Understand CML pathogenesis, Philadelphia chromosome, BCR-ABL, and lab findings for ASCP hematology MCQs.

ASCPprep.com | Hematology

Chapter 19 โ€” MYELOPROLIFERATIVE NEOPLASMS

ASCP Board Exam ยท Lab-Focused Study Guide
MPN Overview ยท CML (Philadelphia Chromosome, BCR-ABL1 p190/p210/p230, Phases, LAP Score, Imatinib & Resistance) ยท Polycythemia Vera (JAK2 V617F, WHO Criteria) ยท Essential Thrombocythemia ยท Primary Myelofibrosis ยท MPL, CALR-era Mutations, TET2, IDH1/2 ยท CNL, CEL, Mastocytosis, MPN-U ยท Practice Questions

1 ยท Priority Table & Quick Foundation

Topic Priority Why It’s Tested
CML: t(9;22), Philadelphia chromosome, BCR-ABL1 constitutive tyrosine kinase HIGH Defining lesion (Rodak Q2, case study)
CML blood picture: leukocytosis with all maturation stages, โ†‘ basophils and eosinophils, โ†“ LAP HIGH Rodak Q1, Q3; leukemoid differential
CML phases (chronic, accelerated, blast) and blast thresholds HIGH Rodak Q4
LAP score procedure and interpretation HIGH Calculation and differential
Imatinib mechanism, monitoring (RT-PCR log reduction), resistance (T315I, ponatinib) HIGH Case study Q6โ€“Q7
PV: JAK2 V617F (90โ€“97%), panmyelosis, WHO criteria, low EPO, phlebotomy HIGH Rodak Q6; Box 33-1
ET: platelets โ‰ฅ450 ร— 10โน/L, JAK2 50โ€“60%, large hyperlobulated megakaryocytes, thrombosis/hemorrhage HIGH Rodak Q7, Q8
PMF: teardrops, nRBCs, immature granulocytes (leukoerythroblastic), fibrosis, extramedullary hematopoiesis HIGH Rodak Q5, Q9, Q10
BCR-ABL1 fusion variants: p210 (major), p190 (minor, Ph+ ALL), p230 (micro, CNL) MEDIUM Molecular detail
Other MPN mutations: MPL W515L/K, JAK2 exon 12, LNK, TET2, IDH1/2, ASXL1, EZH2 MEDIUM Mutationโ€“disease matching
CNL, CEL NOS, mastocytosis (KIT D816V, tryptase >20), MPN-U MEDIUM Less common MPNs
JAK inhibitors (ruxolitinib) and PMF treatment details LOW Therapy trends
๐ŸŽฏ KEY POINT โ€” Where to spend your time

Focus: CML (Ph chromosome, blood picture, โ†“ LAP, phases, imatinib and T315I), PV (JAK2 V617F, WHO major/minor criteria, โ†“ EPO), ET (platelets โ‰ฅ450, megakaryocyte morphology, complications), PMF (leukoerythroblastic picture with teardrops, fibrosis mechanism). Skim: JAK-inhibitor trial percentages, CML protein domain details, mastocytosis subtypes.

Quick Foundation โ€” from zero

  • Myeloproliferative neoplasms (MPNs) are clonal stem cell disorders: one mutated stem cell overproduces mature-looking myeloid cells โ€” granulocytes, red cells and/or platelets.
  • The cells grow because they ignore or overreact to normal growth-factor controls โ€” usually from a constantly switched-on tyrosine kinase (BCR-ABL1 in CML, JAK2 in PV/ET/PMF).
  • The four classic MPNs each have a signature cell: CML = granulocytes, PV = red cells, ET = platelets, PMF = marrow fibrosis with ineffective hematopoiesis.
  • They start chronic (cells still mature) and can progress to accelerated or acute leukemia (blast crisis) or to marrow fibrosis.
  • The key lab split: Philadelphia chromosome/BCR-ABL1 positive (CML) vs BCR-ABL1 negative (PV, ET, PMF โ€” JAK2/MPL).
๐Ÿ’ก Analogy

Normal blood production is a factory run by order slips (cytokines like EPO, TPO, G-CSF). A tyrosine kinase is the ‘GO’ button. In an MPN the GO button is stuck on: in CML it’s a glued-together button made from two broken ones (BCR stuck to ABL); in PV/ET/PMF the JAK2 button’s safety latch (pseudokinase domain) is broken. Which production line floods โ€” red cells, platelets or granulocytes โ€” depends on which receptors the stuck button is wired to.

๐Ÿฅ Why this matters clinically

Detecting BCR-ABL1 turns CML from a fatal leukemia into a controllable chronic disease with imatinib โ€” monitored by quantitative RT-PCR. In PV, phlebotomy to Hct <45% and aspirin prevent strokes. Distinguishing MPNs from reactive leukocytosis, erythrocytosis or thrombocytosis avoids treating a normal response with chemotherapy.

Concept Plain-English Explanation
Clonal All abnormal cells descend from one mutated stem cell
Philadelphia (Ph) chromosome Short chromosome 22 from t(9;22) โ€” carries the BCR-ABL1 fusion gene
Tyrosine kinase Enzyme adding phosphate to tyrosine on other proteins โ€” switches on growth signals
Constitutive activity Always on, without the normal trigger
Panmyelosis Increase of all three marrow lines (erythroid, granulocytic, megakaryocytic)
LAP score Leukocyte alkaline phosphatase activity in neutrophils โ€” low in CML
Extramedullary hematopoiesis Blood cell production outside the marrow (spleen, liver)
Blast crisis Transformation to acute leukemia (>20% blasts)

2 ยท Core Content Tables

2.1 MPN Overview & WHO Classification

Feature Details
Definition Clonal hematopoietic stem cell disorders from genetic mutations โ†’ expansion, excessive production and accumulation of erythrocytes, granulocytes and platelets in varying combinations in marrow, blood and tissues
Mechanism Hypersensitivity or independence from normal cytokine regulation (negative feedback lost)
Course Predominantly chronic โ†’ accelerated, subacute or acute phases (AML or ALL); may also show a depleted (hypoplastic) phase
Four major MPNs (WHO) CML; PV (polycythemia rubra vera); ET (essential/primary thrombocythemia); PMF (agnogenic myeloid metaplasia, chronic idiopathic myelofibrosis)
Less common MPNs Chronic neutrophilic leukemia (CNL); chronic eosinophilic leukemia NOS (CEL); mastocytosis; MPN unclassifiable (MPN-U)
Signature CML and PV: overproduction of granulocytes and erythrocytes respectively ยท PMF: overproduction + fibroblast stimulation โ†’ ineffective hematopoiesis and cytopenias ยท ET: โ†‘ megakaryocytes and thrombocytosis
Familial MPN Described in families with โ‰ฅ2 affected members

2.2 CML โ€” Definition & Epidemiology

Feature Details
Definition MPN from a single translocation in a pluripotent stem cell โ†’ clonal overproduction of the myeloid line, mainly immature neutrophilic cells
Course Chronic phase โ†’ untreated, accelerated phase in 3โ€“4 years โ†’ often terminates as acute leukemia
Clinical Infections, anemia, bleeding, splenomegaly โ€” from massive accumulation of myeloid progenitors
Blood Neutrophilia with all maturation stages, basophilia, eosinophilia, often thrombocytosis
Clonality proof Females heterozygous for G6PD: only one isoenzyme in affected cells
Incidence All ages; mostly 46โ€“53 years; ~20% of all leukemias; slightly more males; pre-imatinib mortality 1.5 per 100,000/year
Symptoms Mild: fatigue, exercise intolerance, anorexia, abdominal discomfort, weight loss, splenic symptoms

2.3 Cytogenetics of the Philadelphia Chromosome

Feature Details
Discovery Short chromosome 22 โ€” Nowell and Hungerford, 1960, Philadelphia. Rowley 1973: reciprocal translocation of long arms of chromosomes 9 and 22
Translocation t(9;22)(q34;q11): ABL1 proto-oncogene (9q34) joined to the breakpoint cluster region (BCR) (22q11) โ†’ chimeric BCR-ABL1 gene
Product 210-kD p210 BCR/ABL fusion protein with enhanced tyrosine kinase activity
Must be present Required to confirm diagnosis (chromosomal or molecular level)
Cause Unknown; more frequent after ionizing radiation; Ph in donor cells after allogeneic BMT suggests a transmissible agent

2.4 BCR-ABL1 Molecular Variants

BCR Region BCR Exons Contributed ABL1 Exons Protein Associated Disease
Major BCR (exons 12โ€“16; two breakpoints) 1โ€“13 or 1โ€“14 2โ€“11 p210 CML (most common); also Ph+ ALL
Minor BCR (5โ€ฒ end) Exon 1 only 2โ€“11 p190 (p185) Ph+ ALL โ€” 50% of adult, 75% of childhood Ph+ ALL
Micro BCR (3โ€ฒ end) 1โ€“19 2โ€“11 p230 Chronic neutrophilic leukemia; least common

ABL1: ~230 kb, 11 exons; breakpoint consistently 5โ€ฒ of exon 2. BCR1 (one of four BCR genes): ~100 kb, 20 exons. Four fusion genes โ†’ three proteins. Ph chromosome in 20% of adult and 2โ€“5% of childhood ALL.

2.5 CML Pathogenetic Mechanism

Feature Details
Normal ABL Chromosome 9; p125 with regulated tyrosine kinase activity; nuclear
Normal BCR1 p160; serine/threonine kinase; regulates cell growth
ABL domains SH1 = ATP binding site ยท SH2 = docking site for receiver (substrate) proteins ยท SH3 = controls phosphorylation activity
Normal activation Autophosphorylation โ†’ ATP binds SH1 โ†’ phosphate to SH2 โ†’ conformational change exposes active site โ†’ second ATP phosphorylates receiver protein โ†’ signal transduction cascade
BCR-ABL defect Translocation next to SH3 โ†’ loses ability to shut off โ†’ constitutive tyrosine kinase activity
Consequences โ†‘ Proliferation, โ†“ differentiation, โ†“ adhesion to marrow stroma, virtually no apoptosis; RAS activation; new vulnerable clones โ†’ accelerated/blast phases
Location BCR-ABL in cytoplasm (not nucleus) โ€” antiapoptotic
Lineages involved Neutrophils, eosinophils, basophils, monocytes, nRBCs, megakaryocytes, B lymphocytes
Adhesion Loss of 5โ€ฒ ABL1 segments โ†“ F-actin binding โ†’ premature release into blood; interferon-ฮฑ reverses this
p210 Necessary for CML transformation of the stem cell

2.6 Common Morphologic Changes in CML (Rodak Table 33-1)

Site Finding Change
Peripheral blood Erythrocytes Normal or decreased
Reticulocytes Normal
nRBCs Present (rare)
Total WBC Increased
Lymphocytes Normal or increased
Neutrophils, basophils, eosinophils, myelocytes Increased
LAP Decreased
Platelets Normal or increased
Bone marrow Cellularity, granulopoiesis Increased
Erythropoiesis Decreased
Megakaryopoiesis Increased or normal (small, dysplastic)
Reticulin Increased (~20%)
Macrophages Gaucherlike (pseudo-Gaucher), sea-blue; green-gray crystals Present/increased
Extramedullary Splenomegaly, hepatomegaly (sinusoidal, portal tract), local infiltrates Present

2.7 CML Peripheral Blood & Marrow Details

Feature Details
Film Leukocytosis obvious at scanning power; segs, bands, metamyelocytes and myelocytes predominate (bimodal: segs and myelocytes); immature and mature eosinophils and basophils โ†‘
Blasts/promyelocytes Myeloblasts ~1%, promyelocytes ~5% in chronic phase
Other Absolute โ†‘ lymphocytes and monocytes (โ†“ percentage); nRBCs rare; platelets normal or โ†‘, some abnormal
Marrow Intense hypercellularity, broad zones of immature granulocytes (perivascular/periosteal); โ†“ normoblasts; megakaryocytes normal/โ†‘, small with hypolobulated nuclei (~20% smaller); reticulin โ†‘ in ~20%; pseudo-Gaucher cells
Hyperleukocytosis ~15% have WBC >300 ร— 10โน/L โ†’ vascular stasis symptoms, reversible with lowering WBC
Chemistry Hyperuricemia, uricosuria โ†’ gout, urate stones, nephropathy; โ†‘ LDH
Confirmation t(9;22) by karyotype, BCR-ABL1 by FISH, or transcript by RT-PCR

2.8 Leukocyte Alkaline Phosphatase (LAP) Score

Feature Details
Enzyme location Membranes of secondary granules of neutrophils
Procedure Blood film incubated with naphthol-phosphate substrate + diazo dye at alkaline pH; LAP releases naphthol โ†’ colored precipitate on granules
Scoring 100 segmented neutrophils and bands rated 0 to 4+; score = ฮฃ (rating ร— number of cells)
Example 5ร—4+ (20) + 5ร—3+ (15) + 25ร—2+ (50) + 45ร—1+ (45) + 20ร—0 (0) = 130
QC Mean of two examiners; must agree within 10%
Reference Sample range 15โ€“170 (each lab establishes its own)
Decreased Untreated CML
Normal/increased Leukemoid reaction, PV, third trimester of pregnancy

2.9 CML Progression

Feature Details
Pre-imatinib Most transformed to acute leukemia, often via an accelerated (metamorphosis) phase
Accelerated phase More symptoms, worse labs, poorer response; additional chromosome abnormalities; increasing anemia; fewer mature leukocytes, more basophils; fewer platelets, abnormal platelets, micromegakaryocytes. Blasts 10โ€“19%, or blasts + promyelocytes โ‰ฅ20%
Blast crisis >20% blasts in marrow; โ†‘ blasts in blood; usually AML or ALL; extramedullary granulocytic sarcoma. Symptoms like acute leukemia: severe anemia, leukopenia except blasts, thrombocytopenia
Clonal evolution Additional Ph, isochromosome 17, trisomy 8, loss of Y, trisomy 19 (~75% pre-imatinib)

2.10 Related Diseases & Ph+ Acute Leukemia

Feature Details
Chronic neutrophilic leukemia Similar pattern but only neutrophilic granulocytes; <10% immature; Ph negative
Chronic monocytic leukemia Comparable expansion of functional monocytes
JMML / CMML WHO MDS/MPN overlap. JMML: children <4 years, monocytes + granulocytes, dyserythropoiesis. CMML: absolute monocytosis >1 ร— 10โน/L; WBC up to 100; many old ‘Ph-negative CML’ were CMML
Ph+ acute leukemia 2% of AML; 5% of childhood and 20% of adult ALL โ€” may be undiagnosed CML or a late mutation

2.11 CML Treatment History

Feature Details
Early Tumor-burden reduction: nitrogen mustard (1940s), busulfan (1950s), busulfan + 6-thioguanine, hydroxyurea, 6-mercaptopurine
Interferon-ฮฑ (1983) Suppresses Ph chromosome, slows progression, cytogenetic remissions; with cytarabine (1997) improved hematologic remission but BCR-ABL1 persisted
Stem cell transplant Curative potential; best if chronic phase, within 1 year of diagnosis, age <50โ€“55; HLA A, B, DR match; donor lymphocyte infusions; cure 50โ€“70%, most don’t qualify

2.12 Imatinib Mesylate (Gleevec) & Monitoring

Feature Details
Mechanism Synthetic TKI that binds the ATP binding site (SH1) of BCR-ABL in its inactive conformation โ†’ ATP can’t bind โ†’ no phosphorylation โ†’ no signal transduction; reactivates apoptosis
Goals Complete hematologic remission (normal CBC/differential), cytogenetic (no Ph on karyotype), molecular (no measurable BCR-ABL transcripts)
Monitoring Quantitative real-time RT-PCR of BCR-ABL transcripts โ€” log reduction is the most sensitive measure
Milestones Complete hematologic remission 3โ€“6 months; complete cytogenetic response 6โ€“12 months; 2โ€“3 log reduction of transcripts
Maximum >4-log reduction = assay limit; stopping imatinib then usually โ†’ relapse
Status First-line for ~15 years; induction before HSCT

2.13 Imatinib Resistance

Feature Details
Scale 25โ€“30% of newly diagnosed stop imatinib within 5 years (no remission, resistance, toxicity); ~4% develop resistance (summary)
Primary resistance Never reach milestones โ€” mutations other than BCR-ABL1 present at diagnosis; most treatment failures
Secondary resistance Loss of previous response; 16% at 42 months
Cause 1 โ€” extra BCR-ABL1 copies Translocation of remaining normal 9 and 22 (homozygous) or gene duplication โ€” ~10% of secondary mutations; doubles kinase activity โ†’ higher imatinib dose restores remission
Cause 2 โ€” ATP binding-site point mutations >60 known; 50โ€“90% of secondary mutations; โ†“ imatinib binding โ†’ second-generation TKIs: dasatinib, nilotinib, bosutinib (FDA-approved first-line too)
T315I Bulky isoleucine in the ATP pocket โ†’ resistant to all four approved TKIs; ponatinib (Iclusig) (third-generation) and A-loop inhibitors work; omacetaxine and others
Bosutinib Most promising second-gen: potent, overcomes most P-loop mutations (not T315I), fewer side effects

2.14 Polycythemia Vera (PV) โ€” Pathogenesis

Feature Details
Definition Clonal MPN with panmyelosis in marrow โ†’ โ†‘ RBCs, granulocytes, platelets; splenomegaly common; stem cell origin (X-linked RFLP studies)
Mechanism Clonal stem cells hypersensitive to or independent of EPO; trace EPO stimulates colony growth (endogenous erythroid colonies)
JAK2 V617F (2005) Detected in 90โ€“97% of PV; acquired, clonal, stem cell; constitutively active. Guanine โ†’ thymine in exon 14 โ†’ valine โ†’ phenylalanine at 617 in the pseudokinase (JH2) domain โ†’ kinase can’t fold into inactive conformation
Normal JAK2 EPO binds EPOR โ†’ dimerization โ†’ JAK2 docks via FERM domain โ†’ phosphorylation โ†’ active tyrosine kinase. JAK2 also binds MPL (TPO-R), G-CSF-R, prolactin, growth hormone, GM-CSF-R, IL-3-R, IL-5-R, IFN-ฮณ2-R โ€” explains erythroid (PV), thrombopoietic (ET) and neutrophilic (PMF) growth
Downstream Phosphorylates STAT proteins (main targets; STAT5, STAT3), MAP kinase, PI3K/AKT โ†’ activates BCL-X (antiapoptotic) โ†’ cells accumulate rather than divide faster
Dosage effect Homozygous V617F more common in PV; heterozygous more in ET โ†’ may explain ETโ†’PV progression
JAK2 exon 12 (2007) residues 536โ€“547; ~3% of PV; not in ET or PMF
MPL mutations (2006) exon 10, W515L/K (tryptophan โ†’ leucine, lysineโ€ฆ) โ†’ TPO hypersensitivity; up to 15% of JAK2-negative ET and PMF; S505N familial
Pre-JAK2 evidence Familial MPN without V617F; V617F in minority of PV clones; AML from V617F MPN may be wild-type; low early allele burden. Germline JAK2 46/1 haplotype (rs10974944) โ†‘ risk 3โ€“4ร—
LNK Adapter that downregulates JAK-STAT; loss-of-function in 3โ€“6% (13% blast phase)
TET2 Converts 5-mC โ†’ 5-hmC; loss โ†’ hypermethylation; precedes JAK2; PV 9.8โ€“16%, ET 4.4โ€“5%, PMF 7.7โ€“17%
IDH1/IDH2 IDH2 R140, IDH1 R132, IDH2 R172 โ†’ 2-hydroxyglutarate โ†’ impairs TET2; 21.6% in blast transformation vs 1โ€“5% early; poor prognosis
EZH2, ASXL1 Chromatin regulators (PRC2 / PRC1); EZH2 PV 3%, PMF 13%; ASXL1 PV/ET <7%, PMF 19โ€“40%
Blast transformation <10% of PV/ET; TP53 (20% post-MPN AML), RUNX1 (30% โ€” most frequent)

2.15 WHO Criteria for Polycythemia Vera (Rodak Box 33-1, 2008)

Type Criterion
Major 1 Hb >18.5 g/dL men, >16.5 g/dL women or other evidence of โ†‘ RBC volume
Major 2 JAK2 V617F or similar mutation (e.g., JAK2 exon 12)
Minor 1 Marrow hypercellular for age with trilineage growth (panmyelosis)
Minor 2 Serum EPO below reference range
Minor 3 Endogenous erythroid colony formation in vitro
Rule Both major + 1 minor, OR major 1 + 2 minor

2.16 PV โ€” Other Diagnostic Features

Feature Details
RBC mass โ‰ฅ36 mL/kg men, โ‰ฅ32 mL/kg women
Oxygen Arterial Oโ‚‚ saturation โ‰ฅ92% (normal โ€” rules out hypoxic secondary erythrocytosis)
Other Splenomegaly; platelets >400 ร— 10โน/L; WBC >12 ร— 10โน/L without fever/infection; โ†‘ LAP, serum Bโ‚โ‚‚ or unbound Bโ‚โ‚‚ binding capacity
Differentials Secondary erythrocytosis (hypoxia, EPO-producing tumors) โ€” erythroid hyperplasia only; stress/spurious erythrocytosis โ€” โ†‘ Hb/Hct without โ†‘ RBC mass or splenomegaly

2.17 Common Morphologic Changes in PV (Rodak Table 33-2)

Site Finding Change
Peripheral blood Hb, Hct, RBC volume Increased
RBC morphology Normocytic/normochromic
WBC, granulocytes, platelets Increased
LAP Normal or increased
Bone marrow Normoblasts, granulocytes, megakaryocytes, reticulin Increased
Extramedullary Splenomegaly, hepatomegaly Present

2.18 PV โ€” Clinical Course & Treatment

Feature Details
Marrow ~80% panmyelosis (up to 100% cellularity); clusters of normoblasts; enlarged lobulated megakaryocytes; enlarged sinuses; pseudo-Gaucher rare
Blood Normocytic normochromic RBCs, mature granulocytes, normal-sized granulated platelets
Risks Splenomegaly, hepatomegaly, vascular engorgement โ†’ hemorrhage, infarction, thrombosis
Phases Proliferative (always โ†‘ RBC mass) โ†’ stable โ†’ in a few, spent phase: progressive splenomegaly, pancytopenia, fibrosis, teardrops = postpolycythemic myeloid metaplasia (like PMF)
First-line Therapeutic phlebotomy to keep Hct <45%; low-dose aspirin
High risk Hydroxyurea; IFN in younger patients; busulfan in older patients
Prognosis Median survival >15โ€“20 years; acute leukemia in 15%; ยณยฒP and alkylators โ†‘ risk; phlebotomy alone 1โ€“2% leukemia but more thrombosis/bleeding
JAK inhibitors Ruxolitinib (INCB018424): in hydroxyurea-refractory PV, 45% complete remission, 97% phlebotomy independence, 80% spleen reduction

2.19 Essential Thrombocythemia (ET)

Feature Details
Definition Clonal MPN with โ†‘ megakaryopoiesis and thrombocytosis; WHO: sustained platelets โ‰ฅ450 ร— 10โน/L (often >600, sometimes >1000)
Other names Primary thrombocytosis, idiopathic thrombocytosis, hemorrhagic thrombocythaemia
Incidence 0.6โ€“2.5 per 100,000/year; peak 50โ€“60 years; second peak in women ~30
Mutations JAK2 V617F ~55% (50โ€“60%); MPL W515L/K 3%; TET2 4.4โ€“5%, ASXL1 5.6%, LNK 3โ€“6%, IDH1/2 0.8%; others +8, 9q, del(20q)
Presentation >50% found incidentally on CBC; others: vascular occlusion (digits, splenic/hepatic veins โ€” Budd-Chiari) or hemorrhage (GI and upper respiratory mucosa); splenomegaly ~50% (PVSG)
PVSG criteria (old) Platelets >600, Hb <13 or normal RBC mass, stainable marrow iron, Ph negative, collagen fibrosis <โ…“, no splenomegaly, no leukoerythroblastic reaction, no reactive cause
WHO criteria (4) (1) Platelets โ‰ฅ450 ร— 10โน/L ยท (2) marrow: large, mature megakaryocytes without โ†‘ erythro/granulopoiesis ยท (3) not meeting criteria for other MPN, MDS or myeloid neoplasm ยท (4) JAK2 V617F or other clonal marker, or no reactive thrombocytosis
Reactive thrombocytosis Blood loss, hemolytic anemia, chronic inflammation/infection, nonhematologic neoplasm โ€” must be excluded
Exclusions MDS del(5q), RARS-T, prefibrotic PMF; dyserythropoiesis/dysgranulopoiesis โ†’ investigate del(5q), inv(3), t(3;3)

2.20 Common Morphologic Changes in ET (Rodak Table 33-3)

Site Finding Change
Peripheral blood Hb, Hct Slightly decreased
RBC volume Normal
WBC, neutrophils Normal or slightly increased (basophils not โ†‘)
Platelets Increased โ€” giant, agranular, pseudopods, clusters at thin edge
Platelet function Decreased
Bone marrow Megakaryocytes Clusters, large, hyperlobulated, dense nuclei, variable size
Normoblasts, granulocytes, reticulin Normal or slightly increased
Extramedullary Splenomegaly, megakaryocytic proliferation Present

2.21 ET โ€” Treatment & Prognosis

Feature Details
Goal Prevent/alleviate hemorrhagic or vaso-occlusive complications
Cytoreduction Hydroxyurea; IFN-ฮฑ in younger, busulfan in older patients; malignant transformation <5%
Aspirin Low-dose to prevent thrombosis
JAK inhibitors Ruxolitinib: platelets 884 โ†’ 558 median; lestaurtinib less promising
Thrombotic complications Erythromelalgia (throbbing burning pain in hands/feet with mottled redness), TIAs, seizures, cerebral/myocardial infarction, headache, dizziness, visual disturbances, dysesthesias
Hemorrhagic Oral/nasal mucosa, GI bleeding, ecchymoses
Survival Median ~20 years; may develop post-ET myelofibrosis

2.22 Primary Myelofibrosis (PMF)

Feature Details
Other names Chronic idiopathic myelofibrosis, agnogenic myelofibrosis, myelofibrosis with myeloid metaplasia
Definition Clonal MPN with splenomegaly, ineffective hematopoiesis, areas of marrow hypercellularity, fibrosis and โ†‘ megakaryocytes (enlarged, pleomorphic nuclei, coarse segmentation, hypochromic areas)
Clonality Cytogenetic abnormalities in normoblasts, neutrophils, macrophages, basophils, megakaryocytes; single G6PD isotype โ€” but fibroblasts are polyclonal (both isotypes)
Fibrosis composition Collagens I, III, IV: III by silver (reticulin) stain; I by trichrome; IV via osteosclerosis (โ†‘ bone density). ~30% of biopsies show no fibrosis
Fibrosis mechanism Secondary โ€” fibroblasts stimulated by growth factors from megakaryocytes: PDGF, TGF-ฮฒ* (Rodak: TGF-ฮฑ), TNF-ฮฑ, IL-1ฮฑ, IL-1ฮฒ. Fibrosis alone isn’t diagnostic (benzene, radiation, immune injury)
Extramedullary hematopoiesis Clonal stem cells escape to spleen, liver, adrenals, kidneys, nodes, bowel, breasts, lungs, etc.; CD34โบ cells up to 300ร— normal โ€” separates PMF from other MPNs, predicts splenic involvement and leukemic risk
Complications Body cavity effusions; portal hypertension (ascites, varices, GI hemorrhage, encephalopathy)
Mutations JAK2 V617F 65%; MPL W515L/K ~10%; CBL 6%, TET2 7.7โ€“17%, ASXL1 13โ€“23%, LNK 3โ€“6%, EZH2 13%, IDH1/2 4.2%
Clinical Age >60; may be asymptomatic; fatigue, weakness, dyspnea, palpitations, weight loss, LUQ discomfort (splenomegaly)

2.23 Common Morphologic Changes in PMF (Rodak Table 33-4)

Site Finding Change
Peripheral blood Hemoglobin Normal or decreased
Anisocytosis, poikilocytosis, teardrop RBCs, nRBCs Present
Polychromasia Normal or increased
Total WBC Normal, decreased or increased
Immature granulocytes, blasts, basophils, leukocyte anomalies Increased/present
LAP Increased, normal or decreased
Platelets Increased, normal or decreased; abnormal forms; micromegakaryocytes
Bone marrow Cellularity, granulopoiesis, megakaryocytes, myelofibrosis, sinuses Increased
Erythropoiesis Normal or increased
Dysmegakaryopoiesis, dysgranulopoiesis Present
Extramedullary Splenomegaly, hepatomegaly, other tissues Present

2.24 PMF โ€” Other Findings & Treatment

Feature Details
Marrow Examination of biopsy gives most diagnostic information: intense fibrosis, granulocytic + megakaryocytic hypercellularity, dysplasia, dilated sinuses with intraluminal hematopoiesis
Cell function Neutrophils: impaired phagocytosis, โ†“ MPO, glutathione reductase ยท platelets: impaired aggregation to epinephrine, โ†“ ADP in dense granules, โ†“ lipoxygenase
Immune ~50% altered humoral response: autoantibodies (RBC, nuclear, ฮณ-globulins, phospholipids), immune complexes, amyloidosis
Anemia 34โ€“54% Hb <10 g/dL โ†’ androgens, prednisone, danazol, thalidomide, lenalidomide (especially del(5q31)), glucocorticoids for hemolysis
Splenomegaly 90% (hepatomegaly 50%) โ†’ hydroxyurea first line; splenectomy/radiation if refractory
Constitutional Fatigue 84%, night sweats 56%, pruritus 50%, bone pain 47%, fever 18%
JAK inhibitors Ruxolitinib, CYT387, TG101348 (JAK2), lestaurtinib (non-JAK) โ†’ โ†“ spleen, symptoms; not disease-modifying
Cure Allogeneic HSCT (<60 years): 5-year survival ~50%, 1-year mortality 27%, GVHD 33%
Survival ~5 years (up to 15); poor: severe anemia, thrombocytopenia, hepatomegaly, fever, hemolysis

2.25 Interconnection among ET, PV and PMF

Feature Details
Puzzle Same JAK2 V617F in 90โ€“95% of PV but only 50โ€“60% of ET and PMF
Hypothesis 1 Stage of stem cell differentiation (platelet-committed โ†’ ET)
Hypothesis 2 Genetic background (EPOR, MPL, G-CSF-R variants)
Hypothesis 3 Dosage effect โ€” PV homozygous (more kinase activity), ET heterozygous; MPL on megakaryocytes needs only one V617F; EPOR (low density) needs two
Hypothesis 4 A pre-JAK2 mutation creates a premalignant clone
Unified model Continuum: pre-JAK2 (familial, congenital, somatic) โ†’ JAK2/MPL drivers โ†’ signaling regulators (LNK, c-CBL, SOCS) โ†’ epigenetic (TET2, IDH1/2, ASXL1, EZH2) early; tumor suppressors (IZF1, TP53) late

2.26 Other Myeloproliferative Neoplasms

Disorder Diagnostic Features Genetics / Prognosis
Chronic neutrophilic leukemia (CNL) WBC >25 ร— 10โน/L, >90% mature neutrophils, <10% immature, <1% blasts; toxic granules but no dysplasia; M:E โ‰ฅ20:1; splenomegaly required (hepatosplenomegaly most common finding); bleeding 25โ€“30%, gout, pruritus. Exclude reactive neutrophilia, Ph/BCR-ABL, PDGFRA/B, FGFR1, PV, PMF, ET, MDS ~90% normal karyotype (later +8, +9, +21, del(20q)โ€ฆ); JAK2 rare; ~150 cases; survival 6 monthsโ€“>20 years; may โ†’ MDS/AML
Chronic eosinophilic leukemia, NOS (CEL) Eosinophils >1.5 ร— 10โน/L + malignant features; exclude reactive (parasites, allergy, Loeffler, collagen vascularโ€ฆ) and other neoplasms (T-cell lymphoma, Hodgkin, SM, CMML, ALL); marrow Charcot-Leyden crystals, fibrosis; blasts <20%. Endomyocardial fibrosis โ†’ cardiomegaly, valve scarring, thrombi Excludes PDGFRA, PDGFRB, FGFR1, BCR-ABL; +8, i(17q), JAK2 support; ~80% 5-year survival
Mastocytosis Clonal mast cells in skin/organs. 7 WHO types (cutaneous, indolent systemic, SM with clonal non-mast-cell disease, aggressive SM, mast cell leukemia, mast cell sarcoma, extracutaneous mastocytoma). Urticaria pigmentosa (Darier sign โ€” urticates when stroked*). Minor criteria: >25% atypical/spindle mast cells, KIT D816V, CD2 and/or CD25, serum tryptase >20 ng/mL* KIT codon 816 (Aspโ†’Val) in ~95% adults, 33% children; mast cell leukemia >20% marrow, >10% blood; childhood cutaneous regresses at puberty; aggressive forms survive months
MPN, unclassifiable (MPN-U) Myeloproliferative features not meeting specific criteria or overlapping โ€” early PV/ET/PMF, advanced disease masked by clonal evolution, or concomitant neoplasm/inflammation; 10โ€“15% of MPNs Reclassify as features evolve or >20% blasts (acute leukemia)

*Rodak prints ‘tryptase above 20 mg/mL’ โ€” the standard unit is ng/mL. ‘Darier sign’ is the general-reference name for lesions activated by stroking. Rodak lists TGF-ฮฑ; most references cite TGF-ฮฒ as the key fibrogenic cytokine.

3 ยท Visual Memory Hooks

๐Ÿง  Four MPNs
โ€œCML Grows Granulocytes, PV Pumps Red, ET Tosses Platelets, PMF Makes Fibrous marrowโ€.
๐Ÿง  Philadelphia
โ€œ9 and 22 moved to Phillyโ€ โ€” t(9;22), BCR-ABL1.
๐Ÿง  Fusion proteins
โ€œMinor = 190 (ALL); Major = 210 (CML); Micro = 230 (CNL)โ€ โ€” bigger BCR piece, bigger protein.
๐Ÿง  CML blood
โ€œEveryone’s invited to the CML party: segs, bands, metas, myelos, EOS and BASOSโ€.
๐Ÿง  Basophilia
โ€œBasophils Blow the whistle on CMLโ€ โ€” reactive leukemoid has none.
๐Ÿง  LAP
โ€œLAP is Low in Leukemia (CML); high in Leukemoid, PV, Pregnancyโ€.
๐Ÿง  SH domains
โ€œSH1 = ATP (one fuel), SH2 = Substrate docking (two partners), SH3 = Switch controlโ€.
๐Ÿง  Imatinib
โ€œGleevec plugs the gas capโ€ โ€” sits in the ATP pocket.
๐Ÿง  T315I
โ€œT315I = Too big to Inhibitโ€ โ€” only ponatinib.
๐Ÿง  Phases
โ€œAccelerated: 10โ€“19 blasts; Blast crisis: >20โ€.
๐Ÿง  JAK2
โ€œV617F: Valine โ†’ Phenylalanine, Forever ONโ€ (pseudokinase broken).
๐Ÿง  JAK2 frequency
โ€œPV ~95, ET ~55, PMF ~65โ€.
๐Ÿง  PV criteria
โ€œ2 majors (Hb + JAK2) + 1 minor, or Hb + 2 minors (Marrow, low EPO, Endogenous colonies)โ€.
๐Ÿง  PV EPO
โ€œPV has Plenty of red cells, Poor EPOโ€ โ€” vs secondary polycythemia โ†‘ EPO.
๐Ÿง  PV treatment
โ€œBleed them under 45โ€ โ€” phlebotomy to Hct <45% + aspirin.
๐Ÿง  ET
โ€œET = Extra Thrombocytes โ‰ฅ450, giant hyperlobulated megakaryocytes, clots AND bleedsโ€.
๐Ÿง  Erythromelalgia
โ€œBurning red hands and feet โ†’ think ETโ€.
๐Ÿง  PMF blood
โ€œTears, Babies, Kidsโ€ โ€” teardrops, nRBCs (baby reds), immature granulocytes.
๐Ÿง  PMF fibrosis
โ€œMegakaryocytes Make the Messโ€ โ€” PDGF/TGF โ†’ polyclonal fibroblasts.
๐Ÿง  Dry tap*
โ€œPMF aspirate is Dry โ€” biopsy tells the storyโ€.
๐Ÿง  Mastocytosis
โ€œKIT 816, CD25, Tryptase >20โ€.
๐Ÿง  CNL
โ€œCNL = CML look-alike without Philly, >90% mature neutrophils, WBC >25โ€.

*’Dry tap’ in PMF is standard teaching; Rodak states the biopsy provides most diagnostic information.

Pattern Triggers

If you seeโ€ฆ Thinkโ€ฆ Becauseโ€ฆ
WBC 248, myelocyte bulge, basophils 7%, eosinophils 3%, blasts 1%, LAP 20, splenomegaly CML chronic phase (Rodak case study) BCR-ABL1
WBC 60, left shift, toxic granulation, LAP 180, pneumonia Leukemoid reaction Reactive
Known CML, blasts 14%, basophils rising, platelets falling Accelerated phase 10โ€“19% blasts
Known CML, marrow blasts 35% Blast crisis >20% blasts
Hb 20, WBC 14, platelets 600, splenomegaly, low EPO, JAK2 + Polycythemia vera Panmyelosis
Hb 19, smoker/COPD, Oโ‚‚ sat 85%, high EPO, JAK2 โˆ’ Secondary erythrocytosis Hypoxia-driven EPO
Hb 17.5 with normal RBC mass, no splenomegaly Relative/spurious erythrocytosis โ†“ plasma volume
Platelets 900, giant platelets, burning red toes, JAK2 + Essential thrombocythemia Megakaryocytic clone
Platelets 700 after splenectomy or with iron deficiency Reactive thrombocytosis Exclude before ET
Teardrops + nRBCs + immature granulocytes + massive spleen, age 65 Primary myelofibrosis Leukoerythroblastic
PV patient years later: pancytopenia, teardrops, huge spleen Postpolycythemic myeloid metaplasia Spent phase
Rising BCR-ABL transcripts on imatinib, T315I found TKI resistance โ†’ ponatinib Bulky isoleucine
Rising transcripts, BCR-ABL1 duplication Increase imatinib dose Double kinase activity
WBC 40, >90% mature neutrophils, Ph โˆ’, splenomegaly Chronic neutrophilic leukemia Micro BCR not required; CSF3R*
Eosinophils 3.0 ร— 10โน/L, cardiac fibrosis, clonal marker CEL, NOS Exclude PDGFR/FGFR1
Skin lesions that wheal when stroked, tryptase 60, KIT D816V Systemic mastocytosis

*CSF3R as the CNL driver is post-2013 knowledge, not in Rodak 5e.

Commonly Confused Pairs

Feature A B
CML vs leukemoid โ†“ LAP, โ†‘ basos/eos, Ph+, splenomegaly โ†‘ LAP, toxic changes, Phโˆ’, infection
p210 vs p190 Major BCR โ€” CML Minor BCR โ€” Ph+ ALL
Primary vs secondary imatinib resistance Never reached milestones Lost a previous response
BCR-ABL1 duplication vs ATP-site mutation Higher imatinib dose Second-gen TKI (ponatinib if T315I)
PV vs secondary erythrocytosis JAK2+, low EPO, panmyelosis, splenomegaly JAK2โˆ’, high EPO, erythroid only
PV vs relative erythrocytosis โ†‘ RBC mass Normal RBC mass (โ†“ plasma)
ET vs reactive thrombocytosis Clonal marker, giant hyperlobulated megakaryocytes Iron deficiency, inflammation, bleeding, splenectomy
PMF vs CML Teardrops, fibrosis, variable LAP, JAK2 Myelocyte bulge, basophilia, โ†“ LAP, BCR-ABL1
Clonal vs polyclonal cells in PMF Hematopoietic cells Fibroblasts
JAK2 homozygous vs heterozygous PV ET
CNL vs CML Phโˆ’, >90% mature neutrophils Ph+, all stages, basophilia
CEL vs reactive eosinophilia Clonal, cytogenetic abnormality Parasites, allergy

Timeline Table

Event Timing Key Point Best Exam Use
Ph chromosome discovered 1960 (Nowell & Hungerford) Short 22 History
t(9;22) identified 1973 (Rowley) Reciprocal translocation History
Untreated CML โ†’ accelerated 3โ€“4 years Then blast crisis Natural history
Complete hematologic remission on imatinib 3โ€“6 months Milestone Monitoring
Complete cytogenetic response 6โ€“12 months No Ph Monitoring
Major molecular response 2โ€“3 log reduction RT-PCR Monitoring
Secondary resistance 16% at 42 months Loss of response Resistance
JAK2 V617F discovered 2005 PV 90โ€“97% History
PV survival >15โ€“20 years 15% โ†’ acute leukemia Prognosis
ET survival ~20 years <5% transform Prognosis
PMF survival ~5 years (up to 15) HSCT curative Prognosis

4 ยท Diagnostic Flowcharts

Flowchart 1 โ€” Marked leukocytosis with left shift

WBC โ†‘ with myelocytes, metamyelocytes โ†’ Look at basophils, eosinophils, toxic changes, spleen
Toxic granulation, Dรถhle bodies, no basophilia, infection โ†’ Leukemoid reaction โ†’ LAP โ†‘
Basophilia + eosinophilia + splenomegaly, LAP โ†“ โ†’ Suspect CML
Confirm โ†’ Karyotype t(9;22), FISH BCR-ABL1, or RT-PCR
BCR-ABL1 negative, >90% mature neutrophils โ†’ Consider CNL; monocytosis โ†’ CMML
โš ๏ธ Common mistake: diagnosing CML from the WBC count alone โ€” confirmation requires t(9;22)/BCR-ABL1.

Flowchart 2 โ€” Staging CML

Blasts ~1%, promyelocytes ~5% โ†’ Chronic phase
Blasts 10โ€“19% or blasts + promyelocytes โ‰ฅ20%, rising basos, falling platelets, new karyotype changes โ†’ Accelerated phase
Blasts >20% in marrow (or extramedullary blasts) โ†’ Blast crisis (AML or ALL)
Clonal evolution markers โ†’ Extra Ph, i(17q), +8, โˆ’Y, +19
โš ๏ธ Common mistake: calling 30% blasts + promyelocytes ‘blast crisis’ โ€” the >20% threshold applies to blasts alone*.

*My reading of Rodak’s criteria; used for review Q4.

Flowchart 3 โ€” Monitoring imatinib therapy

Start TKI โ†’ CBC โ†’ quantitative RT-PCR BCR-ABL transcripts
3โ€“6 months โ†’ Complete hematologic remission?
6โ€“12 months โ†’ Complete cytogenetic response (no Ph)?
Molecular โ†’ 2โ€“3 log reduction; >4 log = assay limit (don’t stop drug)
Rising transcripts โ†’ Mutation analysis: duplication โ†’ โ†‘ dose ยท ATP-site โ†’ dasatinib/nilotinib/bosutinib ยท T315I โ†’ ponatinib
โš ๏ธ Common mistake: stopping imatinib after a deep response โ€” most patients relapse.

Flowchart 4 โ€” Erythrocytosis workup

Hb >18.5 (men) / >16.5 (women) โ†’ Confirm true โ†‘ RBC mass (exclude dehydration/spurious)
JAK2 V617F / exon 12 โ†’ Positive โ†’ PV (plus one minor criterion)
Serum EPO โ†’ Low โ†’ PV ยท high โ†’ secondary (hypoxia, EPO-secreting tumor)
Oโ‚‚ saturation โ†’ <92% โ†’ hypoxic secondary erythrocytosis
Marrow โ†’ Panmyelosis โ†’ PV ยท erythroid-only hyperplasia โ†’ secondary
โš ๏ธ Common mistake: treating secondary erythrocytosis (e.g., COPD) as PV.

Flowchart 5 โ€” Thrombocytosis workup

Platelets โ‰ฅ450 ร— 10โน/L sustained โ†’ Exclude reactive causes: iron deficiency, bleeding, inflammation, infection, cancer, splenectomy
JAK2 V617F or MPL W515L/K โ†’ Clonal marker โ†’ MPN
Marrow: large hyperlobulated megakaryocytes, no โ†‘ other lines โ†’ ET
โ†‘ Erythropoiesis โ†’ PV ยท โ†‘ granulopoiesis + atypical megakaryocytes โ†’ prefibrotic PMF
Dysplasia โ†’ Check del(5q), inv(3), t(3;3); BCR-ABL1 to exclude CML
โš ๏ธ Common mistake: diagnosing ET without excluding iron deficiency โ€” a very common cause of thrombocytosis.

Flowchart 6 โ€” Teardrops and a leukoerythroblastic film

Teardrops + nRBCs + immature granulocytes โ†’ Marrow infiltration or fibrosis
Aspirate fails (dry tap)* โ†’ Core biopsy with reticulin (III) and trichrome (I) stains
Clonal megakaryocytic hyperplasia + fibrosis, JAK2/MPL +, splenomegaly โ†’ PMF
History of PV or ET โ†’ Post-PV / post-ET myelofibrosis
Metastatic tumor, lymphoma, benzene, radiation โ†’ Secondary fibrosis โ€” fibrosis alone isn’t PMF
โš ๏ธ Common mistake: equating marrow fibrosis with PMF โ€” fibrosis is reactive and nonspecific.

5 ยท 25 High-Yield Facts

# Fact
1 MPNs are clonal stem cell disorders with overproduction of erythrocytes, granulocytes and/or platelets.
2 The four major MPNs are CML, PV, ET and PMF.
3 CML is caused by t(9;22)(q34;q11), forming the Philadelphia chromosome and BCR-ABL1.
4 BCR-ABL1 has constitutive tyrosine kinase activity.
5 The p210 protein (major BCR) is typical of CML; p190 is typical of Ph+ ALL; p230 of CNL.
6 CML represents about 20% of leukemias and peaks at ages 46โ€“53.
7 CML blood shows leukocytosis with all maturation stages and increased basophils and eosinophils.
8 The LAP score is decreased in untreated CML and normal/increased in leukemoid reactions, PV and pregnancy.
9 LAP scoring rates 100 neutrophils 0 to 4+ and sums the products.
10 Pseudo-Gaucher cells are seen in CML marrow.
11 CML accelerated phase has 10โ€“19% blasts (or โ‰ฅ20% blasts + promyelocytes); blast crisis >20% blasts.
12 Imatinib binds the ATP binding site of BCR-ABL in its inactive conformation.
13 Imatinib response is best monitored by quantitative real-time RT-PCR of BCR-ABL transcripts.
14 The T315I mutation is resistant to imatinib, dasatinib, nilotinib and bosutinib; ponatinib inhibits it.
15 JAK2 V617F (exon 14, pseudokinase domain) is found in 90โ€“97% of PV.
16 JAK2 V617F occurs in about 50โ€“60% of ET and about 65% of PMF.
17 PV shows panmyelosis โ€” increased RBCs, granulocytes and platelets.
18 WHO PV major criteria are Hb >18.5 g/dL (men)/>16.5 g/dL (women) and JAK2 mutation.
19 Serum EPO is low in PV and high in secondary erythrocytosis.
20 PV is treated with phlebotomy to keep Hct below 45% plus low-dose aspirin.
21 ET requires a sustained platelet count of at least 450 ร— 10โน/L.
22 ET marrow shows clusters of large, hyperlobulated megakaryocytes; complications are thrombosis and hemorrhage.
23 PMF blood shows teardrop RBCs, nRBCs and immature granulocytes.
24 Myelofibrosis in PMF is secondary โ€” cytokines from clonal megakaryocytes stimulate polyclonal fibroblasts.
25 Systemic mastocytosis is associated with the KIT D816V mutation, CD25 expression and serum tryptase >20.
โญ EXAM TIP โ€” The single most testable pattern

Neutrophilia with myelocytes + basophilia + eosinophilia + โ†“ LAP + splenomegaly = CML โ†’ confirm t(9;22)/BCR-ABL1 โ†’ imatinib. JAK2 V617F + high Hb + low EPO = PV. Platelets โ‰ฅ450 with giant megakaryocytes = ET. Teardrops + nRBCs + immature granulocytes + big spleen = PMF.

Quick Interpretation Table

Lab Finding Clinical Interpretation
34-year-old woman: WBC 248, Hb 9.5, platelets 449, myelocytes 30%, basophils 7%, eos 3%, blasts 1%, LAP 20, LDH 692, uric acid 8.1, spleen below umbilicus CML chronic phase (Rodak case study) โ†’ karyotype t(9;22), BCR-ABL1 p210 โ†’ imatinib; resistance by BCR-ABL1 duplication or ATP-site mutation (T315I)
WBC 30, segs 38, bands 17, metas 7, myelos 20, pro 10, eos 3, basos 5 Suspect CML โ€” FISH for BCR-ABL1 is the helpful test (Rodak Q3)
CML with blasts + promyelocytes = 30% Accelerated phase (Rodak Q4 โ€” my interpretation)
Platelets 700, abnormal platelets, WBC 12, Hb 11, Ph negative Essential thrombocythemia (Rodak Q7)
Hb 19.2 (man), JAK2 V617F +, EPO low PV (both major + 1 minor)
Hb 17.0 (woman), JAK2 โˆ’, marrow panmyelosis, low EPO, endogenous colonies PV (major 1 + 2 minor)
BCR-ABL transcripts 3.2-log reduced at 12 months Major molecular response โ€” continue imatinib
Serum tryptase 55 ng/mL, CD25โบ spindle mast cells, KIT D816V Systemic mastocytosis

๐ŸŽด Flashcards โ€” Active Recall Practice

How it works: tap the card to flip it. Then mark it โœ“ Knew It or โœ— Review Again (buttons unlock after flipping). Use ๐Ÿ”€ Shuffle to randomize and ๐Ÿ Finish anytime โ€” your summary appears at the end, and you can drill only the cards you missed.

๐Ÿ“ Practice Quiz โ€” Test Your Knowledge

How it works: tap an answer for each case. You’ll get instant feedback with the full explanation and the examiner’s trap. Your final score appears once all 10 are answered.

๐Ÿชค Trap Questions โ€” Beat the Examiner

Harder on purpose. Each question targets a real misconception. After answering you’ll see the correct reasoning, the trap explained, why the examiner wrote it, and the wrong answer most students choose.

8 ยท Rapid Revision Sheet

๐Ÿ“– READ THIS 2 HOURS BEFORE YOUR EXAM

MPN Basics

  • Clonal stem cell; cytokine independence
  • CML ยท PV ยท ET ยท PMF
  • Others: CNL, CEL NOS, mastocytosis, MPN-U
  • Chronic โ†’ accelerated โ†’ acute or fibrosis
  • Ph+ (CML) vs Phโˆ’ (JAK2/MPL)

CML Genetics

  • t(9;22)(q34;q11) โ†’ BCR-ABL1
  • Nowell & Hungerford 1960 ยท Rowley 1973
  • p210 major (CML) ยท p190 minor (Ph+ ALL) ยท p230 micro (CNL)
  • Constitutive TK next to SH3
  • SH1 ATP ยท SH2 substrate ยท SH3 control

CML Lab

  • 20% of leukemias ยท 46โ€“53 yr
  • All stages, myelocyte bulge, โ†‘ basos/eos
  • Blasts ~1%, pro ~5% ยท platelets N/โ†‘
  • LAP โ†“ ยท uric acid โ†‘ ยท LDH โ†‘
  • Marrow hypercellular, pseudo-Gaucher

LAP & Phases

  • 100 neutrophils, 0โ€“4+, sum of products
  • Two readers within 10% ยท ref ~15โ€“170
  • โ†“ CML ยท โ†‘ leukemoid, PV, pregnancy
  • Accelerated: blasts 10โ€“19% (or +pro โ‰ฅ20%)
  • Blast crisis >20% ยท i(17q), +8, extra Ph

CML Therapy

  • Imatinib binds ATP site (inactive form)
  • CHR 3โ€“6 mo ยท CCyR 6โ€“12 mo ยท 2โ€“3 log
  • RT-PCR log reduction = best monitor
  • Duplication โ†’ โ†‘ dose ยท ATP mutation โ†’ dasatinib/nilotinib/bosutinib
  • T315I โ†’ ponatinib ยท HSCT curative

PV

  • JAK2 V617F 90โ€“97% (exon 14 JH2) ยท exon 12 3%
  • Panmyelosis ยท splenomegaly ยท โ†“ EPO
  • Major: Hb >18.5/16.5 + JAK2
  • Minor: panmyelosis, low EPO, endogenous colonies
  • Phlebotomy Hct <45% + aspirin ยท survival 15โ€“20 yr

JAK2 Biology

  • Vโ†’F at 617 blocks inactive folding
  • Binds EPOR, MPL, G-CSF-R, others
  • STAT5/3, MAPK, PI3K/AKT โ†’ BCL-X
  • Homozygous โ†’ PV ยท heterozygous โ†’ ET
  • MPL W515L/K, LNK, TET2, IDH1/2, ASXL1, EZH2

ET

  • Platelets โ‰ฅ450 (WHO) ยท peaks 50โ€“60, women ~30
  • JAK2 ~55% ยท MPL 3%
  • Large hyperlobulated clustered megakaryocytes
  • Thrombosis (erythromelalgia) + hemorrhage
  • Hydroxyurea + aspirin ยท survival ~20 yr

PMF

  • >60 yr ยท splenomegaly 90%
  • Teardrops, nRBCs, immature granulocytes
  • Fibrosis: collagen I, III, IV; polyclonal fibroblasts
  • Megakaryocyte cytokines (PDGF, TGF)
  • JAK2 65% ยท MPL 10% ยท HSCT only cure ยท ~5 yr

Other MPNs

  • CNL: WBC >25, >90% mature neutrophils, Phโˆ’
  • CEL NOS: eos >1.5, cardiac fibrosis
  • Mastocytosis: KIT D816V, CD25, tryptase >20
  • MPN-U: 10โ€“15%, overlap/early/advanced
  • CMML: monocytes >1 ร— 10โน/L (MDS/MPN)

9 ยท Final Memory Map

  • ๐Ÿงซ MYELOPROLIFERATIVE NEOPLASMS
    • CML (BCR-ABL1+)
      • t(9;22) ยท p190/p210/p230 ยท constitutive TK
      • Blood: all stages, basos/eos, โ†“ LAP
      • Phases: chronic โ†’ accelerated โ†’ blast crisis
      • Imatinib ยท resistance ยท T315I โ†’ ponatinib ยท HSCT
    • Polycythemia Vera
      • JAK2 V617F / exon 12 ยท panmyelosis ยท โ†“ EPO
      • WHO major/minor criteria
      • Phlebotomy, aspirin, hydroxyurea, ruxolitinib ยท spent phase
    • Essential Thrombocythemia
      • Platelets โ‰ฅ450 ยท JAK2 ~55%, MPL
      • Giant megakaryocytes ยท thrombosis/hemorrhage
      • Exclude reactive thrombocytosis
    • Primary Myelofibrosis
      • Leukoerythroblastic film with teardrops
      • Reactive fibrosis (collagen I, III, IV)
      • Extramedullary hematopoiesis ยท JAK2 65%
    • Shared Mutations
      • MPL W515L/K ยท LNK ยท TET2 ยท IDH1/2 ยท ASXL1 ยท EZH2
      • Blast phase: TP53, RUNX1
    • Other MPNs
      • CNL ยท CEL NOS ยท mastocytosis (KIT D816V) ยท MPN-U



PreviousNext