scholarly journals MS4A3 Promotes Differentiation in Chronic Myeloid Leukemia by Enhancing Common β Chain Cytokine Receptor Endocytosis

Blood ◽  
2021 ◽  
Author(s):  
Helong Zhao ◽  
Anthony D Pomicter ◽  
Anna M Eiring ◽  
Anca Franzini ◽  
Jonathan Ahmann ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Targeted Delivery ◽  
Myeloid Leukemia ◽  
Ex Vivo ◽  
Transmembrane Protein ◽  
Chronic Phase ◽  
Aberrant Methylation ◽  
Blast Phase ◽  
Β Chain

The chronic phase of chronic myeloid leukemia (CP-CML) is characterized by excessive production of maturating myeloid cells. As CML stem/progenitor cells (LSPCs) are poised to cycle and differentiate, LSPCs must balance conservation and differentiation to avoid exhaustion, similar to normal hematopoiesis under stress. Since BCR-ABL1 tyrosine kinase inhibitors (TKIs) eliminate differentiating cells, but spare BCR-ABL1-independent LSPCs, understanding the mechanisms that regulate LSPC differentiation may inform strategies to eliminate LSPCs. Upon performing a meta-analysis of published CML transcriptomes, we discovered that low expression of the MS4A3 transmembrane protein is a universal characteristic of LSPC quiescence, BCR-ABL1 independence, and transformation to blast phase. Several mechanisms are involved in suppressing MS4A3, including aberrant methylation and a MECOM-C/EBPε axis. Contrary to previous reports, we find that MS4A3 does not function as a G1/S phase inhibitor, but promotes endocytosis of common β chain (βc) cytokine receptors upon GM-CSF/IL-3 stimulation, enhancing downstream signaling and cellular differentiation. This suggests that LSPCs downregulate MS4A3 to evade βc cytokine-induced differentiation and maintain a more primitive, TKI-insensitive state. Accordingly, knockdown or deletion of MS4A3/Ms4a3 promotes TKI resistance and survival of CML cells ex vivo and enhance leukemogenesis in vivo, while targeted delivery of exogenous MS4A3 protein promotes differentiation. These data support a model in which MS4A3 governs response to differentiating myeloid cytokines, providing a unifying mechanism for the differentiation block characteristic of CML quiescence and blast phase CML. Promoting MS4A3 re-expression or delivery of ectopic MS4A3 may help eliminating LSPCs in vivo.

scholarly journals Chronic myeloid leukemia (CML) with P190BCR-ABL: analysis of characteristics, outcomes, and prognostic significance

Blood ◽  
2009 ◽  
Vol 114 (11) ◽  
pp. 2232-2235 ◽  
Author(s):  
Dushyant Verma ◽  
Hagop M. Kantarjian ◽  
Dan Jones ◽  
Rajyalakshmi Luthra ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Prognostic Significance ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Blast Phase ◽  
Complete Hematologic Response ◽  
Risk Patients

Abstract The most common BCR-ABL transcripts in chronic myeloid leukemia (CML) are e13a2(b2a2) and e14a2(b3a2). Other transcripts such as e1a2 are rare and their outcome with tyrosine kinase inhibitors (TKI) therapy is undefined. We analyzed 1292 CML patients and identified 14 with only e1a2 transcripts, 9 in chronic phase (CP), 1 in accelerated phase (AP), and 4 in blast phase (BP). Of the CP, 4 achieved complete hematologic response (CHR); 2, complete cytogenetic response (CCyR); 2, partial cytogenetic response (PCyR), and 1 did not respond to imatinib. Five patients progressed to myeloid BP (3), lymphoid BP (1), or AP (1). The AP patient received various TKIs sequentially and achieved only CHR. BP patients received hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, adriamycin, dexamethasone) plus imatinib/dasatinib or idarubicin plus cytarabine (Ara-C); 2 did not respond, 1 had CCyR, and 1 short-lasting complete molecular response (CMR). Overall, cytogenetic responses lasted 3 to 18 months; only 2 achieved major molecular response (MMR) on TKI. P190BCR-ABL CML is rare and is associated with an inferior outcome to therapy with TKI. These patients need to be identified as high-risk patients.

Transplantation of Immunodeficient Mice with Chronic Myeloid Leukemia (CML) Cells from Chronic Phase Patients Reveals a Hierarchy of CD34+ Aldehyde Dehydrogenase-Positive Cells with Short- and Long-Term Repopulating Activity and Transient Responsiveness to Imatinib Mesylate in Vivo.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2960-2960
Author(s):  
Oliver Christ ◽  
Wolfgang Eisterer ◽  
Xiaoyan Jiang ◽  
Emily Pang ◽  
Karen Leung ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Aldehyde Dehydrogenase ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Leukemic Cells ◽  
Majority Population ◽  
Normal Human

Abstract Transplantation of sublethally irradiated NOD/SCID or NOD/SCID-β2microglobulin (β2m) null mice with cells from most chronic phase chronic myeloid leukemia (CML) patients results in the regeneration in the mice of primarily normal human hematopoietic cells. This is due to the usual predominance of normal cells within the most primitive subsets of bone marrow or blood cells in these patients. To date, no markers that allow the most primitive normal and leukemic cells to be differentially isolated from chronic phase CML samples have been identified except those reflecting an increased turnover of the leukemic cells. As an alternative approach to characterizing chronic phase CML stem cells, we have identified particular patient samples that contain predominantly leukemic LTC-ICs and have found that transplants of these samples regenerate a predominance of leukemic cells in both NOD/SCID and NOD/SCID-β2m null mice. To investigate the biological and phenotypic properties of CML cells that have short- and longterm repopulating activity, we transplanted sublethally irradiated NOD/SCID and NOD/SCID-β2m null mice with FACS-sorted subsets of lin- CML cells from 2 such samples and then monitored their output of cells in the bone marrow of the mice for up to 12 weeks. The CD34+CD38+ CML cells produced a rapid but transient wave of mainly myeloid progeny that peaked at 3 weeks whereas the CD34+CD38− cells produced a more delayed but persistent wave of cells in both types of mice that included some lymphoid progeny although the latter represented a markedly reduced proportion of the total relative to the cells produced by normal human bone marrow. These patterns were seen in both recipient genotypes but cell output was enhanced in NOD/SCID-β2m null mice as expected for short-term repopulating cells. In additional studies with 3 patients’ samples, both types of repopulating cells were found primarily in the aldehyde dehydrogenase-positive fraction based on their staining with BODIPY-labeled amino acetaldehyde. To test the feasibility of the CML xenograft model for evaluating novel treatments in vivo, groups of NOD/SCID mice repopulated to high levels with leukemic cells (49±8%) 7 weeks after being transplanted with 3x107 CD34+ CML cells, were injected with 50 mg/kg imatinib mesylate (or not) i.p. twice daily for 10 days. Bone marrow samples obtained from the imatinib mesylate-treated mice 2, 4, 12 and 22 weeks after initiation of this treatment, initially showed a more rapid and greater decline of human leukemic cells (>2-fold as assessed by both FACS and quantitative real-time PCR); however by 5 months after completion of the treatment, the level of human cells in the bone marrow of both the imatinib mesylate-treated and untreated mice was the same. Taken together, these findings demonstrate that the CML clone in chronic phase patients contains a similar hierarchy of short and longterm repopulating cells as is found in normal adult bone marrow, and that the CML repopulating cells have, in addition to their ability to sustain the clone, a greater innate resistance to the toxic effects that imatinib mesylate has in vivo on the majority population of more differentiated CML cells.

Complete Remission of Accelerated Phase Chronic Myeloid Leukemia by Treatment With Leukemia-Reactive Cytotoxic T Lymphocytes

Blood ◽  
1999 ◽  
Vol 94 (4) ◽  
pp. 1201-1208 ◽  
Author(s):  
J.H. Frederik Falkenburg ◽  
Amon R. Wafelman ◽  
Peter Joosten ◽  
Willem M. Smit ◽  
Cornelis A.M. van Bergen ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Progenitor Cells ◽  
Myeloid Leukemia ◽  
Cytotoxic T Lymphocyte ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Donor Lymphocyte Infusion ◽  
Leukemic Cells

Relapse of chronic myeloid leukemia (CML) in chronic phase after allogeneic stem cell transplantation (SCT) can be successfully treated by donor lymphocyte infusion (DLI). However, relapse of accelerated phase CML, blast crisis, or acute leukemia after allogeneic SCT are resistant to DLI in the majority of cases. In vitro-selected and expanded leukemia-reactive T-cell lines may be more effective in inducing an antileukemic response in vivo. To treat a patient with accelerated phase CML after allogeneic SCT, leukemia-reactive cytotoxic T-lymphocyte (CTL) lines were generated from her HLA-identical donor. Using a modification of a limiting dilution assay, T cells were isolated from the donor, selected based on their ability to inhibit the in vitro growth of CML progenitor cells, and subsequently expanded in vitro to generate CTL lines. Three CTL lines were generated that lysed the leukemic cells from the patient and inhibited the growth of leukemic progenitor cells. The CTL did not react with lymphocytes from donor or recipient and did not affect donor hematopoietic progenitor cells. The 3 leukemia-reactive CTL lines were infused at 5-week intervals at a cumulative dose of 3.2 × 109 CTL. Shortly after the third infusion, complete eradication of the leukemic cells was observed, as shown by cytogenetic analysis, fluorescence in situ hybridization, molecular analysis of BCR/ABL-mRNA, and chimerism studies. These results show that in vitro cultured leukemia-reactive CTL lines selected on their ability to inhibit the proliferation of leukemic progenitor cells in vitro can be successfully applied to treat accelerated phase CML after allogeneic SCT.

scholarly journals Bosutinib Versus Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia: Results From the BELA Trial

2012 ◽  
Vol 30 (28) ◽  
pp. 3486-3492 ◽  
Author(s):  
Jorge E. Cortes ◽  
Dong-Wook Kim ◽  
Hagop M. Kantarjian ◽  
Tim H. Brümmendorf ◽  
Irina Dyagil ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Phase Iii ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Blast Phase ◽  
End Point

Purpose Bosutinib is an oral Src/Abl tyrosine kinase inhibitor. The phase III Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia (BELA) trial compared bosutinib with imatinib in newly diagnosed, chronic-phase chronic myeloid leukemia (CML). Patients and Methods A total of 502 patients were randomly assigned 1:1 to bosutinib 500 mg per day or imatinib 400 mg per day. Results The complete cytogenetic response (CCyR) rate at 12 months was not different for bosutinib (70%; 95% CI, 64% to 76%) versus imatinib (68%; 95% CI, 62% to 74%; two-sided P = .601); therefore, the study did not achieve its primary end point. The major molecular response (MMR) rate at 12 months was higher with bosutinib (41%; 95% CI, 35% to 47%) compared with imatinib (27%; 95% CI, 22% to 33%; two-sided P < .001). Time to CCyR and MMR was faster with bosutinib compared with imatinib (two-sided P < .001 for both). On-treatment transformation to accelerated/blast phase occurred in four patients (2%) on bosutinib compared with 10 patients (4%) on imatinib. A total of three CML-related deaths occurred on the bosutinib arm compared with eight on the imatinib arm. The safety profiles of bosutinib and imatinib were distinct; GI and liver-related events were more frequent with bosutinib, whereas neutropenia, musculoskeletal disorders, and edema were more frequent with imatinib. Conclusion This ongoing trial did not meet its primary end point of CCyR at 12 months, despite the observed higher MMR rate at 12 months, faster times to CCyR and MMR, fewer on-treatment transformations to accelerated/blast phase, and fewer CML-related deaths with bosutinib compared with imatinib. Each drug had a distinct safety profile.

scholarly journals Characteristics and outcomes of patients with chronic myeloid leukemia and T315I mutation following failure of imatinib mesylate therapy

Blood ◽  
2008 ◽  
Vol 112 (1) ◽  
pp. 53-55 ◽  
Author(s):  
Elias Jabbour ◽  
Hagop Kantarjian ◽  
Dan Jones ◽  
Megan Breeden ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mutation Detection ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Patient Characteristics ◽  
Blast Phase ◽  
T315i Mutation ◽  
New Mutations

AbstractChronic myeloid leukemia (CML) with T315I mutation has been reported to have poor prognosis. We analyzed 27 patients with T315I, including 20 who developed T315I after imatinib failure (representing 11% of 186 patients with imatinib failure), and 7 of 23 who developed new mutations after second tyrosine kinase inhibitor (TKI). Median follow-up from mutation detection was 18 months. At the time of T315I detection, 10 were in chronic phase (CP), 9 in accelerated phase, and 8 in blast phase. Except for the lack of response to second TKIs (P = .002), there was no difference in patient characteristics and outcome between patients with T315I and those with other or no mutations. Patients in CP had a 2-year survival rate of 87%. Although the T315I mutation is resistant to currently available TKIs, survival of patients with T315I remains mostly dependent on the stage of the disease, with many CP patients having an indolent course.

High Levels of Circulating HSP70 Levels in Patients with Chronic Myeloid Leukemia and Correlation with Resistance to Therapy with Imatinib.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2922-2922
Author(s):  
Richard Tseng ◽  
Chen-Hsiung Yeh ◽  
Iman Jilani ◽  
Zhong Zhang ◽  
Hagop Kantarjian ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Blast Crisis ◽  
Death Receptor ◽  
Chronic Phase ◽  
Leukemic Cells ◽  
Hsp70 Protein ◽  
N 93

Abstract Cellular increase in the heat shock protein 70 (HSP70) inhibits death receptor and mitochondria-initiated signaling for apoptosis. In Vitro and in vivo data from patients with chronic myeloid leukemia (CML) indicates that overexpression of HSP70 in leukemic cells is associated with resistance to imatinib. The HSP70 protein is detectable in the plasma and has been reported to represent a marker for cardiovascular stress as well as prostate cancer. We measured HSP70 in the plasma of 139 patients with CML using a sandwich assay based on meso scale technology and correlated levels of HSP70 protein in plasma with clinical behavior. All samples were collected prior to initiating imatinib therapy. The levels of HSP70 in CML patients in chronic phase (N=93) were not significantly (P=0.08) different from those in patients with CML in accelerated/blast crisis (N=46) (median 33.24 ng/ml, range: 3.892–128.172 ng/ml Vs median 26.57 ng/ml, range: 4.498–114.746 ng/ml, respectively). However, CML patients had significantly (P<0.0001) higher levels of HSP70 than normal control (N=95, median=4.17 ng/ml, range:1.746–24.684 ng/ml). There was significant correlation between plasma levels of HSP70 and platelets (r=0.54), WBC (r=0.32), and basophils (r=0.31) in patients in chronic phase and with platelets (r=0.72), blasts (r=0.39), and basophils (r=0.50) in patients in Acc/Bl phase. Patients in chronic phase and high levels above the median had significantly (P=0.02) higher rate of progression to ACC/Bl phase while on therapy with imatinib (figure). In addition these patients appear to have a tendency toward shorter survival (P=0.07). There was no significant correlation between plasma HSP70 levels and survival in patients with ACC/Bl phase. This data support the reported role of HSP70 in the resistance to imatinib in patients with CML and potentially plasma HSP70 levels may represent a marker for resistance in patients with chronic phase CML. Figure Figure

Evidence for a positive role of SHIP in the BCR-ABL–mediated transformation of primitive murine hematopoietic cells and in human chronic myeloid leukemia

Blood ◽  
2003 ◽  
Vol 102 (8) ◽  
pp. 2976-2984 ◽  
Author(s):  
Xiaoyan Jiang ◽  
Matthew Stuible ◽  
Yves Chalandon ◽  
Andra Li ◽  
Wing Yiu Chan ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Fluorescent Protein ◽  
Chronic Phase ◽  
Leukemic Cells ◽  
Mouse Bone Marrow ◽  
Positive Role ◽  
Hematopoietic Stem

Abstract Previous studies suggested that the SH2-containing inositol-5-phosphatase (SHIP) may play a tumor suppressor-like function in BCR-ABL–mediated leukemogenesis. To investigate this possibility, we first developed a new assay for quantitating transplantable multilineage leukemia-initiating cells (L-ICs) in hematopoietic stem cell (HSC)–enriched mouse bone marrow (BM) cells transduced with a BCR-ABL–GFP (green fluorescent protein) retrovirus. The frequency of L-ICs (1 of 430 Sca-1+lin– cells) was 7-fold lower than the frequency of HSCs in the Sca-1+lin– subset transduced with a control virus (1 of 65 cells). Forced BCRABL expression was also accompanied by a loss of regular HSC activity consistent with the acquisition of an increased probability of differentiation. Interestingly, the frequency and in vivo behavior of wild-type (+/+) and SHIP–/– L-ICs were indistinguishable, and in vitro, Sca-1+lin– BCR-ABL–transduced SHIP–/– cells showed a modestly reduced factor independence. Comparison of different populations of cells from patients with chronic myeloid leukemia (CML) in chronic phase and normal human BM showed that the reduced expression of full-length SHIP proteins seen in the more mature (CD34–lin+) leukemic cells is not mirrored in the more primitive (CD34+lin–) leukemic cells. Thus, SHIP expression appears to be differently altered in the early and late stages of differentiation of BCR-ABL–transformed cells, underscoring the importance of the cellular context in which its mechanistic effects are analyzed.

scholarly journals High Level Engraftment of NOD/SCID Mice by Primitive Normal and Leukemic Hematopoietic Cells From Patients With Chronic Myeloid Leukemia in Chronic Phase

Blood ◽  
1998 ◽  
Vol 91 (7) ◽  
pp. 2406-2414 ◽  
Author(s):  
J.C.Y. Wang ◽  
T. Lapidot ◽  
J.D. Cashman ◽  
M. Doedens ◽  
L. Addy ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Human Cells ◽  
Scid Mice ◽  
Leukemic Cells ◽  
Human Cd34 ◽  
Cd34 Cells ◽  
High Level

Abstract We have previously shown that intravenously injected peripheral blood (PB) or bone marrow (BM) cells from newly diagnosed chronic myeloid leukemia (CML) patients can engraft the BM of sublethally irradiated severe combined immunodeficient (SCID) mice. We now report engraftment results for chronic phase CML cells in nonobese diabetic (NOD)/SCID recipients which show the superiority of this latter model. Transplantation of NOD/SCID mice with 7 to 10 × 107 patient PB or BM cells resulted in the continuing presence of human cells in the BM of the mice for up to 7 months, and primitive human CD34+ cells, including those detectable as colony-forming cells (CFC), as long-term culture-initiating cells, or by their coexpression of Thy-1, were found in a higher proportion of the NOD/SCID recipients analyzed, and at higher levels than were seen previously in SCID recipients. The human CFC and total human cells present in the BM of the NOD/SCID mice transplanted with CML cells also contained higher proportions of leukemic cells than were obtained in the SCID model, and NOD/SCID mice could be repopulated with transplants of enriched CD34+ cells from patients with CML. These results suggest that the NOD/SCID mouse may allow greater engraftment and amplification of both normal and leukemic (Ph+) cells sufficient for the quantitation and characterization of the normal and leukemic stem cells present in patients with CML. In addition, this model should make practical the investigation of mechanisms underlying progression of the disease and the development of more effective in vivo therapies.

scholarly journals BCR-ABL gene rearrangement and expression of primitive hematopoietic progenitors in chronic myeloid leukemia

Blood ◽  
1993 ◽  
Vol 81 (11) ◽  
pp. 2898-2902 ◽  
Author(s):  
A Bedi ◽  
BA Zehnbauer ◽  
MI Collector ◽  
JP Barber ◽  
MS Zicha ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Gene Rearrangement ◽  
Chronic Phase ◽  
Proliferation And Differentiation ◽  
Leukemic Clone ◽  
Polymerase Chain ◽  
Progenitor Compartment

Abstract Chronic myeloid leukemia (CML) is characterized by an initial chronic phase of expanded yet orderly clonal hematopoiesis that is distinguished by the BCR-ABL gene rearrangement. We found that although the mature myeloid compartment in patients with CML was expanded and entirely derived from the dominant leukemic clone, the primitive hematopoietic progenitor compartment did not show a corresponding expansion and was substantially enriched for cells without the BCR-ABL gene rearrangement. More importantly, primitive progenitors exhibiting the BCR-ABL gene rearrangement did not express either the BCR-ABL hybrid mRNA or fusion protein (P210). Expression of P210 protein and BCR-ABL mRNA increased with myeloid commitment in vivo as well as with growth factor-induced proliferation and differentiation of the primitive CML progenitors in vitro. This differential expression of BCR- ABL between primitive and mature CML progenitors may explain the expansion of the leukemic clone at the level of mature myeloid progenitors and granulocytes without a concomitant expansion of primitive CML progenitors. Because BCR-ABL mRNA is minimally expressed or may be absent in primitive CML progenitors, these cells may escape detection by reverse transcriptase-polymerase chain reaction and eradication by antisense oligonucleotides targeted against BCR-ABL mRNA.

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