia-chromosome (Ph) negative ALL, aged 16–65 years, who relapsed after first CR (CR1) between 1998 and 2008. A total of 332 patients were included in this study. The median age of them was 35 years, and 165 patients were male. Median duration of CR1 was 290 days (range 15–7162 days), and median follow-up time after relapse was 319 days (range 3–3689 days). Fifty-eight and 4 of them relapsed after allogeneic and autologous HSCT in CR1, respectively. The overall survival (OS) rate was not significantly different between patients who relapsed after allogeneic HSCT in CR1 and those who relapsed after chemotherapy only (50.0% vs. 43.4% at 1 year and 10.6% vs. 16.3% at 5 year, respectively). Among 270 patients who relapsed after chemotherapy only, 234 patients received salvage chemotherapy after relapse, and 123 patients achieved CR2 (52.5%). Sixty-two patients out of those 123 patients underwent allogeneic HSCT in CR2. Median duration between the achievement of CR2 with salvage chemotherapy and allogeneic HSCT in CR2 was 76 days. OS rate was significantly better in patients who underwent allogeneic HSCT in CR2 following salvage chemotherapy than those who did not (74.1% vs. 55.1% at 1 year and 44.7% vs. 11.6% at 5 year, respectively) by a landmark analysis limiting patients who were surviving without disease at 76 days after the achievement of CR2. In multivariate analysis of factors that included allogeneic HSCT in CR2 following salvage chemotherapy as a time-dependent covariate, lower white blood cell count at relapse (less than 10000/μl) and allogeneic HSCT in CR2 were associated with better OS rate among patients who achieved CR2 following salvage chemotherapy. Forty-six patients underwent allogeneic HSCT in non-CR after receiving salvage chemotherapy. A part of them survived long, and 5 year OS rate was 20.9%. In conclusion, the prognosis of adult patients with relapsed Ph-negative ALL is poor. Allogeneic HSCT after first relapse could improve the prognosis. Disclosures: No relevant conflicts of interest to declare.

Expression of SOCS1 and SOCS3 Genes with Human Cytomegalovirus Infection After Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3038-3038
Author(s):  
Tae Hyang Lee ◽  
Ji Yoon Lee ◽  
Sohye Park ◽  
Jae-Ho Yoon ◽  
Seung Hwan Shin ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Statistical Significance ◽  
Myelogenous Leukemia ◽  
Cmv Infection ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Acute Myelogenous ◽  
Cmv Reactivation

Abstract Abstract 3038 Background: After allogeneic hematopoietic stem cell transplantation (HSCT), cytomegalovirus (CMV) infection is highly prevalent in recipients. Although the suppressor of cytokine signaling (SOCS) genes are mainly regarded as pivotal negative feedback regulators for signaling of cytokines, the expression pattern of SOCS genes in CMV infections remains largely unexplored. To understand the molecular mechanism of cytokine cascades associated with CMV infection, we investigated the expression of SOCS genes from various types of hematologic malignancies after allogeneic HSCT. Methods: In the present study, we investigated SOCS1 and SOCS3 gene expressions, in order to examine the feasibility of SOCS genes as a promising therapeutic target as well as a prognostic predictor in CMV infection. A total of 99 recipients with acute myelogenous leukemia (AML; n=64), acute lymphoblastic leukemia (ALL; n=23), myelodysplastic syndrome (MDS; n=12), who received allogeneic HSCT and 55 normal donors were included. Real-time quantitative polymerase chain reaction (RQ-PCR) was used and all sample analyses were performed in triplicate. Results: The expression levels of the SOCS3 gene were clearly decreased in recipients compared to normal donors, including in the Pre-HSCT, Post-HSCT No CMV, and Post-HSCT CMV subgroups (P=0.0007, P=0.0009, and P=0.0014, respectively). Meanwhile, expressions of SOCS1 gene were significantly decreased in the Pre-HSCT, Post-HSCT No CMV, and normal donors, when compared to Post-HSCT CMV subgroup (P=0.026, P=0.0129, and P<0.0001, respectively), suggesting a correlation between expression of SOCS genes and CMV reactivation. In addition, expression of SOCS1 gene was remarkably increased in patients who received allogeneic HSCT with myeloablative conditioning (MAC), compared to reduced-intensity conditioning transplantation (RIST) and normal donors (P=0.0119, P=0.0002, respectively), while, both regimen with MAC and RIST showed a decreasing pattern with statistical significance compared to normal donors (P=0.0037, P=0.0024, respectively). Notably, SOCS1 gene expression in acute lymphoblastic leukemia and myelodysplastic syndrome recipients were higher than acute myelogenous leukemia, when compare to normal donors (P=0.0239). Furthermore, high expression of SOCS1 gene unarguably showed high mortality (P=0.0068). In AML patients, decreased SOCS3 gene was detected (P=0.0007) and overall high expression of SOCS3 gene was displayed high mortality, but there is no statistical significance. Conclusions: We firstly report that the SOCS genes are differently expressed in human CMV infection after allogeneic HSCT, suggesting a correlation between cytokines by modulation of SOCS genes associated with CMV reactivation. This result provides a new platform for studying CMV immunobiology and these genes may be a potential of diagnostic and therapeutic targets in post-allogeneic HSCT associated with CMV infection. Disclosures: No relevant conflicts of interest to declare.

Inherited and Acquired RUNX1 Mutations in Hematologic Disorders

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. SCI-5-SCI-5
Author(s):  
Nancy A. Speck ◽  
Xiongwei Cai ◽  
Jingping Ge ◽  
Philip J. Mason
Keyword(s):  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Conflicts Of Interest ◽  
P53 Protein ◽  
Lymphoblastic Leukemia ◽  
Genotoxic Stress ◽  
Myelogenous Leukemia ◽  
Phenotypic Properties ◽  
Hematopoietic Stem ◽  
Protein Levels

Abstract RUNX1, a DNA binding subunit of core binding factors, is frequently mutated or rearranged in hematopoietic malignancies, including acute myelogenous leukemia (AML), chronic myelomonocytic leukemia, acute lymphoblastic leukemia, and myelodysplastic syndrome (MDS). Mutations in RUNX1 can be early events in leukemia, and generate a long-lived pre-leukemic stem cell (pre-LSC). Additionally, it has been reported that loss of function RUNX1 mutations are particularly frequent in radiation-associated MDS and AML, suggesting that pre-existing RUNX1 mutations in a pre-LSC may predispose patients to MDS/AML following DNA damage. Discussion will focus on the phenotypic properties of Runx1-deficient pre-LSCs, and the mechanisms by which Runx1 deficiency contributes to these phenotypes. Pan-hematopoietic Runx1 loss in mice causes a G1 to S-cell cycle delay and decreases apoptosis of pre-LSCs. Runx1-deficient pre-LSCs are radiation- and chemotherapy-resistant, and this correlates with decreased p53 protein levels and an attenuated p53 pathway response. Both p53 protein levels and apoptosis are increased following treatment with Nutlin-3. Runx1-deficient pre-LSCs are smaller, consume less glucose, and produce less ATP than normal hematopoietic stem cells (HSCs). Runx1-deficient stem and progenitor cells have lower overall ribosomal content and skewing in the relative amounts of rRNA and mRNA encoding ribosomal proteins. Analysis of AKT pathway components suggests that the decreased ribosome biogenesis is unlikely to be primarily caused by lower AKT signaling. We hypothesize that one or more of the above-mentioned properties (low p53 levels, decreased metabolism) render Runx1-deficient pre-LSCs less sensitive to genotoxic stress than normal HSCs, allowing a Runx1-deficient pre-LSC population to both perdure and expand in the bone marrow. Disclosures: No relevant conflicts of interest to declare.

CD34+CD38-CD58- leukemia-Propagating Cells at Diagnosis Could Identify Patients at High-Risk for Relapse in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3795-3795
Author(s):  
Yuan Kong ◽  
Lan-Ping Xu ◽  
Yan-Rong Liu ◽  
Ya-Zhen Qin ◽  
Yu-Qian Sun ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Hematopoietic Stem Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Philadelphia Chromosome ◽  
Hematopoietic Stem ◽  
Peking University

Abstract Background: Relapse of Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ALL) may result from the persistence of leukemia stem cells sometimes termed leukemia-propagating cells (LPCs). We recently found that Ph+ALL LPCs are enriched in the CD34+CD38-CD58- fraction using anti-CD122-conditioned NOD/SCID xenograft assay by intra-bone marrow injection, which translating to adverse clinical outcomes (Kong Y, et al. Leukemia 2014. accepted). Despite the widespread use of abelson tyrosine kinase inhibitors (TKIs) in Ph+ALL, allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the best curative option. However, whether the prognostic significance of the identified LPCs phenotype to identify patients at high risk for relapse could retain in Ph+ALL after allo-HSCT, if any, is unknown. Aims: To investigate the prognostic significance of the candidate CD34+CD38-CD58- LPCs in Ph+ALL subjects underwent allo-HSCT. Methods: A total of 80 consecutive adults (18-60 years) with Ph+ALL underwent allo-HSCT were eligible for the study at Peking University Institute of Hematology from January 1, 2009 to December 31, 2013. Imatinib was routinely administered in subjects pre- and post-HSCT as previously reported. A multi-parameter flow cytometry analysis of CD58-FITC/CD10-PE/CD19-APC-Cy7/CD34-PerCP/CD45-Vioblue/ CD38-APC on gated leukemia blasts of bone marrow was performed at diagnosis. Furthermore, minimal residual disease (MRD) was monitored by BCR/ABL transcripts in bone marrow samples at diagnosis, directly before transplantation, as well as serially at 1, 2, 3, 6, 9, 12,24,36,60 months post-HSCT and at relapse using real-time quantitative polymerase chain reaction. Cumulative incidences of relapse (CIR) and non-relapse mortality were calculated using the Kalbfleisch and Prentice method. Leukemia-free survival (LFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared using the log-rank test. Factors at a level of P<0.1 were included as variables in the multivariate Cox regression model. The study was approved by the Ethics Committee of Peking University People’s Hospital. Results: On the basis of blasts phenotypes at diagnosis, subjects were stratified into CD34+CD38-CD58- group (N=15) and other phenotype group (N=65). The demographic and clinical characteristics showed no significant difference between the two phenotype groups. Median follow-up was 25.5 mo (range, 6-65 mo) for all subjects and 33 mo (range, 6-65 mo) for survivors. During the MRD monitoring, significantly higher levels of BCR/ABL transcripts were detected in subjects in CD34+CD38-CD58- group than persons in other phenotype group especially at 3 mo post-HSCT [0.12(0-152.4)% vs. 0(0-100)%, P=0.001]. Additionally, CD34+CD38-CD58- LPCs phenotype directly correlated with higher 3-year CIR (63.2% [58.2-68.1%] vs. 5.3% [5.1-5.5%]; P<0.0001), worse LFS (30.2% [8.1-56.6%] vs. 78.7% [64.5-87.7%]; P=0.001) and OS (37.7% [12.6-63.2%] vs. 82.3% [68.5-90.4%]; P=0.0004). Multivariate analyses indicated that CD34+CD38-CD58- LPCs phenotype at diagnosis and BCR-ABL reduction at 3 mo post-HSCT were independent risk factors for relapse, LFS and OS in adults with Ph+ALL underwent allo-HSCT. Summary/Conclusion: Our data suggest that a candidate CD34+CD38-CD58- LPCs phenotype at diagnosis allows rapid identification of high-risk patients for relapse even after allo-HSCT. Risk-stratification post-HSCT therapy incorporating analysis of CD34+CD38-CD58- LPCs phenotype at diagnosis promises to benefit the adults with Ph+ALL in the future. Acknowledgment: Supported by the National Natural Science Foundation of China (grant nos. 81370638&81230013), the Beijing Municipal Science and Technology Program (grant no. Z141100000214011), and Peking University People’s Hospital Research and Development Funds (grant no. RDB2012-23). Disclosures No relevant conflicts of interest to declare.

scholarly journals Stress Hematopoiesis Reveals Abnormal Control of Self-Renewal, Lineage-Bias and Myeloid Differentiation in Mll Partial Tandem Duplication (Mll-PTD) Hematopoietic Stem/Progenitor Cells

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3501-3501
Author(s):  
Yue Zhang ◽  
Xiaomei Yan ◽  
Goro Sashida ◽  
Xinghui Zhao ◽  
Yalan Rao ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tandem Duplication ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Myelogenous Leukemia ◽  
Myeloid Differentiation ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Mll Gene ◽  
Partial Tandem Duplication

Abstract Abstract 3501 Rearrangements of the Mixed-Lineage Leukemia (MLL) gene occur in a variety of aggressive human leukemias. The most common ones are balanced translocations in which the genomic sequences encoding the N-terminal portion of MLL are fused to sequences encoding the C-terminus of another translocation partner in acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL). Another mechanism for disrupting the MLL gene in myelodysplastic syndrome (MDS) and AML, but rarely seen in ALL, is partial tandem duplication (MLL-PTD). The MLL–PTD was first identified in de novo AML with a normal karyotype or trisomy 11. Cloning of this region revealed partial duplications within the 5′ region of the MLL gene. These duplications consist of an in-frame repetition of MLL exons in a 5′–3′ direction and produce an elongated protein. The incidence of MLL–PTD was 8% in unselected adult and childhood AML and 5% in MDS. However, the mechanism by which MLL-PTD contributes to MDS and AML development and maintenance is currently unknown. Mll-PTD knock-in mouse model, its expression is regulated by endogenous promoter, has been generated to study the function of Mll-PTD in vitro and in vivo and to identify its downstream targets. This mouse model provides a powerful genetic tool to identify disruptions in normal cellular regulation as a result of this mutation, as well as a model to characterize the contribution of the Mll-PTD in leukemogenesis. Herein, we investigated hematopoietic stem/progenitor cell (HSPC) phenotypes of Mll-PTD knock-in mice. Although HSPCs (Lin−Sca1+Kit+ (LSK)/SLAM+ and LSK) in MllPTD/WT mice are reduced in absolute number in steady state due to increased apoptosis, they have a proliferative advantage in colony replating assays, CFU-spleen assays, and competitive transplantation assays over wild-type HSPCs. The MllPTD/WT–derived phenotypic short-term (ST)-HSCs/multipotent progenitors (MPPs) and granulocyte/macrophage progenitors (GMPs) have self-renewal capability, rescuing hematopoiesis by giving rise to long-term repopulating cells in recipient mice with an unexpected myeloid differentiation blockade and lymphoid-lineage bias. However, MllPTD/WT HSPCs never develop leukemia in primary or recipient mice, suggesting that additional genetic and/or epigenetic defects are necessary for full leukemogenic transformation. In conclusion, the MllPTD/WT mouse model provides unique genetic and biochemical tool to identify new targets and pathways responsible for the altered differentiation/repopulating properties, self-renewal activity, lineage bias and myeloid differentiation blockade relevant to MLL-PTD MDS and AML. This model should also help us to understand the underlying mechanism(s) for each of the phenotypes we found in this study and facilitate improved therapies and patient outcomes in the future. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Analysis of the Expression of PHTF1 and Related Genes in Acute Lymphoblastic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4988-4988
Author(s):  
Xin Huang ◽  
Suxia Geng ◽  
Jianyu Weng ◽  
Zesheng Lu ◽  
Linji Zeng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Hematologic Malignancies ◽  
Expression Level ◽  
Newly Diagnosed ◽  
Healthy Individuals ◽  
Apoptosis Pathway ◽  
Cell Proliferation Inhibition

Abstract Background: In the human T-cell acute lymphoblastic leukemia (T-ALL) cell line Molt-4, siRNA-mediated suppression of BCL11B expression was shown to inhibit proliferation and induce apoptosis, which may be related to PHTF1 gene expression, and the FEM1B and Apaf-1 genes may be downstream of PHTF1. In this study, we analyzed the expression level of PHTF1 and related genes in patients with ALL to clarify the role of the PHTF1-FEM1b-Apaf-1 pathway in hematologic malignancies. Methods: Fifteen newly diagnosed and untreated patients with AML, fourteen newly diagnosed and untreated patients with CML in chronic phase, twenty-two newly diagnosed and untreated patients with ALL, and six newly diagnosed and untreated patients with CLL were recruited. Peripheral blood mononuclear cells (PBMCs) from ten healthy individuals (HIs) served as controls. PBMCs were separated using the Ficoll-Hypaque gradient centrifugation method. All procedures were conducted in accordance with the guidelines of the Medical Ethics committees of the Health Bureau of Guangdong Province, China.Real-time PCR was used to determine the gene expression level of PHTF1 in hematologic malignancies. The PHTF1, BCL11B, FEM1B and Apaf-1 gene expression levels and correlations were analyzed in patients with primary ALL and healthy individuals (HIs). Results: PHTF1 overexpression was found in recently diagnosed AML (p <0.001), CML-CP (p<0.001), and ALL (p= 0.016) patients in comparison with HIs. The PHTF1 expression level in CLL patients was not significantly different compared with HIs (p= 0.165). FEM1b and Apaf-1 overexpression was found in recently diagnosed ALL (p<0.005) patients compared with HIs. Positively correlated expression was found for the PHTF1, FEM1b and Apaf-1 genes in patients with ALL (p<0.005) and HIs (p<0.005), and positively correlated expression was found for the PHTF1 and BCL11B genes in HIs (p<0.005). Conclusions: PHTF1 acts as a tumor suppressor gene, and its overexpression might be related to cell proliferation, inhibition and apoptosis. PHTF1 and BCL11B gene disorders may contribute to T-ALL pathogenesis. PHTF1 might be a therapeutic target for triggering the PHTF1-FEM1b-Apaf-1 apoptosis pathway in primary acute lymphoblastic leukemia. Acknowledgment The project was sponsored by grants from National Natural Science Foundation of China (No. 81100384, No. 81270648, No.91129720, and No. 30771980) Disclosures No relevant conflicts of interest to declare.

scholarly journals IKZF1deletions Coupled with CD20 Expression Represents a Novel High-Risk Subtype in Adult B-Cell Progenitor Acute Lymphoblastic Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4474-4474
Author(s):  
Bingqing Tang ◽  
Zhixiang Wang ◽  
Dainan Lin ◽  
Xianjun He ◽  
Zihong Cai ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
B Cell ◽  
Validation Cohort ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Stem ◽  
Poor Outcome ◽  
Cd20 Expression ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Genetic deletions of IKZF1 are associated with poor prognosis in B-cell acute lymphoblastic leukemia (B-ALL). Here we investigated the effect of IKZF1 deletions (IKZF1 del) plus with immunotype in adult B-ALL in PDT-ALL-2016 cohort. This cohort study involved 161 patients with B-ALL from 2016 to 2019, with detailed information about IKZF1 del and CD20 expression. Validation cohort consists N= patients from TARGET cohort. IKZF1 del was detected in 36.0% of patients with 3-year event-free survival (EFS) of 37.2±6.7% and overall survival (OS) of 51.1±7.3%, compared to IKZF1 wild-type (IKZF1 wt) with EFS 55.4±5.1% (P&lt;0.01) and OS 74.6±4.5% (P&lt;0.05), respectively. CD20 expression was also associated with inferior EFS than CD20-negative group (P&lt;0.05). Furthermore, IKZF1 del coupled with CD20 expression, termed as IKZF1 del/CD20+, comprised 12.4% of patients with 3-year EFS of 25.0±9.7% compared with IKZF1 wt (P&lt;0.05 ) and IKZF1 del/CD20- (P&lt;0.05 ) groups, respectively. Multivariable analyses demonstrated independence of IKZF1 del/CD20+ with highest hazard ratio for EFS and OS. Furthermore, the prognostic strength of IKZF1 del/CD20+ was confirmed in TARGET validation cohort. Eighty-one patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT). Notably, neither IKZF1 del(P=0.6288), CD20 (P=0.0705) or IKZF1 del/CD20 (P=0.3410) groups were identified as poor outcome in allo-HSCT cohort. Collectively, our data demonstrate that IKZF1 del/CD20+ represents a very high-risk subtype in adult B-ALL; and particularly, allo-HSCT could overcome the poor outcome of IKZF1 del and IKZF1 del/CD20+. Disclosures No relevant conflicts of interest to declare.

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