Coexistence of Chronic Myelogenous Leukemia and Multiple Myeloma

Tanaka, Masahide; Kimura, Reiji; Matsutani, Akira; Zaitsu, Ken; Oka, Yoshitomo; Ōizumi, Kōtaro

doi:10.1159/000040843

Cited by 23 publications

(14 citation statements)

References 12 publications

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“…Until this report, only two reports of patient BCR-ABL fusions were detected using PCR amplification and gene sequencing; however, no molecular mechanistic data regarding expressed BCR-ABL protein was previously reported in MM (28,29). The literature supports the existence of a relationship between MM and CML as well as a relationship between MM and the myeloproliferative disorders (59,60). It is important to mention that the BCR-ABL fusion was most prominent in one lot of H929 cells, but an additional high molecular band for both BCR and ABL could be detected in other lots of H929 cells from different vendors and separate academic laboratories (Fig.…”

Section: Discussionmentioning

confidence: 91%

Detection of a rare BCR–ABL tyrosine kinase fusion protein in H929 multiple myeloma cells using immunoprecipitation (IP)-tandem mass spectrometry (MS/MS)

Breitkopf

Yuan

Pihán

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Hypothesis directed proteomics offers higher throughput over global analyses. We show that immunoprecipitation (IP)-tandem mass spectrometry (LC-MS/MS) in H929 multiple myeloma (MM) cancer cells led to the discovery of a rare and unexpected BCR-ABL fusion, informing a therapeutic intervention using imatinib (Gleevec). BCR-ABL is the driving mutation in chronic myeloid leukemia (CML) and is uncommon to other cancers. Three different IP-MS experiments central to cell signaling pathways were sufficient to discover a BCR-ABL fusion in H929 cells: phosphotyrosine (pY) peptide IP, p85 regulatory subunit of phosphoinositide-3-kinase (PI3K) IP, and the GRB2 adaptor IP. The pY peptides inform tyrosine kinase activity, p85 IP informs the activating adaptors and receptor tyrosine kinases (RTKs) involved in AKT activation and GRB2 IP identifies RTKs and adaptors leading to ERK activation. Integration of the bait-prey data from the three separate experiments identified the BCR-ABL protein complex, which was confirmed by biochemistry, cytogenetic methods, and DNA sequencing revealed the e14a2 fusion transcript. The tyrosine phosphatase SHP2 and the GAB2 adaptor protein, important for MAPK signaling, were common to all three IP-MS experiments. The comparative treatment of tyrosine kinase inhibitor (TKI) drugs revealed only imatinib, the standard of care in CML, was inhibitory to BCR-ABL leading to down-regulation of pERK and pS6K and inhibiting cell proliferation. These data suggest a model for directed proteomics from patient tumor samples for selecting the appropriate TKI drug(s) based on IP and LC-MS/MS. The data also suggest that MM patients, in addition to CML patients, may benefit from BCR-ABL diagnostic screening.targeted therapies | personalized medicine | protein-protein interactions P roteomics studies over the last decade have provided significant advancements in our understanding of the functional landscape of proteins, their posttranslational modifications and the protein-protein interactions (PPI) (1-3). This is especially important for diseases such as cancer because proteins and their transient posttranslational modifications (PTMs) reflect the changes cells undergo during pathogenic development. Modern high-resolution mass spectrometers are well suited for these analyses and have led the efforts in this field of proteomics, allowing researchers to analyze dynamic changes in cell lines or tissue and to distinguish between normal and unhealthy states (4, 5). PPI networks and phosphoproteomics are important for understanding the function and regulation of pathways leading to cell growth and proliferation in diseases such as cancer. The advantage of analyzing purified protein complexes is the ability to identify specific interacting proteins and posttranslational modifications that may otherwise go undetected in large-scale global analyses. This can be achieved by performing an immunoprecipitation (IP) with a bait protein and analyzing the prey proteins using microcapillary-tandem mass spectrometry (LC-MS/MS) (6-1...

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Section: Discussionmentioning

confidence: 91%

Detection of a rare BCR–ABL tyrosine kinase fusion protein in H929 multiple myeloma cells using immunoprecipitation (IP)-tandem mass spectrometry (MS/MS)

Breitkopf

Yuan

Pihán

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…It has been previously suspected [11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91], but not systematically evaluated and proven, that Ph – MPN-B-CLL is the most common combination in patients with two different haematological neoplasms (fig. 3; online suppl.…”

Section: Discussionmentioning

confidence: 99%

Simultaneous and Sequential Concurrent Myeloproliferative and Lymphoproliferative Neoplasms

Jonigk

Kreipe

et al. 2012

Acta Haematol

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Concurrent manifestation of two chronic-stage myeloid and lymphoid/plasmacytoid neoplasms in one patient is rare and occurs in ≤1% of patients. There has been no systematic analysis of which combinations are frequent/infrequent and whether two concurrent diseases in one patient are clonally related or represent independent diseases. We therefore characterised a series of cases from our own archive (n = 65) and collected a large number of previously reported cases of patients in whom myeloid and lymphoid/plasmacytoid neoplasms co-occurred (n = 185). The most frequent combination was Philadelphia chromosome-negative myeloproliferative neoplasm with concurrent B cell chronic lymphocytic leukaemia, accounting for approximately 50% of double-disease patients. We compared the quantity of unsorted bone marrow cell-derived JAK2^V617F and KIT^D816V alleles with the quantity of the lymphoid/plasmacytoid compartment and analysed a subfraction of cases with fluorescence in situ hybridisation. Although a common aberrant progenitor has been reported in some cases in the literature, we found evidence of two independent chronic-stage myeloid and lymphoid/plasmacytoid neoplasms.

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“…In the remaining patients, aberrant clonal karyotypes may include add (8), add(9), add(21), del(20q), del(11q) and del(12p) (3). In the present case, no clonal chromosome abnormalities were identified by the conventional cytogenetic method.…”

Section: Discussionmentioning

confidence: 53%

Concurrent chronic neutrophilic leukemia blast crisis and multiple myeloma: A case report and literature review

Shi

et al. 2015

Oncology Letters

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Abstract. The current study presents the case of a 78-year-old male with concurrent chronic neutrophilic leukemia (CNL) and multiple myeloma (MM) who developed acute myeloid leukemia after two years of treatment with hydroxyurea, cyclophosphamide, prednisone and thalidomide. The patient presented with mature neutrophilic leukocytosis, hepatosplenomegaly, a high neutrophil alkaline phosphatase score and an absence of the Philadelphia chromosome or the BCR-ABL fusion gene. A bone marrow aspirate smear and biopsy indicated that the CNL coexisted with a plasma cell neoplasm. In addition, monoclonal λ-paraproteinemia was detected by serum protein immunofixation electrophoresis, and bone lesions were identified in multiple vertebrae. The patient achieved complete remission following one cycle of induction chemotherapy with the decitabine regimen in combination with the low-dose cytarabine, aclarubicin and granulocyte-colony stimulating factor (CAG) priming regimen. The occurrence of CNL and MM concurrently is extremely rare and thus, it has only been reported in a small number of cases. The occurrence of CNL and MM in the same patient as two distinct hematological malignancies indicates the neoplastic transformation of a pluripotent stem cell. Decitabine combined with the CAG priming regimen may present a good therapeutic strategy for elderly patients with secondary acute myeloid leukemia.

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Coexistence of Chronic Myelogenous Leukemia and Multiple Myeloma

Cited by 23 publications

References 12 publications

Detection of a rare BCR–ABL tyrosine kinase fusion protein in H929 multiple myeloma cells using immunoprecipitation (IP)-tandem mass spectrometry (MS/MS)

Detection of a rare BCR–ABL tyrosine kinase fusion protein in H929 multiple myeloma cells using immunoprecipitation (IP)-tandem mass spectrometry (MS/MS)

Simultaneous and Sequential Concurrent Myeloproliferative and Lymphoproliferative Neoplasms

Concurrent chronic neutrophilic leukemia blast crisis and multiple myeloma: A case report and literature review

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