Cases Of Chronic Myelogenous Leukemia Research Articles

Secondary Hairy Cell Leukemia in a Patient With Chronic Myelogenous Leukemia Following Treatment With Tyrosine Kinase Inhibitors: Report of an Extremely Rare Case and Review of the Literature

The occurrence of chronic myelogenous leukemia (CML) and hairy cell leukemia (HCL) in the same patient is extremely rare. The reported cases had either CML and HCL occurring simultaneously or development of CML after HCL. We report an unusual case of CML with subsequent development of HCL after treatment with tyrosine kinase inhibitors. The diagnosis was challenging both clinically and pathologically due to the expected side effects of tyrosine kinase inhibitors and low levels of hairy cells initially. We further showed that the CML and HCL are not clonally related, in contrast to the only case in which clonality study was performed. To our knowledge, this is the first report of HCL developing in patients with CML. J Med Cases. 2012;3(1):39-42 doi: https://doi.org/10.4021/jmc404w

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Frequency of different Bcr-abl Fusion Transcripts in CML Patients in Pakistan

Bcr-abl translocation has been found to be the hallmark of chronic myelogenous leukemia. It is present in 90-95% cases of chronic myelogenous leukemia. The present study was performed to check the frequency of Bcr-abl fusion transcripts in Pakistani chronic myelogenous leukemia patients. The frequency of Bcr-abl fusion transcript was determined by using RT-PCR. RNA was isolated from the peripheral blood of 23 CML patients using TRIzol reagent. It was reverse transcribed by using MMLV reverse transcriptase enzyme followed by RT-PCR. RT-PCR was done by using two combinations of primers (BCR-C, CA3) and (B2B, CA3). The PCR product was analysed on 3% Agarose gel. Results: All 23 samples were positive for Bcr-abl translocation. Out of 23 samples 13 (56.5%) were positive for b2a2 type transcript. B3a2 transcript was observed in 6 (26%) out of 23 samples. Other samples gave unusual bands of around 209 bp referring to fusion fragments other than b2a2 or b3a2. None of 23 samples was positive for e1a2 type transcript. In Pakistani population b2a2 type transcript is most frequent in contrast to the studies conducted on other populations. That is perhaps due to the ethnic differences.

Secondary Hairy Cell Leukemia in a Patient With Chronic Myelogenous Leukemia Following Treatment With Tyrosine Kinase Inhibitors: Report of an Extremely Rare Case and Review of the Literature

The occurrence of chronic myelogenous leukemia (CML) and hairy cell leukemia (HCL) in the same patient is extremely rare. The reported cases had either CML and HCL occurring simultaneously or development of CML after HCL. We report an unusual case of CML with subsequent development of HCL after treatment with tyrosine kinase inhibitors. The diagnosis was challenging both clinically and pathologically due to the expected side effects of tyrosine kinase inhibitors and low levels of hairy cells initially. We further showed that the CML and HCL are not clonally related, in contrast to the only case in which clonality study was performed. To our knowledge, this is the first report of HCL developing in patients with CML. J Med Cases. 2012;3(1):39-42 doi: https://doi.org/10.4021/jmc404w

BCR-JAK2 fusion as a result of a translocation (9;22)(p24;q11.2) in a patient with CML-like myeloproliferative disease

Translocation (9;22)(q34;q11.2) resulting in BCR/ABL1 fusion at the molecular level is the hallmark of chronic myelogenous leukemia (CML). Variants of the Philadelphia translocation and complex translocations involving BCR have been reported in myeloproliferative disorders (MPD). A rare translocation, t(9;22)(p24;q11.2), resulting in a novel BCR-JAK2 fusion has been reported in a handful of cases of CML and acute myelogenous leukemia (AML). We present clinical-pathological and cytogenetic evaluation of a patient with Philadelphia-chromosome negative CML/MPD harboring a t(9;22)(p24;q11.2) resulting in BCR-JAK2 fusion. Fluorescence in situ hybridization and molecular characterization of the translocation confirmed a BCR-JAK2 fusion and helped delineate the breakpoints upstream of exon 1 of minor cluster region of BCR gene and likely intron 18 of the JAK2 gene, resulting in an in-frame transcript This case provides convincing support, along with two previous case-reports, for a role for activation of the Janus kinase 2 in evolution of myeloproliferative disease. The recurrent, albeit rare, nature of the breakpoints within BCR and JAK2 suggests a potential new diagnostic target that should be interrogated in Ph-negative CML/MPD patients.

Meta-analysis of human leukocyte antigen genetic polymorphisms and susceptibility to chronic myelogenous leukemia in Chinese population

Human leukocyte antigen (HLA) genetic polymorphisms are assumed to be correlated to the risk of chronic myelogenous leukemia (CML) in various ethnicities. Up to now, no clear consensus has been reached. Our goal is to address this issue in Chinese population. By searching the data in PubMed, Embase and four Chinese databases (prior to July 2010), the association of HLA genetic polymorphisms with CML has been fixed as the research objective. We studied a totality of 12 studies, comprising 2281 CML cases and 41000 health controls. The data demonstrated that HLA-A*11, A*74, HLA-B*40, B*47, B*55 and B*81 alleles were correlated with the increasing risk of CML. Nevertheless, HLA-DRB1*13 allele seemed to contribute to the genetic protection to CML. Conclusively we suggested that certain HLA alleles might be in association with the pathogenesis of CML in Chinese population. Due to little statistical scale, larger studies and particularly in a mono-people background, our hypothesis need to be further investigated in the future.

Clinical and laboratory features of leukemias at the time of diagnosis: An analysis of 1,004 consecutive patients

To determine the major presenting features of the most frequent leukemias and to describe the period from the first symptoms to the final diagnosis, we analyzed the records of 1,004 consecutive patients with acute (AL) and chronic (CL) leukemias diagnosed between 2004 and 2009. In 24% of AL and 63% of CL, the diagnosis was made incidentally. In contrast to the frequency of the symptoms, their spectrum did not differ from historical studies, and fatigue and weakness were the most frequent symptoms observed [with the exception of acute promyelocytic leukemia (APL) where bleeding predominated]. More profound cytopenia was found in AL compared to CL. The median time from the first symptoms to final diagnosis was 3 weeks in AL and 4 weeks in CL. APL had the shortest time to a definitive diagnosis (2 weeks); however, a very short duration of symptoms was also observed in CML (3 weeks). This study is the largest series reported to date on symptoms in leukemia patients at the time of diagnosis, and the first such report that reflects on clinical practice in the new millennium.

Bortezomib treatment causes remission in a Ph+ALL patient and reveals FoxO as a theranostic marker

BCR-ABL is a key mediator in the pathogenesis of all cases of chronic myelogenous leukemia (CML) and a subset of precursor B-acute lymphoblastic leukemia (Ph+ALL). Previous animal and cell-based studies have shown that the expression of members of the Forkhead family of tumor suppressors, including FoxO3, is suppressed in BCR-ABL-expressing cells. Furthermore, it has been reported that the proteasomal degradation pathway plays an important role in suppression of FoxO expression in BCR-ABL-transformed cells. In this study, a patient diagnosed with Ph+ALL and refractory to standard therapies was treated with a proteasome inhibitor (bortezomib)-based chemotherapy regimen. This treatment resulted in complete hematologic, cytogenetic and molecular remission with excellent performance status for >4 years since her initial diagnosis. FoxO3 was not detectable within the blasts of this patient at diagnosis and was ‘rescued’ following treatment with bortezomib therapy, leading to her recovery. As a next step, in the attempt to propose FoXO3 as a therapeutic target and a theranostic marker, we further validated FoxO3 expression in human bone marrow biopsy samples. Human core biopsy samples of Ph+ALL and Ph-negative-negative ALL, along with uninvolved controls, revealed that FoxO3 down-regulation was specific to Ph+ALL. This study provides support that FoxO3 is a good biomarker for BCR-ABL-mediated leukemogenesis. Additionally, proteasomal inhibition by bortezomib may be a promising therapeutic option in Philadelphia-positive ALL, where FoxO3 is downregulated. See commentary: Out Foxing Bcr-Abl

Successful treatment with nilotinib after imatinib failure in a CML patient with a four-way Ph chromosome translocation and point mutations in BCR/ABL gene

Chronic myelogenous leukemia (CML) is characterized by Philadelphia (Ph) chromosome with a chimeric gene BCR-ABL created by reciprocal t(9:22) (q34;q11) translocation. Variant Ph chromosome translocations involving chromosomes other than 9 and 22 are found in 5-10% of CML cases. We here report a CML patient who carries a four-way Ph chromosome translocation, t(9;22;15;19) (q34;q11;q15;q13). The patient was diagnosed in 1997 and initially treated with hydroxyurea. In 2002, treatment with imatinib, a selective BCR-ABL tyrosine kinase inhibitor (TKI), was started but Ph-positive chromosomes remained at the levels of 42-65%, indicating imatinib failure. In 2006, the point mutations of F359I and L387M were detected in BCR/ABL gene, which may be related to imatinib failure. Treatment with nilotinib, a TKI with high target specificity, was then started which resulted in durable major molecular response. Administration of nilotinib offered an effective treatment in a CML patient with variant Ph chromosome translocations and BCR-ABL point mutations after imatinib failure.

Chronic Myelogenous Leukemia with Mild Basophilia as the Predominant Manifestation at Presentation

Chronic myelogenous leukemia (CML) is a clonal hematological malignancy typically presenting with basophilia and massive proliferation of differentiating myeloid cells. We report an atypical case of CML in which mild basophilia was the sole manifestation at presentation, and the condition persisted for 27 months with no sign of progression. This case reconfirms the importance of basophilia as a clinical manifestation of CML, and BCR-ABL FISH analysis should always be applied to cases of basophilia, even when the basophilia is modest and no other features of CML are present.

Megakaryocytic blast crisis in a chronic myeloid leukemia patient with a rare variant of Philadelphia rearrangement t(9;22; 22) and a constitutional translocation t(3;7)

Megakaryocytic blast crisis occurs extremely rarely, accounting for <3% of cases of chronic myelogenous leukemia in blastic transformation. In chronic myeloid leukemia, a variant Philadelphia translocation is reported in 2–10% of cases. We report an unusual case of megakaryocytic blast crisis with the Philadelphia variant rearrangement t(9;22; 22) and a constitutional translocation t(3;7). The breakpoint in the 22q13 region was involved in this translocation. The chromosome region 22q13 harbors MKL1 gene, which is engaged in a specific translocation associated with acute megakaryoblastic leukemia. Study of deregulation of these four genes could contribute to better understanding of the effects of the t(9;22; 22) rearrangement in a megakaryocytic blast crisis.

Del(15q) is a recurrent minor-route cytogenetic abnormality in the clonal evolution of chronic myelogenous leukemia

The del(15q) chromosomal abnormality is known to occur in acute leukemias, but has rarely been described in chronic myelogenous leukemia (CML). Described here are five cases of CML associated with del(15q): four men and one woman. Bone marrow aspirate smears showed increased blasts in all cases at the time of del(15q) detection, in accelerated phase in two cases and myeloid blast phase in three. Conventional cytogenetic analysis showed t(9;22) and del(15q), as well as other inconsistent clonal abnormalities. All patients received imatinib mesylate; four received additional chemotherapy, and two had allogeneic stem cell transplantation (ASCT). Of the three patients who did not receive ASCT, one died, one was in persistent blast phase, and one was in clinical remission with molecular evidence of residual disease at 16, 6, and 34 months, respectively, after identification of the del(15q). Of the two patients who had ASCT, one died and one was in clinical remission with molecular evidence of disease at 15 and 64 months, respectively, after identification of the del(15q). These findings indicate that del(15q) is a recurrent cytogenetic abnormality that may be seen at initial presentation of advanced disease or may emerge during disease progression. Del(15q) appears to be associated with a poor prognosis in CML.

Mast cell burden and reticulin fibrosis in the myeloproliferative neoplasms: A computer-assisted image analysis study

The mast cell has been associated with fibrosis in many different tissues, organs, and different disease processes including hematopoietic malignancies. Mast cells are often increased in the bone marrow of patients with primary bone marrow disorders, and patients with systemic mastocytosis often have a second concomitant neoplastic disease of the bone marrow. The goals of the current study were to determine the role the mast cell has in the pathogenesis of myeloproliferative neoplasms (MPN) and to correlate the mast cell burden with the degree of reticulin fibrosis. We used computer-assisted image analysis of bone marrow core biopsies stained for mast cell tryptase from patients with myeloproliferative neoplasms [31 cases: 12 chronic myelogenous leukemia (CML), 6 primary myelofibrosis (PMF), 4 essential thrombocythemia (ET), 4 polycythemia vera (PV), and 5 chronic myeloproliferative disorder, unclassifiable (CMPD-U)]. Although the number of cases of some subtypes of MPN was small, the results suggested that PMF and ET each had significantly more mast cells than both CML and control cases ( P<0.01 and 0.05, respectively, Mann–Whitney test). CMPD-U and PV showed no significant differences from the control cases, but the CML cases had significantly fewer mast cells than our control cases ( P=0.02, Mann–Whitney test). In addition, the quantity of mast cells seen in the bone marrows of MPN patients correlated with reticulin fibrosis ( P=0.04, Mann–Whitney test). Our studies highlight the different mast cell quantities in different myeloproliferative neoplasms and suggest a direct role for the mast cell in intramedullary fibrosis. Further studies are warranted to confirm our observation and to study the mechanisms by which mast cells contribute to fibrosis in the MPN setting.

High diagnostic value of morphologic examination and molecular analysis of bone marrow biopsies in a case of BCR-ABL+ CML with clusters of blasts

We report a clinical case of chronic myelogenous leukaemia (CML) with regional B-lymphoblastic transformation. Peripheral leukocytosis of 160 x 10(9)/L, splenomegaly and fatigue suggested CML. In peripheral blood and bone marrow smears, white blood cells in all maturation stages and only few blasts were seen and therefore the diagnosis of chronic phase CML was proposed. Cytogenetics performed on peripheral blood cells revealed the characteristic t(9;22)(q34;q11) translocation as solitary abnormality. Analyzing the bone marrow biopsy a focal nodular B-lymphoid blast component was additionally seen. BCR-ABL FISH analysis demonstrated 31% atypical split signals in the B-lymphoid blasts and in the maturing myeloid cells, furthermore, BCR-ABL fusion transcripts were seen in the RT-PCR assay. Imatinib-based therapy led to temporary regression of peripheral leukocytosis. Bone marrow examination 3 weeks after therapy induction demonstrated considerably reduced cellularity and the proportion of B-lymphoid blasts had decreased to 20% of the nuclear cells. BCR-ABL FISH analysis still presented 21% atypical split signals but levels of BCR-ABL transcripts had significantly fallen indicating a rather favourable prognosis. However, 3 months after diagnosis the patient relapsed and developed an immunodeficiency with soor esophagitis and aspergillus pneumonia. A therapy with dasatinib was not successful and the patient died in consequence of immunodeficiency. This report demonstrates the high diagnostic value of bone marrow biopsy in the evaluation of CML. Besides morphology investigation of diverse methods including RT-PCR and FISH performed on diagnostic bone marrow biopsies are obligatory for ideal monitoring of drug response.

T(3;9;22) 3-Way Chromosome Translocation in Chronic Myeloid Leukemia is Associated with Poor Prognosis

Chronic myelogenous leukemia (CML) is genetically characterized by the reciprocal translocation of chromosome 9 and 22. Around 5–8% of CML develop complex variant Ph translocations involving one or more chromosomal regions besides 9 and 22. Chromosome 3 is not frequently involved in complex translocations in CML. We report in this study a case of CML displaying a t(3;9;22) 3-way translocation. A review of the literature appears to indicate that CML patients with this translocation tend to have an aggressive course and poor outcome. Additional 3-way chromosome translocations associated with CML are also reviewed.

BCR-ABL alternative splicing as a common mechanism for imatinib resistance: evidence from molecular dynamics simulations.

Rare cases of chronic myelogenous leukemia (CML) express high levels of alternatively spliced BCR-ABL mRNA with a 35-bp insertion (35INS) between ABL kinase domain exons 8 and 9. This insertion results in a frameshift leading to the addition of 10 residues and truncation of 653 residues due to early termination. Sensitive PCR-based testing showed that 32 of 52 (62%) imatinib-resistant CML patients in chronic phase and 8 of 38 (21%) in accelerated or blast crisis expressed varying levels of the alternatively spliced BCR-ABL mRNA. A three-dimensional structural model of the 35INS ABL kinase domain complexed with imatinib was built using homology modeling, followed by molecular dynamics simulations. Simulation results showed that the new residues cause a significant global conformational change, altering imatinib binding in a way similar to that of the T315I mutation and, therefore, providing resistance to imatinib that depends on the level of expression.

Efficient Duplex Real-Time Quantitative RT-PCR of BCR-ABL and ABL Gene Transcripts for Monitoring of Minimal Residual Disease

BCL-ABL fusion gene can be found in 100% chronic myelogenous leukemia (CML) and about 25% adult acute lympholid leukemia where its expression level is a crucial parameter for monitoring of minimal residual disease (MRD). Depending on the breakpoint in BCR, exon 2 of ABL (a2) joins with exons 1 (e1), 13 (b2), or 14 (b3), or rarely to exon 19 (e19) of BCR resulting in chimeric proteins of p190, p210 and p230, respectively. The c-ABL gene is one of the best controls for MRD detection by real-time quantitative RT-PCR (RQ-RT-PCR). In most studies published before, PCR probes were labeled by single fluorescence such as FAM, and BCR-ABL and ABL transcripts were detected in separate PCR reactions.Purpose: To design and evaluate a duplex, real-time quantitative RT-PCR (RQ-RT-PCR) system labeled with double fluorescence Taqman probes to simultaneously measure both BCR-ABL and ABL transcripts.Methods:Positive controls are plasmids containing full-length target sequence of BCR-ABLP210 and ABL. 70 cases of CML bone marrow samples collected in Nanfang Hospital from Jane 2005 to July 2008 were examined. Patients were untreated ones and those treated with STI571 or allo-hematological stem cell transplantation. RQ-RT-PCR value=copies of BCR-ABL/copies of ABL. The results are compared with fluorescence chromosomal in situ hybridization (FISH) for BCR-ABL.Probes and primers recommended by Europe Anti-Cancer group in 2003 were used as gold standard control; probe and primers for bcr-ablP210 gene are ENF541, ENP501 and ENR561, respectively; probe and primers for abl gene are ENPr1043, ENF1003 and ENR1063, respectively. Both Taqman probes are FAM labed.For duplex RQ-RT-PCR, HEX labeled probe is used for the ABL gene, along with corresponding primers, ENP541 labeled with FAM fluorescence and ENF501 and ENR561 were also used for BCR-ABLP210.The experiments were carried out in the same tube on a Biorad Opticon2 RQ-PCR unit. The end concentration is 0.3μmoL/L for primers and 0. 2 μmoL/L for probe. The PCR reaction was carried out in 25μL. PCR condition is at 50°C×2min+95°C×10min, then followed 95°C×15s+60°C×1min for 50cycle.Result: Testing using serial dilutions of plasmid positive control suggested that HEX-FAM duplex is readily amplified with the FAM Taqman probes of BCR-ABLP210, and the HEX-ABL results is same with those with FAM-ABL (recommeded by Europe Anti-Cancer group). Coefficiency of variation among different experiments is less than 5%. The 70 CML cases can be divide into 3 groups based on FISH value: ≥10% (n=32), 0.5% 10% (n=27) and negative (n=11). The corresponding RQ-PCR ratio of BCR-ABL/ABL are 0.590±0.264, 0.044±0.041 and (9.46±6.99)×10|4, respectively, P<0.01 between each group.Conclusion: We have established an efficient duplex RQ-RT-PCR method with FAM and HEX Taqman probes. This approach enables acquisition of more information from each test and hence reduces the amount of sample needed for each test. We believe this method will be useful to MRD monitoring in CML and BCL-ABL + B-ALL.

Progressive Chromatin Repression and Promoter Methylation of a-catenin Correlates with AML Transformation in Patients with and without 5q Deletions.

Background: Loss of the long arm of chromosome (Ch) 5 or complete loss of Ch 5 is frequent in de novo MDS and AML. Epigenetic modifications of tumor suppressor genes, including aberrant DNA methylation, may play an important role in the progression of MDS and AML. Cell signaling is regulated by a-catenin, which forms a trimolecular complex with E-cadherin (ECAD) and b-catenin that links with actin-containing filaments of the cytoskeleton. Studies have reported reduced expression of a-catenin in MDS and AML patients with 5q deletion as compared to those without 5q deletion. Whether promoter methylation of the a-catenin gene is responsible for this decreased expression is controversial. To explore the potential role of a-catenin in the pathogenesis of AML transformation, we (a) determined the tumor specificity of methylation in AML and non- myeloid malignancies and (b) frequency of methylation in patients with −5/del(5q) MDS/AML and those with normal cytogenetics; (c) performed bioinformatics and experimental analysis of the a-catenin adhesion complex and local 5q31.1 genes to investigate mechanisms of epigenetic silencing; and (d) performed a detailed analysis of primary AML samples correlating promoter methylation, a-catenin expression, and chromatin conformation.Methods and Results: Using methylation sensitive PCR, we found that methylation of the a-catenin promoter gene was specific for myeloid malignancy. No methylation was observed in 19 acute lymphocytic leukemia cases, 20 chronic myelogenous leukemia cases, or in 99 primary gastric and esophageal samples where a-catenin has been implicated as a tumor suppressor gene. In those patients with AML and an associated 5q deletion the frequency was 31% (8/26) as compared to those without a 5q deletion with 13% (16/120). Bioinformatics analyses of the Valk et al., 2004 leukemia database provide supportive data for under expression of a-catenin in non-5/del (5q) AML cases. We quantitated a-catenin mRNA expression by Q-PCR in our cohort. Expression was lowest in AML patients with a-catenin methylation (n=9), but also in a subset of patients without promoter methylation (n=17), suggesting alternative mechanisms of inactivation. In contrast to AML, methylation of a-catenin was rare in myelodysplastic syndrome (MDS). Although p15 was methylated in over 50% of these cases as a positive control, only 2/18 MDS cases with 5q deletion (11%) and 1/13 MDS cases with 5q intact (8%) were methylated at the a-catenin promoter. The three positive cases were RAEB-2 (1) or RAEB-t (2), suggesting that a-catenin methylation may be most important in promoting transformation from MDS to AML. To explain a potential lack of correlation of methylation with decreased a-catenin in MDS and AML, we investigated a-catenin chromatin in a myeloid stem cell progression model and in primary AML samples. We performed chromatin immunoprecipitation on the CTNNA1 promoter using two active chromatin histone marks, H3K9Ac and H3K4me2 and two inactive marks, H3K9me2 and H3K27me3. In cell lines and primary leukemia samples where a-catenin was highly expressed (N=4), activation marks were present and repression marks absent. In cell lines and primary samples with low a-catenin expression and methylation of the promoter (N=4), the opposite pattern was observed. So called “bivalent” chromatin with mixed marks, no a-catenin methylation, and intermediated mRNA expression levels were observed with 7 additional cases (2 cell lines, 5 primary AML).Conclusions: Our data indicate that methylation of a-catenin is common in AML patients with 5q deletion but also observed in cases with normal chromosome 5 copy number. We propose a model of progressive inactivation of the a-catenin locus with AML transformation, with methylation representing a late stage event. The tissue-specificity of our results and in vivo chromatin observations in primary AML samples have implications for the timing and combinatorial therapy of MDS/AML with HDAC inhibitors and methylation inhibitors. Additionally, it appears that inactivation of adhesion molecules (ECAD, a-catenin) are frequent events overall in AML, suggesting a new pathway of transformation from MDS to AML.

Type B Core Binding Factor β/Smooth Muscle Myosin Heavy Chain Fusion Transcript in Myeloid Blast Phase of Chronic Myeloid Leukemia: Correlation with Nuclear and Cytoplasmic Localization of the Fusion Protein

BackgroundInv(16)(p13q22) or the rare t(16;16)(p13;q22) is characteristic of the M4Eo type of acute myeloid leukemia and results in the fusion of the core binding factor β gene (CBFB) at 16q22 with the smooth muscle myosin heavy chain gene (MYH11) at 16p13. The fusion transcript CBFB/MYH11 plays an important role in leukemogenesis. Many variations of this fusion transcript have been reported, with type A being most common and occurring in > 85% of cases. Patients and MethodsWe studied the fusion transcripts in 4 cases of chronic myelogenous leukemia in myeloid blast phase with inv(16)(p13q22). ResultsSequencing analysis revealed type B fusion transcript in 3 of the 4 cases. Immunohistochemistry demonstrated both nuclear and cytoplasmic staining for the fusion protein. ConclusionAlthough the biologic significance of this finding is unknown, the high frequency of an unusual type of fusion transcript in the chronic myelogenous leukemia cases in blast phase in which inv(16)(p13q22) first occurred at the time of blast transformation suggests that the type B transcript might play a role in disease progression. The effect of the additional smooth muscle myosin heavy chain sequences in the type B fusion on subcellular localization of the protein product is also suggested.

The spectrum of adult B‐lymphoid leukemias with BCR‐ABL: Molecular diagnostic, cytogenetic, and clinical laboratory perspectives

The Philadelphia (Ph) chromosome is characteristic of chronic myelogenous leukemia (CML), but it is also the most frequent cytogenetic abnormality in precursor B-lymphoblastic leukemia (ALL) of adults. The vast majority of CML patients have a BCR-ABL translocation that yields a 210 kD (p210) oncoprotein, whereas adult Ph-positive ALL cases can present with either a p190 or a p210 oncoprotein, or both. Considering that 30% of the patients with CML that progress to blast crisis will have a lymphoblastic presentation, adults presenting with a p210 ALL may have either a de novo ALL or CML presenting for the first time in lymphoblastic phase. To identify the distinguishing features, cases of p190-ALL, p210-ALL, and lymphoblastic CML were compared. In spite of significant overlap between the three entities, a number of features were found to aid in their differentiation. p210-ALL patients present at a younger age with blasts that frequently show loss of expression of CD34, whereas p190-ALL patients present with marked increase in peripheral blast percentage. Interestingly, bone marrow findings characteristic of a myeloproliferative disorder are specific, but are not sensitive for lymphoblastic CML. This study suggests that despite the similarities between these leukemias, p190-ALL, p210-ALL, and lymphoblastic phase CML likely represent three distinct diseases.